Article

Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monotherapy or added to metformin, is primarily as a result of a reduction in fat tissue

December 2009
Diabetes Obesity and Metabolism 11(12):1163-72

December 2009
11(12):1163-72

DOI:10.1111/j.1463-1326.2009.01158.x

Source
PubMed

Authors:

Johan Jendle

Örebro University

Michael A Nauck

Diabeteszentrum Bad Lauterberg

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The effect on body composition of liraglutide, a once-daily human glucagon-like peptide-1 analogue, as monotherapy or added to metformin was examined in patients with type 2 diabetes (T2D). These were randomized, double-blind, parallel-group trials of 26 [Liraglutide Effect and Action in Diabetes-2 (LEAD-2)] and 52 weeks (LEAD-3). Patients with T2D, aged 18-80 years, body mass index (BMI) < or =40 kg/m(2) (LEAD-2), < or =45 kg/m(2) (LEAD-3) and HbA1c 7.0-11.0% were included. Patients were randomized to liraglutide 1.8, 1.2 or 0.6 mg/day, placebo or glimepiride 4 mg/day, all combined with metformin 1.5-2 g/day in LEAD-2 and to liraglutide 1.8, 1.2 or glimepiride 8 mg/day in LEAD-3. LEAD-2/3: total lean body tissue, fat tissue and fat percentage were measured. LEAD-2: adipose tissue area and hepatic steatosis were assessed. LEAD-2: fat percentage with liraglutide 1.2 and 1.8 mg/metformin was significantly reduced vs. glimepiride/metformin (p < 0.05) but not vs. placebo. Visceral and subcutaneous adipose tissue areas were reduced from baseline in all liraglutide/metformin arms. Except with liraglutide 0.6 mg/metformin, reductions were significantly different vs. changes seen with glimepiride (p < 0.05) but not with placebo. Liver-to-spleen attenuation ratio increased with liraglutide 1.8 mg/metformin possibly indicating reduced hepatic steatosis. LEAD-3: reductions in fat mass and fat percentage with liraglutide monotherapy were significantly different vs. increases with glimepiride (p < 0.01). Liraglutide (monotherapy or added to metformin) significantly reduced fat mass and fat percentage vs. glimepiride in patients with T2D.

Effect of Liraglutide on Fat Mass Percentage Among Overweight and Obese Adults with Type 2 Diabetes: A Systematic Review

Article

Full-text available

Oct 2023

Background: Obesity and type 2 diabetes mellitus (T2DM) are two global public health problems. Liraglutide, a glucagon-like peptide 1 analogue (GLP-1), is considered an effective option for weight loss. Hence, it is meaningful to understand the impact of GLP-1 therapy on body composition, particularly fat mass percentage (%), in determining health risks associated with obesity. The current meta-analysis and systematic review aimed to appraise and summarize available studies regarding the efficacy of liraglutide on fat mass (%), anthropometrics and glycemic control. Methods: Three databases were searched up to March 2022 for randomized clinical trials (RCTs) and studies that evaluated the efficacy of liraglutide on T2DM patients: Cochrane Central Register of Controlled Trials, Web of Science, and PUBMED: Cochrane Central Register of Controlled Trials, Web of Science, and PUBMED. If at least two studies had the same outcome and treatment, a random effect model meta-analysis was used to report pooled mean difference (MD) and 95% confidence interval (CI). The protocol of this review was registered in PROSPERO under registration number CRD42022313002. Results: From the 4031 articles identified and reviewed, only 5 studies (N = 263 patients) matched the inclusion criteria. Only two out of 3 RCTs have complete data to produce forest plots. No significant changes were observed from the pooled MD for body fat % [-0.56 (-2.63, 1.26)] and weight [-0.68 (-2.63, 1.26)]. A significant change in Hba1c with a pooled MD of -1.25 (-2.13, -0.36) (p = 0.006) was observed. I2 tests were above the threshold of 50% for weight and Hba1c, indicating heterogeneity among the included studies. Conclusion: This review suggests that liraglutide is effective in glycemic control with no significant effect on weight and fat mass % among overweight patients with T2DM. It is important to note, however, that the certainty of the available evidence is weak.

The Effectiveness of GLP-1 Receptor Agonist Semaglutide on Body Composition in Elderly Obese Diabetic Patients: A Pilot Study

Article

Full-text available

Sep 2022

Background and objectives: This study aimed to investigate the changes in obesity severity, glucose metabolism, and body composition in patients with obesity and type 2 diabetes mellitus treated with glucagon-like peptide 1 receptor agonist (GLP1-RA) semaglutide. Materials and methods: Body weight (BW), metabolic parameters, and body composition were examined before and 3 months after semaglutide administration. The mass of body fat (FM), fat weight percentage (%FM), mass of skeletal muscle (MM), skeletal MM percentage (%MM), and limb muscles were measured using the bioelectrical impedance method. Results: Semaglutide dramatically reduced the weight, the body mass index (BMI), and the levels of the glucose metabolic markers, including fasting blood glucose and hemoglobin A1c, and accelerated the loss of excess BW. FM, MM, and %FM after semaglutide treatment also decreased. Conversely, semaglutide had no effect on the %MM after 3 months. In limb muscle analyses, right upper and lower leg muscle percentages, left upper and lower leg muscles, and the ratios of the lower/upper muscles were maintained by semaglutide treatment. Conclusions: These results suggest that the GLP1-RA semaglutide effectively reduces body adiposity while maintaining the MM in obese type 2 diabetic patients.

GLP-1 receptor agonists: evolution and advancement in the treatment of type 2 diabetes mellitusEvoluzione del ruolo dei GLP-1 agonisti recettoriali nel nuovo paradigma del diabete mellito tipo 2

Article

Full-text available

Jul 2021

R. Candido

Type 2 diabetes mellitus is a progressive disease, associated with multiple cardiovascular risk factors (obesity, hypertension, dyslipidemia) and with the development of micro- and macro-vascular complications. Several anti-diabetic drugs commonly used, such as sulfonylureas, thiazolidinediones and insulin induce weight gain and have modest or negative effects on cardiovascular risk factors and cardiovascular events. In this context, the GLP-1 receptor agonists (GLP-1 RA) instead have an important action on glycemic control and β-cell dysfunction, show favorable effects on body weight, hypertension and lipid profile, have a reduced risk of hypoglycemia and more recently have demonstrated clear benefits on major cardiovascular events, cardiovascular mortality and renal damage. In these years it has been an evolution on the role of the GLP-1 RA in the new paradigm of type 2 diabetes. For this reason the GLP-1 RA find place at any moment of the cardiovascular and renal continuum, from the initial one for controlling blood glucose and the different risk factors to the most advanced when cardiovascular damage is already present. The GLP-1 RA therefore represent a key elements in the management of patients with type 2 diabetes at any time in the natural history of the disease both for glycemic control and for the prevention of CV and renal events. KEY WORDS GLP-1 receptor agonists; type 2 diabetes; cardiovascular risk factors; cardiovascular disease; cardiovascular outcome trials.

Glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: An update

Article

Full-text available

Aug 2020

Non-alcoholic fatty liver disease (NAFLD) is the predominant cause of chronic liver disease worldwide. NAFLD progresses in some cases to non-alcoholic steatohepatitis (NASH), which is characterized, in addition to liver fat deposition, by hepatocyte ballooning, inflammation and liver fibrosis, and in some cases may lead to hepatocellular carcinoma. NAFLD prevalence increases along with the rising incidence of type 2 diabetes mellitus (T2DM). Currently, lifestyle interventions and weight loss are used as the major therapeutic strategy in the vast majority of patients with NAFLD. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used in the management of T2DM and do not have major side effects like hypoglycemia. In patients with NAFLD, the GLP-1 receptor production is down-regulated. Recently, several animal and human studies have emphasized the role of GLP-1RAs in ameliorating liver fat accumulation, alleviating the inflammatory environment and preventing NAFLD progression to NASH. In this review, we summarize the updated literature data on the beneficial effects of GLP-1RAs in NAFLD/NASH. Finally, as GLP-1RAs seem to be an attractive therapeutic option for T2DM patients with concomitant NAFLD, we discuss whether GLP-1RAs should represent the first line pharmacotherapy for these patients.

Gut-Pancreas-Liver Axis as a Target for Treatment of NAFLD/NASH

Article

Full-text available

Aug 2020
INT J MOL SCI

Non-alcoholic fatty liver disease (NAFLD) represents the most common form of chronic liver disease worldwide. Due to its association with obesity and diabetes and the fall in hepatitis C virus morbidity, cirrhosis in NAFLD is becoming the most frequent indication to liver transplantation, but the pathogenetic mechanisms are still not completely understood. The so-called gut-liver axis has gained enormous interest when data showed that its alteration can lead to NAFLD development and might favor the occurrence of non-alcoholic steatohepatitis (NASH). Moreover, several therapeutic approaches targeting the gut-pancreas-liver axis, e.g., incretins, showed promising results in NASH treatment. In this review, we describe the role of incretin hormones in NAFLD/NASH pathogenesis and treatment and how metagenomic/metabolomic alterations in the gut microbiota can lead to NASH in the presence of gut barrier modifications favoring the passage of bacteria or bacterial products in the portal circulation, i.e., bacterial translocation.

An insight on medicinal attributes of 1,2,3‐ and 1,2,4‐triazole derivatives as alpha-amylase and alpha-glucosidase inhibitors

Article

Full-text available

Sep 2023
MOL DIVERS

Diabetes Mellitus (DM) is the globe’s common leading disease which is caused by high consumption of glucose. DM compiles groups of metabolic disorders which are characterized by inadequate secretion of insulin from pancreas, resulting in hyperglycemia condition. Many enzymes play a vital role in the metabolism of carbohydrate known as α-amylase and α-glucosidase which is calcium metalloenzyme that leads to breakdown of complex polysaccharides into glucose. To tackle this problem, search for newer antidiabetic drugs is the utmost need for the treatment and/or management of increasing diabetic burden. The inhibition of α-amylase and α-glucosidase is one of the effective therapeutic approaches for the development of antidiabetic therapeutics. The exhaustive literature survey has shown the importance of medicinally privileged triazole specifically 1,2,3‐triazol and 1,2,4‐triazoles scaffold tethered, fused and/or clubbed with other heterocyclic rings structures as promising agents for designing and development of novel antidiabetic therapeutics. Molecular hybrids namely pyridazine-triazole, pyrazoline-triazole, benzothiazole-triazole, benzimidazole‐triazole, curcumin-triazole, (bis)coumarin-triazole, acridine-9-carboxamide linked triazole, quinazolinone-triazole, xanthone-triazole, thiazolo-triazole, thiosemicarbazide-triazole, and indole clubbed-triazole are few examples which have shown promising antidiabetic activity by inhibiting α-amylase and/or α-glucosidase. The present review summarizes the structure–activity relationship (SAR), enzyme inhibitory activity including IC50 values, percentage inhibition, kinetic studies, molecular docking studies, and patents filed of the both scaffolds as alpha-amylase and alpha-glucosidase inhibitors, which may be used for further development of potent inhibitors against both enzymes.

The effects of glucagon-like peptide-1 receptor agonists on adipose tissues in patients with type 2 diabetes: A meta-analysis of randomised controlled trials

Article

Full-text available

Jul 2022
PLOS ONE

Aims Glucagon‑like peptide 1 receptor agonist (GLP-1RA) treatment can improve adipose distribution. We performed this meta-analysis to investigate whether GLP-1RAs preferentially reduce visceral adipose tissue (VAT) over subcutaneous adipose tissue (SAT) in patients with type 2 diabetes. Materials and methods We searched MEDLINE and the Cochrane Library for randomised controlled trials explicitly reporting changes in VAT and SAT. A random-effects model was performed to estimate the weighted mean difference (MD) for VAT and SAT. Heterogeneity among the studies was assessed using I ² statistics, and publication bias was assessed using Egger’s tests. Meta-regression was performed to identify the correlation between changes in adipose tissues and changes in body weight and glycated haemoglobin level. Results Ten trials with 924 patients were enrolled in the meta-analysis. GLP-1RA treatment led to similar absolute area (cm ² ) reductions in VAT (MD -21.13 cm ² , 95% CI [-29.82, -12.44]) and SAT (MD -22.89 cm ² , 95% CI [-29.83, -15.95]). No significant publication bias was detected, and this result was stable in the sensitivity and subgroup analyses. Moreover, GLP-1RA treatment resulted in a greater reduction in VAT and SAT in the subgroup with a greater reduction in body weight. The absolute area reduction in VAT was significantly correlated with the reduction in body weight (r = 6.324, p = 0.035). Conclusions GLP-1RA treatment leads to significant and similar absolute reductions in VAT and SAT, and the reduction in adipose tissues may be correlated with the reduction in body weight.

Nonalcoholic Steatohepatitis (NASH) and Atherosclerosis: Explaining Their Pathophysiology, Association and the Role of Incretin-Based Drugs

Article

Full-text available

May 2022

Nonalcoholic steatohepatitis (NASH) is the most severe manifestation of nonalcoholic fatty liver disease (NAFLD), a common complication of type 2 diabetes, and may lead to cirrhosis and hepatocellular carcinoma. Oxidative stress and liver cell damage are the major triggers of the severe hepatic inflammation that characterizes NASH, which is highly correlated with atherosclerosis and coronary artery disease. Regarding drug therapy, research on the role of GLP-1 analogues and DPP4 inhibitors, novel classes of antidiabetic drugs, is growing. In this review, we outline the association between NASH and atherosclerosis, the underlying molecular mechanisms, and the effects of incretin-based drugs, especially GLP-1 RAs, for the therapeutic management of these conditions.

Comparison of Beinaglutide Versus Metformin for Weight Loss in Overweight and Obese Non-diabetic Patients

Article

Full-text available

Dec 2021

Purpose We compared the efficacy and safety of beinaglutide, a glucagon-like peptide-1 (GLP-1) analogue with metformin in lowering the bodyweight of patients who were overweight/obese and non-diabetic. Patients and Methods Seventy-eight non-diabetic patients were randomly selected and beinaglutide or metformin was administered for 12 weeks. The primary endpoints were changes in body weight and the proportions of patients who lost≥5 and≥10% of their baseline body weights. Results A total of 64 patients completed the study; patients in the beinaglutide group exhibited more bodyweight loss than those in the metformin group [(9.5±0.8%; 9.1±0.9 kg) and (5.1±0.9%; 4.5±0.8 kg), respectively, corresponding to a difference of approximately 4.5 kg (95% confidence interval, 2.2–6.9 kg; P<0.01)]. In the beinaglutide group, 90.6 and 40.6% of the patients lost≥5 and≥10% of their body weight, respectively, whereas, in the metformin group, these rates were 46.9 and 12.5%, respectively (P<0.01 and P<0.05). Weight loss following beinaglutide treatment mainly resulted from the loss of fat mass. Compared to metformin, beinaglutide induced a greater decrease in the body mass index, weight circumference, percent body fat, and body fat mass (total, trunk, limb, android, and gynoid). Additionally, beinaglutide decreased serum insulin levels and ameliorated insulin resistance. Conclusions Beinaglutide is more efficient than metformin at reducing weight and fat mass in patients who are overweight/obese and non-diabetic. Beinaglutide may be a useful therapeutic option for overweight/obesity control in the Chinese population.

Beneficial effects of long-term liraglutide monotherapy on glycemic control and diabetic microangiopathies in a female Japanese diabetic patient with familial partial lipodystrophy 1

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Jan 2021

Post-transplant diabetes mellitus and preexisting liver disease- A bidirectional relationship affecting treatment and management

Article

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Jun 2020
WORLD J GASTROENTERO

Liver cirrhosis and diabetes mellitus (DM) are both common conditions with significant socioeconomic burden and impact on morbidity and mortality. A bidirectional relationship exists between DM and liver cirrhosis regarding both etiology and disease-related complications. Type 2 DM (T2DM) is a wellrecognized risk factor for chronic liver disease and vice-versa, DM may develop as a complication of cirrhosis, irrespective of its etiology. Liver transplantation (LT) represents an important treatment option for patients with end-stage liver disease due to non-alcoholic fatty liver disease (NAFLD), which represents a hepatic manifestation of metabolic syndrome and a common complication of T2DM. The metabolic risk factors including immunosuppressive drugs, can contribute to persistent or de novo development of DM and NAFLD after LT. T2DM, obesity, cardiovascular morbidities and renal impairment, frequently associated with metabolic syndrome and NAFLD, may have negative impact on short and long-term outcomes following LT. The treatment of DM in the context of chronic liver disease and post-transplant is challenging, but new emerging therapies such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium–glucose cotransporter 2 inhibitors (SGLT2i) targeting multiple mechanisms in the shared pathophysiology of disorders such as oxidative stress and chronic inflammation are a promising tool in future patient management.

Emerging role of GLP-1 receptor agonists in the treatment of obesity

Article

Full-text available

Jul 2010

The prevalence of obesity has increased dramatically in recent decades, both in the US and worldwide. Pharmacotherapy can augment the weight-reducing effects of lifestyle modification and can facilitate long-term weight maintenance. However, there is a paucity of pharmacologic agents approved for the treatment of obesity, and the use of existing weight loss medications is frequently limited by contraindications, drug interactions, adverse effects, limited coverage by third-party payers, and cost. In recent years, there has been an increased understanding and appreciation of the role of gastrointestinal hormones in the control of body weight. One such hormone, GLP-1, also plays an important role in glucose homeostasis. GLP-1 receptor agonists, such as exenatide and liraglutide, have been developed and are already approved for the treatment of type 2 diabetes. There has also been interest in the use of GLP-1 receptor agonists for the treatment of obesity in nondiabetic patients. This review explores the potential utility and limitations of exenatide and liraglutide as therapeutic agents for obesity.

Medicamentos antidiabéticos utilizados com a finalidade de perda de peso

Article

Full-text available

Nov 2023

O presente estudo objetivou realizar um levantamento bibliográfico de medicamentos antidiabéticos utilizados para emagrecimento e suas consequências para a saúde humana. Os medicamentos mais comumente relatados na literatura foram Metformina, Liraglutida e Semaglutida. Os três medicamentos demonstraram ser efetivos no emagrecimento, tendo a Liraglutida efeito mais pronunciado, inclusive em estudos clínicos. Metformina e Semaglutida demonstraram reduzir peso principalmente quando associados à prática de exercício físico e mudança de hábito alimentar. Entretanto, esses medicamentos ainda não foram aprovados com a finalidade de emagrecimento, e uma série de efeitos colaterais foram relatados, principalmente associados ao sistema gastrointestinal como náusea, vômito e diarréia. Com base nos dados avaliados, a melhor forma de reduzir o peso corporal continua sendo a prática de atividade física e mudança do estilo de vida, e uma vez que tais práticas não são suficientes pode-se optar pelo uso de anorexígeno com a devida prescrição e orientação de um profissional de saúde. Destacamos ainda a maior necessidade do farmacêutico, responsável pela interface entre o medicamento e o paciente, no processo de educação para evitar o uso irracional de medicamentos antidiabéticos no intuito de emagrecer.

GLP-1RA Liraglutide and Semaglutide Improves Obesity-Induced Muscle Atrophy via SIRT1 Pathway

Article

Full-text available

Aug 2023

Background: Obesity is related to the loss of skeletal muscle mass and function (sarcopenia). The co-existence of obesity and sarcopenia is called sarcopenic obesity (SO). Glucagon like peptide-1 receptor agonists (GLP-1RA) are widely used in the treatment of diabetes and obesity. However, the protective effects of GLP-1RA on skeletal muscle in obesity and SO are not clear. This study investigated the effects of GLP-1RA liraglutide and semaglutide on obesity-induced muscle atrophy and explored the underlying mechanisms. Methods: Thirty-six male C57BL/6J mice were randomly divided into two groups and fed a regular diet and a high-fat diet for 18 weeks, respectively. After establishing an obesity model, mice were further divided into six groups: control group, liraglutide (LIRA) group, semaglutide (SEMA) group, high-fat diet (HFD) group, HFD + LIRA group, HFD + SEMA group, and subcutaneous injection for 4 weeks. The body weight, muscle mass, muscle strength, glycolipid metabolism, muscle atrophy markers, myogenic differentiation markers, GLUT4 and SIRT1 were analyzed. C2C12 myotube cells treated with palmitic acid (PA) were divided into four groups: control group, PA group, PA + LIRA group, PA + SEMA group. The changes in glucose uptake, myotube diameter, lipid droplet infiltration, markers of muscle atrophy, myogenic differentiation markers, GLUT4 and SIRT1 were analyzed, and the changes in related indicators were observed after the addition of SIRT1 inhibitor EX527. Results: Liraglutide and semaglutide reduced HFD-induced body weight gain, excessive lipid accumulation and improved muscle atrophy. Liraglutide and semaglutide eliminated the increase of muscle atrophy markers in skeletal muscle and C2C12 myotubes. Liraglutide and semaglutide restored impaired glucose tolerance and insulin resistance. However, these beneficial effects were attenuated by inhibiting SIRT1 expression. Conclusion: Liraglutide and semaglutide protects skeletal muscle against obesity-induced muscle atrophy via the SIRT1 pathway.

A Comprehensive Review on Weight Loss Associated with Anti-Diabetic Medications

Article

Full-text available

Apr 2023

Obesity is a complex metabolic condition that can have a negative impact on one’s health and even result in mortality. The management of obesity has been addressed in a number of ways, including lifestyle changes, medication using appetite suppressants and thermogenics, and bariatric surgery for individuals who are severely obese. Liraglutide and semaglutide are two of the five Food and Drug Administration (FDA)-approved anti-obesity drugs that are FDA-approved agents for the treatment of type 2 diabetes mellitus (T2DM) patients. In order to highlight the positive effects of these drugs as anti-obesity treatments, we analyzed the weight loss effects of T2DM agents that have demonstrated weight loss effects in this study by evaluating clinical studies that were published for each agent. Many clinical studies have revealed that some antihyperglycemic medications can help people lose weight, while others either cause weight gain or neutral results. Acarbose has mild weight loss effects and metformin and sodium-dependent glucose cotransporter proteins-2 (SGLT-2) inhibitors have modest weight loss effects; however, some glucagon-like peptide-1 (GLP-1) receptor agonists had the greatest impact on weight loss. Dipeptidyl peptidase 4 (DPP-4) inhibitors showed a neutral or mild weight loss effect. To sum up, some of the GLP-1 agonist drugs show promise as weight-loss treatments.

GLP-1 analogues in the treatment of obesity and non-alcoholic fatty liver disease

Article

Full-text available

Feb 2023
PHMD/ Postepy Hig Med Dosw

Type two diabetes has become a civilization disease in the recent years, and the accompanying obesity, metabolic syndrome and non-alcoholic fatty liver are often the inseparable components of the clinical presentation in patients with diabetes of this type. The treatment of each of these elements is important for optimal metabolic control of the patients, as well as directly affecting their life expectancy. However, The ideal solution would be to take as few drugs as possible, preferably drugs that have a beneficial effect on several coexisting diseases at the same time. In the recent years, there have been more and more reports about the pleiotropic effect of drugs affecting the incretin axis - GLP-1 analogues. The presented paper provides an overview of the latest knowledge on the effect of GLP-1 receptor agonists on weight reduction and reduction of changes in the course of non-alcoholic fatty liver disease.

GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives

Article

Full-text available

Jan 2023
INT J MOL SCI

To date, non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease, affecting up to 70% of patients with diabetes. Currently, there are no specific drugs available for its treatment. Beyond their anti-hyperglycemic effect and the surprising role of cardio- and nephroprotection, GLP-1 receptor agonists (GLP-1 RAs) have shown a significant impact on body weight and clinical, biochemical and histological markers of fatty liver and fibrosis in patients with NAFLD. Therefore, GLP-1 RAs could be a weapon for the treatment of both diabetes mellitus and NAFLD. The aim of this review is to summarize the evidence currently available on the role of GLP-1 RAs in the treatment of NAFLD and to hypothesize potential future scenarios.

Exenatide increases CTRP3 gene expression in adipose cells by inhibiting adipogenesis and induces apoptosis

Article

Sep 2022
TOXICOL IN VITRO

Considering the rapidly increasing prevalence of obesity worldwide, the number of weight control drugs is very few. Incretin-based therapies are currently being developed to achieve weight control, and Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RA) are used in incretin-based therapies. This study aimed to investigate the cytotoxicity of exenatide, a GLP-1A, on 3T3-L1 adipocytes and the effect of exenatide on the expression of adipogenesis-related genes, insulin and glucose levels, and apoptosis. Cytotoxic activity of exenatide on 3T3-L1 adipocytes was determined by MTT method. Gene expression levels were determined by qPCR. Apoptosis studies were performed on the Muse Cell Analyzer. C1q/TNF-related protein-3 (CTRP3) expression levels were found to be higher in exenatide treated adipocyte cells than in control cells (p < 0.001). Adipocyte cells treated with exenatide were found to have lower PPAR-γ gene expression levels when compared to control adipocyte cells (p < 0.001). Intracellular insulin (p < 0.001) and glucose levels were higher in 3T3-L1 adipocytes treated with exenatide compared to control adipocyte cells. Total apoptosis increased approximately 1.5 times as a result of exenatide administration. The increase in CTRP3 gene expression, which is thought to be a new biomarker for obesity, and the decrease in PPAR-γ gene expression indicate that exenatide is a promising new pharmacotherapeutic agent in the treatment of obesity by regulating the expression of genes related to adipogenesis and lipogenesis and inducing apoptosis.

Pharmacometabolomic profiles in type 2 diabetic subjects treated with liraglutide or glimepiride

Article

Full-text available

Dec 2021
CARDIOVASC DIABETOL

Background Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) leads to multiple metabolic changes, reduction in glucose levels and body weight are well established. In people with type 2 diabetes, GLP-1 RAs reduce the risk of cardiovascular (CV) disease and may also potentially represent a treatment for fatty liver disease. The mechanisms behind these effects are still not fully elucidated. The aim of the study was to investigate whether treatment with liraglutide is associated with favourable metabolic changes in cases of both CV disease and fatty liver disease. Methods In a prespecified post-hoc analysis of a double-blind, placebo-controlled trial in 62 individuals with type 2 diabetes (GLP-1 RA liraglutide or glimepiride, both in combination with metformin), we evaluated the changes in plasma molecular lipids and polar metabolites after 18 weeks of treatment. The lipids and polar metabolites were measured by using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOFMS). Results In total, 340 lipids and other metabolites were identified, covering 14 lipid classes, bile acids, free fatty acids, amino acids and other polar metabolites. We observed more significant changes in the metabolome following liraglutide treatment compared to with glimepiride, particularly as regards decreased levels of cholesterol esters hexocyl-ceramides, lysophosphatidylcholines, sphingolipids and phosphatidylcholines with alkyl ether structure. In the liraglutide-treated group, lipids were reduced by approximately 15% from baseline, compared to a 10% decrease in the glimepiride group. At the pathway level, the liraglutide treatment was associated with lipid, bile acid as well as glucose metabolism, while glimepiride treatment was associated with tryptophan metabolism, carbohydrate metabolism, and glycerophospholipid metabolism. Conclusions Compared with glimepiride, liraglutide treatment led to greater changes in the circulating metabolome, particularly regarding lipid metabolism involving sphingolipids, including ceramides. Our findings are hypothesis-generating and shed light on the underlying biological mechanisms of the CV benefits observed with GLP-1 RAs in outcome studies. Further studies investigating the role of GLP-1 RAs on ceramides and CV disease including fatty liver disease are warranted. Trial registration: NCT01425580

GLP-1 Receptor Agonists in Diabetic Kidney Disease: From Physiology to Clinical Outcomes

Article

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Aug 2021

Diabetic kidney disease (DKD) is one of the most common complications in type 2 diabetes mellitus (T2D) and a major cause of morbidity and mortality in diabetes. Despite the widespread use of nephroprotective treatment of T2D, the incidence of DKD is increasing, and it is expected to become the fifth cause of death worldwide within 20 years. Previous studies have demonstrated that GLP-1 receptor agonists (GLP-1 RA) have improved macrovascular and microvascular outcomes independent of glycemic differences, including DKD. GLP-1Ras’ improvement on kidney physiology is mediated by natriuresis, reduction in hyperfiltration and renin-angiotensin-aldosterone system (RAAS) activity and anti-inflammatory properties. These findings translate into improved clinical outcomes such as an enhanced urine albumin-to-creatinine ratio (UACR) and a reduction in renal impairment and the need for renal replacement therapies (RRT). In this article, we review the role of GLP-1RAs on the mechanisms and effect in DKD and their clinical efficacy.

Cardiorenal effects of newer antidiabetic agents

Article

May 2020

Chronic kidney disease is a major problem of public health and is associated with increased cardiovascular mortality and morbidity. Its treatment includes multifactorial intervention: optimal blood pressure and intensive glycaemic control. There are many studies – clinical and experimental – demonstrating that classic and newer antidiabetic agents delay the progression of diabetic nephropathy. Glucagon-like-peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporters-2 (SGLT-2) inhibitors have renoprotective action. Furthermore, these antidiabetic agents have beneficial effects to the cardiovascular system, including weight loss and blood pressure reduction. Large, randomized, placebo-controlled outcome trials have showed that SGLT-2 inhibitors and GLP-1 receptor agonists are able to reduce cardiovascular events. Therefore, the present review aims to summarize the existing data regarding the effect of newer antidiabetic agents on kidney function and cardiovascular system.

Management of Diabetes in Candidates for Liver Transplantation and in Transplant Recipients

Article

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Jun 2021

Diabetes is common in patients waitlisted for liver transplantation because of end-stage liver disease or hepatocellular cancer as well as in posttransplant phase (posttransplantation diabetes mellitus). In both conditions, the presence of diabetes severely affects disease burden and long-term clinical outcomes; careful monitoring and appropriate treatment are pivotal to reduce cardiovascular events and graft and recipients' death. We thoroughly reviewed the epidemiology of diabetes in the transplant setting and the different therapeutic options, from lifestyle intervention to antidiabetic drug use-including the most recent drug classes available-and to the inclusion of bariatric surgery in the treatment cascade. In waitlisted patients, the old paradigm that insulin should be the treatment of choice in the presence of severe liver dysfunction is no longer valid; novel antidiabetic agents may provide adequate glucose control without the risk of hypoglycemia, also offering cardiovascular protection. The same evidence applies to the posttransplant phase, where oral or injectable noninsulin agents should be considered to treat patients to target, limiting the impact of disease on daily living, without interaction with immunosuppressive regimens. The increasing prevalence of liver disease of metabolic origin (nonalcoholic fatty liver) among liver transplant candidates, also having a higher risk of noncirrhotic hepatocellular cancer, is likely to accelerate the acceptance of new drugs and invasive procedures, as suggested by international guidelines. Intensive lifestyle intervention programs remain however mandatory, both before and after transplantation. Achievement of adequate control is mandatory to increase candidacy, to prevent delisting, and to improve long-term outcomes.

Optimal Cut-Off Values of Visceral Fat Area for Predicting Metabolic Syndrome Among Type 2 Diabetes Patients in Ningbo, China

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Full-text available

Mar 2021

Objective: To examine the optimal cut-off values of visceral fat area (VFA) for predicting metabolic syndrome (MetS) among type 2 diabetes (T2D) patients in Ningbo China. Methods: A total of 1017 subjects were selected from T2D patients who accepted standardized management by the National Standardized Metabolic Disease Management Center at Ningbo First Hospital from March 2018 to January 2020. Demography and medical information were collected through questionnaires. Regional adiposity was examined by a visceral fat analyzer using the dual bioelectrical impedance method. Results: Overall, 769 (75.6%) T2D patients were defined to have MetS. Patients with MetS had higher anthropometric values and biomarkers, compared to those without MetS. VFA was significantly correlated with risk factors of MetS. Further logistic regression models showed that VFA was significantly associated with MetS in men (OR=1.02) and in women (OR=1.03) (P<0.001 for both genders) after controlling for related factors. Receiver-operating characteristic curve analysis demonstrated that the optimal cut-off values of VFA were 84.7 cm2 for men and 81.1 cm2 for women to predict MetS in T2D patients. Conclusion: VFA was associated with MetS and could be an independent predictor of MetS in T2D patients. Clinical trial registration: www.ClinicalTrials.gov, number: NCT03811470.

Effect of liraglutide treatment on body mass index and weight parameters in children and adolescents with type 2 diabetes: Post hoc analysis of the ellipse trial

Article

Full-text available

Feb 2021

Background Weight loss in children and adolescents with type 2 diabetes (T2D) is associated with improved glycaemic control. Objectives To assess the effects of liraglutide vs placebo on body mass index (BMI) and weight parameters in children and adolescents with T2D using data from the ellipse trial (NCT01541215). Methods The ellipse trial randomized participants (10‐<17 years old, BMI >85th percentile, T2D, glycated haemoglobin [HbA1c] 7.0%‐11.0% [if diet‐ and exercise‐treated] or 6.5% to 11.0% [if treated with metformin, basal insulin or both]) to liraglutide or placebo. This post‐hoc analysis evaluated changes from baseline to weeks 26 and 52 in absolute BMI, percent change in BMI and other weight‐related parameters. Changes were assessed by liraglutide overall (all doses) and liraglutide by dose (0.6, 1.2 and 1.8 mg/day) vs placebo using a pattern mixture model of observed data, with missing observations imputed from each treatment group. Results In total, 134 participants were included. There were statistically significant differences between groups in certain parameters, including absolute BMI (estimated treatment difference [ETD] –0.89 kg/m²; 95% confidence interval [CI] –1.71,–0.06) and percent change in BMI (ETD –2.73%; 95% CI –5.15,–0.30) at week 52, but none at week 26. Dose‐dependent effects were not observed for liraglutide vs placebo for all BMI/weight parameters. Conclusions Compared with placebo, liraglutide was associated with statistically significant reductions in BMI/weight parameters at week 52, but not week 26, in children and adolescents with T2D.

Effects of antidiabetic agents on steatosis and fibrosis biomarkers in type 2 diabetes: A real‐world data analysis

Article

Full-text available

Jan 2021

Background & Aims There is intense research for drugs able to reduce disease progression in NAFLD. We aimed to test the impact of novel antidiabetic drugs (dipeptidyl‐peptidase‐4 inhibitors – DPP‐4Is, glucagon‐like peptide‐1 receptor agonists – GLP‐1RAs, sodium‐glucose cotransporter‐2 inhibitors – SGLT‐2Is) on non‐invasive biomarkers of steatosis (Fatty liver index, FLI) and fibrosis (Fibrosis‐4 score, FIB‐4) in patients with type 2 diabetes (T2D). Methods Clinical, anthropometric and biochemical parameters were retrospectively analyzed in 637 consecutive T2D patients switched from metformin w/wo sulfonylureas and/or pioglitazone to DPP‐4Is, GLP‐1RAs and SGLT‐2Is in a tertiary care setting. 165 patients maintained on original treatments served as controls. The effects on FLI and FIB‐4 at 6‐ and 12‐month follow‐up were analyzed by logistic regression after adjustment for baseline differences, computed by propensity scores, and additional adjustment for changes in glycosylated hemoglobin (HbA1c) and BMI. Results BMI, HbA1c and aminotrasferases significantly decreased following switching to GLP‐1RAs and SGLT2‐Is, compared with both controls and DPP‐4Is, whereas only HbA1c was reduced on DPP‐4Is. FLI and FIB‐4 were reduced on GLP‐1RA and SGLT‐2I; logistic regression analysis confirmed a significant improvement of both biomarkers after adjustment for propensity score. The shift of FIB‐4 values towards the category ruling out advanced fibrosis was maintained after additional adjustment for confounders. These effects were confirmed in a sensitivity analysis on effect size. Conclusions GLP‐1RAs and SGLT‐2Is improve biomarkers of steatosis and fibrosis, in keeping with beneficial effects on liver disease progression, and should be considered the treatment of choice in T2D.

GLP‐1 agonists for obesity and type 2 diabetes in children: Systematic review and meta‐analysis

Article

Dec 2020

Pharmacological options for management of obesity and type 2 diabetes mellitus (T2DM) in children are limited. We aimed to synthesize published randomized controlled trial (RCT) evidence on the efficacy of glucagon‐like peptide‐1 (GLP‐1) agonists in T2DM, pre‐diabetes, and obesity in children aged <18 years. Inclusion criteria were RCTs of any GLP‐1 agonist, solely or in conjunction with other drugs, for the treatment of obesity, pre‐diabetes, and/or T2DM in children aged <18 years old. Nine studies met the inclusion criteria (two for T2DM, one for pre‐diabetes, and six for obesity without diabetes). In total, 286 children were allocated to GLP‐1 agonist therapy. Compared with controls, GLP‐1 agonist therapy reduced HbA1c by −0.30% (95% confidence interval [CI] −0.57, −0.04) with a larger effect in children with (pre‐)diabetes (−0.72%; 95% CI −1.17, −0.28; three studies) than in children with obesity (−0.08%; 95% CI −0.13, −0.02; four studies). Conversely, GLP‐1 agonist therapy reduced body weight more in children with obesity (−2.74 kg; 95% CI −3.77, −1.70; six studies) than in children with T2DM (−0.97 kg; 95% CI −2.01, 0.08; two studies). Adverse effects included gastrointestinal symptoms and minor hypoglycemic episodes, but not severe hypoglycemia. GLP‐1 agonists are efficacious in treating children with obesity and/or T2DM. Effect sizes are comparable with those reported in adults.

β-catenin mediates the effect of GLP-1 receptor agonist on ameliorating hepatic steatosis induced by high fructose diet

Article

Full-text available

Sep 2020
EUR J HISTOCHEM

The hypoglycemic drug GLP-1 receptor agonist can ameliorate hepatic steatosis but the mechanism is not clear. Intake of high fructose leads to non-alcoholic fatty liver disease by stimulating lipid synthesis, and β-catenin is the key molecule for realizing GLP-1 function in extrahepatic tissues; with the discovery of GLP-1 receptor in liver, we speculate that β-catenin might mediate GLP-1 receptor agonist on ameliorating hepatic steatosis induced by high fructose. Wistar rats were fed with high fructose diet for 8 weeks and then treated with GLP-1 receptor agonist exenatide for 4 weeks; the changes of lipid synthesis pathway factors, the expression and nuclear translocation of β-catenin, and the hepatic steatosis of the rats were observed. After the intervention of exenatide, the hepatic steatosis induced by high fructose was improved, the nuclear translocation and expression of β-catenin were facilitated, and the mRNA and protein expression of the upstream regulator SREBP-1 and the downstream key enzymes ACC, FAS and SCD-1 of de novo lipogenesis were down-regulated. GLP-1 receptor agonist may ameliorate hepatic steatosis induced by high fructose by β-catenin regulating de novo lipogenesis pathway. GLP-1 receptor agonist may be a potential new drug for the treatment of non-alcoholic fatty liver disease, and the β-catenin may be an important target for the drug therapy.

Comparison of tofogliflozin versus glimepiride as the third oral agent added to metformin plus DPP ‐4 inhibitor in Japanese type 2 diabetes patients: a randomized, 24‐week, open label, controlled trial ( STOP‐OB )

Article

Full-text available

Apr 2020

Metformin plus a dipeptidyl peptidase‐4 inhibitor (DPP‐4i) is the most common therapy for Japanese patients with type 2 diabetes mellitus. This 24‐week, multicenter, open‐label, parallel‐group trial randomized patients on dual therapy to add‐on tofogliflozin (20 mg/day, n = 33) or glimepiride (0.5 mg/day, n = 31). The primary outcome was change in body fat percentage. The secondary outcomes included changes in HbA1c, fat mass, fat‐free mass, liver function parameters and uric acid. Tofogliflozin and glimepiride reduced HbA1c to similar extents. Body fat percentage did not change from baseline in either group. Fat mass was reduced by tofogliflozin but was increased by glimepiride (by −2.0 ± 1.7 kg and + 1.6 ± 1.6, p = 0.002). Fat‐free mass was also reduced by tofogliflozin and increased by glimepiride (by −1.3 ± 1.3 kg and + 0.9 ± 2.0, p < 0.001). Alanine aminotransferase and uric acid levels were reduced by tofogliflozin (p = 0.006 and p < 0.001, respectively). These data provide novel information useful for selecting the third oral agent for patients whose diabetes is inadequately controlled with metformin plus DPP‐4i dual therapy. This article is protected by copyright. All rights reserved.

Effects of liraglutide on metabolic syndrome in WBN/Kob diabetic fatty rats supplemented with a high‐fat diet

Article

Full-text available

Mar 2020

Background: Liraglutide, a GLP-1 receptor agonist, has recently been used to treat metabolic syndrome (MS) because of its anti-diabetic and anti-obesity effects. We have previously shown that Wistar Bonn Kobori diabetic and fatty (WBN/Kob-Lepr fa , WBKDF) rats fed a high-fat diet (HFD) developed MS including marked obesity, hyperglycemia, and dyslipidemia. To obtain further information on WBKDF-HFD rats as a severe MS model, we performed a pharmacological investigation into the anti-MS effects of liraglutide in this model. Methods: Seven-week-old male WBKDF-HFD rats were allocated to three groups (N = 8 in each group): a vehicle group, a low-dose liraglutide group, and a high-dose liraglutide group. They received subcutaneous injections of either saline or liraglutide at doses of 75 or 300 μg/kg body weight once daily for 4 weeks. Results: Results showed that liraglutide treatment reduced body weight gain and food intake in a dose-dependent manner. The marked hyperglycemia and the glucose tolerance were also significantly ameliorated in the liraglutide-treated groups. Moreover, liraglutide also reduced the plasma triglyceride concentration and liver fat accumulation. Conclusions: The present study demonstrated that liraglutide could significantly alleviate MS in WBKDF-HFD rats, and the reaction to liraglutide is similar to human patients with MS. WBKDF-HFD rats are therefore considered to be a useful model for research on severe human MS.

Favorable liver and skeletal muscle changes in patients with MASLD and T2DM receiving glucagon-like peptide-1 receptor agonist: A prospective cohort study

Article

Jun 2024
MEDICINE

To investigate changes in skeletal muscle mass and fat fraction in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (T2DM) undergoing treatment with Semaglutide for 6months. This single-arm pilot study included 21 patients with MASLD who received semaglutide for T2DM. Body weight, metabolic parameters, liver enzymes, fibrosis markers, skeletal muscle index (cm ² /m ² ), and fat fraction (%) at the L3 level using the two-point Dixon method on magnetic resonance imaging (MRI), as well as liver steatosis and liver stiffness assessed using MRI-based proton density fat fraction (MRI-PDFF) and MR elastography, respectively, were prospectively examined before and 6 months after semaglutide administration. The mean age of the patients was 53 years and 47.6% were females. The median liver steatosis-fraction (%) and skeletal muscle steatosis-fraction values (%) significantly decreased (22.0 vs 12.0; P = .0014) and (12.8 vs 9.9; P = .0416) at baseline and 6 months, respectively, while maintaining muscle mass during treatment. Semaglutide also dramatically reduced hemoglobin A1c (%) (6.8 vs 5.8, P = .0003), AST (IU/L) (54 vs 26, P < .0001), ALT (IU/L) (80 vs 34, P = .0004), and γ-GTP (IU/L) levels (64 vs 34, P = .0007). Although not statistically significant, Body weight (kg) (79.9 vs 77.4), body mass index (BMI) (kg/m ² ) (28.9 vs 27.6), and liver stiffness (kPa) (28.9 vs 27.6) showed a decreasing trend. Fibrosis markers such as M2BPGi, type IV collagen, and skeletal muscle area did not differ. Semaglutide demonstrated favorable effects on liver and skeletal muscle steatosis, promoting improved liver function and diabetic status.

The effect of subcutaneous Lixisenatide on weight loss in patients with type 2 Diabetes Mellitus: Systematic review and Meta-Analysis of randomized controlled trials

Article

Mar 2024
DIABETES RES CLIN PR

GLP-1RA Essentials in Gastroenterology: Side Effect Management, Precautions for Endoscopy and Applications for Gastrointestinal Disease Treatment

Article

Full-text available

Feb 2024

Amidst the obesity and type II diabetes mellitus (T2DM) epidemics, glucagon-like peptide-1 receptor agonists (GLP-1RAs) stand out as a promising therapeutic ally, achieving notable success in glycemic control and weight management. While GLP-1RAs’ positive clinical outcomes are commendable, they introduce significant gastrointestinal (GI) challenges, emphasizing the pivotal role of gastroenterologists in understanding and managing these implications. Physicians should be vigilant of potential complications if endoscopy is indicated and considered. A protocol coined “The Three E’s: Education, Escalation, and Effective Management” is essential as the first defense against GLP-1RA-induced dyspepsia, necessitating routine GI consultations. Awareness and intervention of potential aspiration due to GLP-1RA-induced gastroparesis are vital in clinical management. Furthermore, the evolving recognition of GLP-1RAs’ beneficial effects on non-alcoholic steatohepatitis (NASH) suggests gastroenterologists will increasingly prescribe them. Thus, a comprehensive understanding of pharmacological properties and potential GI complications, including the undetermined cancer risk landscape, becomes paramount. This review accentuates the nuances of GLP-1RA therapy from a gastroenterological lens, juxtaposing the therapeutic potential, manageable side effects, and circumstantial challenges, ensuring that GI specialists remain at the forefront of holistic care in obesity and T2DM management.

Effect of Liraglutide on Weight Loss and BMI Among Patients Who Are Overweight and Obese with Type 2 Diabetes: A Systematic Review and Meta-analysis

Article

Full-text available

Dec 2023

Objectives: This study assessed the effect of liraglutide as a monotherapy and add-on to metformin on weight loss and BMI, among patients with Type 2 diabetes (T2D) who are overweight or obese. Methods: The following databases were assessed to identify relevant papers published until July 2023: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PubMed), clinicaltrial.gov, and Web of Science. All clinical trials evaluating the effect of liraglutide on weight loss and BMI in patients with T2D who are obese or overweight, treated for at least 2 months, were included in the review. All analysis and risk of bias assessment was done using Cochrane Review Manager software, version 5.4.1 (Cochrane, London, UK). A random-effects model with inverse variance was used to synthesise the results. Results: In total, 10 randomised controlled trials involving 945 participants were included in the meta-analysis. Treatment with liraglutide with or without metformin for more than 2 months led to a significant weight loss (mean difference: -4.75 kg; 95% confidence interval: -7.02–-2.48; p<0.01). Liraglutide supplementation also led to a significant decrease in BMI (mean difference: -2.07; 95% confidence interval: -2.75–-1.39; p<0.01). However, the decrease in weight and BMI was not statistically significant as compared to treatment with other oral hypoglycaemic drugs or placebo. Conclusion: Liraglutide used alone or as adjunctive therapy to metformin produces reduction in weight and BMI when administered in adult patients with T2D who are obese or overweight.

Liraglutide treatment for the prevention of glucose tolerance deterioration in women with prior gestational diabetes mellitus: A 52‐week randomized controlled clinical trial

Article

Oct 2023

Aim We investigated the effect of 52‐week treatment with liraglutide, a glucagon‐like peptide 1 receptor agonist, on glucose tolerance and incretin effect in women with previous gestational diabetes mellitus (pGDM). Materials and Methods Women with overweight/obesity and pGDM were randomized to once daily subcutaneous liraglutide 1.8 mg or placebo for 52 weeks. Participants underwent oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion at baseline and at 52 weeks, and an additional OGTT after the drug wash‐out. Results In total, 104 women [age: mean ± SD, 38 ± 5 years; fasting plasma glucose (FPG): 5.5 ± 0.4 mmol/L; glycated haemoglobin (HbA1c): 33 ± 4 mmol/mol, bodyweight: 88.2 ± 14.8 kg, body mass index: 31.1 ± 4.3 kg/m ² ] were assigned to liraglutide (n = 49) or placebo (n = 55). Estimated treatment difference (ETD) for area under curve during OGTT was −173 (95% confidence interval −250 to −97) mmol/L × min, p < .0001, but after wash‐out the difference disappeared [ETD 58 (−30 to 146) mmol/L × min, p = .536]. Liraglutide reduced FPG [ETD −0.2 (−0.4 to −0.1) mmol/L, p = .018], HbA1c [−2.2 (−3.5 to −0.8) mmol/mol, p = .018] and bodyweight [−3.9 (−6.2 to −1.6) kg, p = .012]. No change in the incretin effect was observed. The number of women with prediabetes was reduced from 64% to 10% with liraglutide vs. 50% with placebo [adjusted odds ratio 0.10 (0.03‐0.32), p = .002]. Conclusions Treatment with liraglutide for 52 weeks improved glucose tolerance, FPG, HbA1c and bodyweight in women with overweight/obesity and pGDM. Progression to prediabetes while on drug was markedly reduced, but after a 1‐week drug wash‐out, the effect was lost.

The effects of GLP-1 receptor agonists on visceral fat and liver ectopic fat in an adult population with or without diabetes and nonalcoholic fatty liver disease: A systematic review and meta-analysis

Article

Full-text available

Aug 2023
PLOS ONE

Aim: To uncover the effect of GLP-1 receptor agonists (GLP-1 RAs) on the visceral- and hepatic fat content of adults. Methods: PubMed, EMBASE, Cochrane Library, and Web of Science were searched from inception until November 2022. Randomized controlled trials (RCTs) of GLP-1Ras was extracted, including reports of effects on visceral adipose tissue and hepatic fat content in individuals with type 2 diabetes, non-type 2 diabetes, NAFLD (non-alcoholic fatty liver disease), and non-NAFLD. Meta-analyses used random-effects models. Results: 1736 individuals in the 30 qualified RCTs were included, comprising 1363 people with type 2 diabetes and 318 with NFLD. GLP-1 RAs reduced visceral adipose tissue (standard mean difference [SMD] = -0.59, 95% CI [-0.83, -0.36], P<0.00001) and hepatic fat content (weighted mean difference [WMD] = -3.09, 95% CI [-4.16, -2.02], P<0.00001) compared to other control treatment. Subgroup analysis showed that GLP-1Ras dramatically decreased visceral fat in patients with type 2 diabetes (SMD = -0.49, 95% CI [-0.69, -0.29] P<0.00001), NAFLD (SMD = -0.99, 95% CI [-1.64, -0.34] P = 0.003), non-type 2 diabetes (SMD = -1.38, 95% CI [-2.44, -0.32] P = 0.01), and non-NAFLD (SMD = -0.53, 95% CI [-0.78, -0.28] P<0.0001). GLP-1Ras reduced the liver fat level of type 2 diabetes (WMD = -3.15, 95% CI [-4.14, -2.15] P<0.00001), NAFLD (WMD = -3.83, 95% CI [-6.30, -1.37] P = 0.002), and type 2 diabetes with NAFLD (WMD = -4.27, 95% CI [-6.80, -1.74] P = 0.0009), while showed no impact on the hepatic fat content in non-Type 2 diabetes (WMD = -12.48, 95% CI [-45.19, 20.24] P = 0.45). Conclusions: LP-1 RAs significantly reduce visceral- and liver fat content in adults.

Endoscopic Ultrasound Guided Gastric Botulinum Toxin Injections versus Glucagon like peptide 1 Receptor Agonist in weight loss. A Prospective randomized study

Preprint

Full-text available

Jul 2023

Purpose In this study, we compared safety, feasibility, and efficacy of Endoscopic Ultrasound (EUS) guided Botulinum toxin A (BTA) injection versus Glucagon like Peptide 1 (GLP-1) agonists in treatment of obesity. The two intervention techniques were paired with a number of lifestyle changes, such as a diet of 2000 calories per day for males and 1800 calories per day for women, and moderate daily cardiovascular exercise (at least 30 minutes, five days a week) for four months. Over the course of a 16-week follow-up period, body weight was measured. Methods 40 patients were included in this study, 20 in each group. The 1st group underwent BTA injections via EUS, while the 2nd group received GLP 1 receptor agonist. Results In the 1st group, there was a significant weight loss from (107.30±11.41 kg) at baseline to (94.75±12.65 kg) after 4 months of treatment (p value <0.001). In the 2nd there was significant weight loss from (123.28±17.17 kg) at baseline to (109.75±14.37 kg) after 4 months (p value <0.001). Significant reduction of BMI was reported in both groups after 4 months of treatment; 1st group, from (40.53±4.41 kg/m2) at baseline to (35.78±4.82 kg/m2) (p. value <0.001), 2nd group from (44.15±5.94 kg/m2) to (39.40±5.68 kg/m2) (p value <0.001). Conclusion EUS guided BTA injections and GLP-1 RA receptor agonist injections both could be effective and safe procedures for treatment of obesity. Trial registration: NCT05268627, initial release 27/1/2022

GLP-1 analogs and regional adiposity: A systematic review and meta-analysis

Article

May 2023
OBES REV

Background: Glucagon-like peptide 1 (GLP-1) analogs regulate body weight and liver steatosis. Different body adipose tissue (AT) depots exhibit biological variability. Accordingly, GLP-1 analog effects on AT distribution are unclear. Objectives: To investigate GLP1-analog effects on adiposity distribution. Search methods: PubMed, Cochrane, and Scopus databases were screened for eligible randomized human trials. Pre-defined endpoints included visceral AT (VAT), subcutaneous AT (SAT), total AT (TAT), epicardial AT (EAT), liver AT (LAT), and waist-to-hip ratio (W:H). Search was conducted until May 17, 2022. Data collection and analysis: Data extraction and bias assessment were performed by two independent investigators. Treatment effects were estimated using random effects models. Analyses were performed on Review Manager v5.3. Main results: Out of the 367 screened studies, 45 were included in the systematic review and 35 were used in the meta-analysis. GLP-1 analogs reduced VAT, SAT, TAT, LAT, and EAT, with non-significant effects on W:H. Overall bias risk was low. Conclusions: GLP-1 analog treatment reduces TAT, affecting most studied AT depots, including the pathogenic VAT, EAT, and LAT. GLP-1 analogs may have significant roles in combating metabolic, obesity-associated diseases via reductions of key AT depot volumes.

Diabetes and fatty liver: Involvement of incretin and its benefit for fatty liver management

Article

Full-text available

May 2023

Fatty liver disease is defined as liver condition characterized by hepatic steatosis, closely related to pathological conditions in type 2 diabetes and obesity. The high prevalence of fatty liver disease in obese patients with type 2 diabetes reached 70%, reflecting the importance of these conditions with fatty liver. Although the exact pathological mechanism of fatty liver disease, specifically non-alcoholic fatty liver disease (NAFLD) remains not completely revealed, insulin resistance is suggested as the major mechanism that bridged the development of NAFLD. Indeed, loss of the incretin effect leads to insulin resistance. Since incretin is closely related to insulin resistance and the resistance of insulin associated with the development of fatty liver disease, this pathway suggested a potential me-chanism that explains the association between type 2 diabetes and NAFLD. Furthermore, recent studies indicated that NAFLD is associated with impaired glucagon-like peptide-1, resulting in decreased incretin effect. Nevertheless, improving the incretin effect becomes a reasonable approach to manage fatty liver disease. This review elucidates the involvement of incretin in fatty liver disease and recent studies of incretin as the management for fatty liver disease.

Medical therapy

Chapter

Jan 2023

Safety and Efficacy of Liraglutide on Reducing Visceral and Ectopic Fat in Adults with or without Type 2 Diabetes Mellitus: A Systematic Review and Meta‐analysis

Article

Oct 2022

Aim: To assess the efficacy and safety of liraglutide to reduce visceral and ectopic fat in adults with or without type 2 diabetes mellitus(T2DM). Methods: Four databases were searched up to 6 May 2022 for RCTs assessing effect of liraglutide on visceral and ectopic fat. The mean and standard deviation (SD) of the values of visceral fat, ectopic fat, and body mass index (BMI) were calculated. Subgroup analyses were performed based on the type of disease (T2DM or non-T2DM), duration of intervention, dosage of liraglutide, and whether life interventions were added to liraglutide therapy. We extracted and integrated the safety assessments reported in each article. Results: Sixteen RCTs with a total of 845 participants were included in the meta-analysis. Liraglutide could significantly decrease visceral fat (SMD = -0.72, 95% CI [-1.12, -0.33]), liver fat (SMD = -0.78, 95% CI [-1.24, -0.32]), and BMI (WMD = -1.44, 95% CI [-1.95, -0.92]) in adult patients with or without T2DM when compared to control group. However, reduction of epicardial fat by liraglutide (SMD = -0.74, 95% CI [-1.82,0.34]) was not statistically significant. Subgroup analysis revealed that an adequate dosage (≥1.8 mg/day) and appropriate duration of treatment (ranging from 16 to 40 weeks) were the decisive factors for liraglutide to effectively reduce visceral fat. Mild gastrointestinal reactions were the main adverse event of liraglutide. Conclusions: Liraglutide significantly and safely reduces visceral and ectopic liver fat irrespective of T2DM status, and reduces visceral fat provided adequate dosage and duration of therapy are ensured. This article is protected by copyright. All rights reserved.

The pathophysiology of gut-liver connection

Chapter

Apr 2021

The physiological functions of the liver and the intestine are intimately connected by tightly regulated mechanisms. The liver secretes bile acids in the intestine, which are fundamental in lipid digestion but also regulate the composition of the gut microbiota. In turn, the intestine regulates the synthesis of bile acids by a feedback loop based on the FXR/FGF-19 axis, and secretes in the blood stream a number of incretins that participate in glucose and lipid metabolism, at least in part by modulating hepatic functions. Moreover, alteration of the gut permeability induced by a variety of factors (including dysbiosis) deeply influences the quantity and quality of metabolites and bacterial products that reach the liver via the portal blood and modulate hepatic molecular pathways. The dysregulation of the gut-liver axis plays therefore a crucial role in the pathogenesis of many metabolic diseases, and is actively studied in the context of nonalcoholic fatty liver disease (NAFLD). Strategies aiming at restoring intestinal permeability, modulating dysbiosis, or influencing molecular pathways involved in the regulation of the gut-liver axis have actively been investigated as potential new therapies for NAFLD. In the present chapter, the physiopathological bases of the "leaky gut hypothesis" and their relevance to the development of NAFLD will be presented in details. Moreover, current knowledge on incretins and bile acid pathway modulation in NAFLD will be discussed.

Obesity, Ectopic Fat and Type 2 Diabetes

Chapter

Mar 2022

Obesity represents a major risk factor for the development of impaired glucose tolerance and type 2 diabetes. In this chapter, the authors focus on the causes and consequences of visceral and ectopic fat accumulation and its relevance to the development of type 2 diabetes. Attention is given to biomarkers that allow a more exact identification of those patients at risk for metabolic disease. The clinical features that lead to a better understanding of those factors influencing the risk for diabetes and cardiovascular disease can be studied by means of the two ends of a clinical spectrum of people with obesity and metabolic health. An individual's ability to expand adipose tissue and factors involved in body fat distribution seems to be modified both by genetic/epigenetic factors, hormonal effects, and environmental factors. Finally, some therapeutic options are reviewed.

Clinical insights into management options for recurrent type 2 diabetes and cardiovascular risk after metabolic-bariatric surgery

Article

Mar 2022
NUTR METAB CARDIOVAS

Aims Long-term clinical trials evaluating the effects of metabolic-bariatric surgery (MBS) on type 2 diabetes (T2D) demonstrate that a significant proportion of patients either fail to achieve remission or experience T2D recurrence over time. Furthermore, patients with recurrent T2D might require reinstitution of pharmacotherapy to control comorbidities (hypertension, dyslipidemia). This paper reviews therapeutic options in patients with T2D relapse. Data Synthesis Although presently there is no recommended pharmacological strategy, the available data support GLP-1 analogues (GLP-1a) as the most suitable option to control hyperglycemia post-MBS. Beside their efficacy in lowering glycemia and body weight while preserving lean mass, GLP-1a exert cardiovascular/renal-protection and are also safe and well tolerated in surgical patients. In addition, the s.c. route of administration of these medications circumvents the problem of changes in oral drugs bioavailability following MBS. Of note, the available data refers to liraglutide and needs to be confirmed with weekly GLP-1a agents. Information regarding the impact of MBS on the pharmacokinetics of lipid lowering and anti-hypertensive drugs is scarce and inconclusive. The findings indicate that timing from intervention is particularly important because of adaptive intestinal mechanisms. Conclusions The recurrence of T2D following MBS is a clinically relevant issue. GLP-1a therapy represents the best option to improve glycemic and weight control with good tolerability. Long-term clinical trials will clarify the impact of these drugs on cardiovascular outcomes. A close monitoring of MBS patients is advised to guide drug dosage adjustments and ensure the control of cardiovascular risk factors.

Dapiglutide, a novel dual GLP‐1 and GLP‐2 receptor agonist, attenuates intestinal insufficiency in a murine model of short bowel

Article

Oct 2021

Background: Extensive intestinal resection may lead to short bowel syndrome resulting in intestinal insufficiency or intestinal failure (IF). Intestinal insufficiency and IF involve deficiency of the proglucagon-derived hormones, GLP-1 and GLP-2. Two major problems of short bowel (SB) are epithelial surface loss and accelerated transit. Standard treatment now targets intestinal adaptation with a GLP-2 analogue, to enlarge absorptive surface area. It is possible that additional benefit can be gained from combination of GLP-1 and GLP-2 activity, with the aim to enlarge intestinal surface area and also slow intestinal transit. Methods: The GLP-1 and GLP-2 specific effects of the novel dual GLP-1 and GLP-2 receptor agonist dapiglutide (rINN) were characterized in rodents. Furthermore, in a murine SB model of intestinal insufficiency with 40% ileocecal resection, the influence of dapiglutide on intestinal growth, body weight, food intake, volume status and stool water content was tested against vehicle and sham operated male mice. Results: Dapiglutide significantly improves oral glucose tolerance, reduces intestinal transit time and promotes intestinal growth. In the SB mouse model, dapiglutide promotes body weight recovery, despite unchanged liquid diet intake. Dapiglutide promotes significant intestinal growth, as indicated by significantly increased villus height, as well as intestinal length. Furthermore, dapiglutide reduces stool water losses, resulting in reduced plasma aldosterone. Conclusion: Dapiglutide possesses specific and potent GLP-1 and GLP-2 receptor agonist effects in rodents. In the murine SB model, combined unimolecular GLP-1R and GLP-2R stimulation with dapiglutide potently attenuates intestinal insufficiency and potentially also IF. This article is protected by copyright. All rights reserved.

Liraglutide changes body composition and lowers added sugar intake in overweight persons with insulin pump‐treated type 1 diabetes

Article

Sep 2021

Aims: A large proportion of persons with type 1 diabetes needs a therapeutic strategy that addresses glucose as well as weight management. Liraglutide as add-on to insulin therapy meets this criterion. Materials and methods: A 26-week randomized placebo-controlled study investigated the efficacy and safety of liraglutide 1.8 mg daily in 44 overweight adults with insulin pump-treated type 1 diabetes and glucose levels above target and demonstrated significant HbA1c- and body weight-reducing effects. For secondary outcome analysis dual X-ray absorptiometry scans were completed at Week 0 and 26, and questionnaire-based food frequency recordings were obtained at Week 0, 13 and 26 to characterize liraglutide-induced changes in body composition and food intake. Results: Total fat and lean body mass decreased in liraglutide treated participants (fat mass -4.6 kg (95%CI -5.7;-3.5), p<0.001; lean mass -2.5 kg (-3.2;-1.7), p<0.001) but remained stable in placebo treated (fat mass -0.3 kg (-1.3;0.8), p=0.604; lean mass 0.0 kg (-0.7;0.7), p=0.965), (between-group p-values <0.001). Participants reduced their energy intake numerically more in the liraglutide arm (-1.1 MJ (-2.0;-0.02), p=0.02) than in the placebo arm (-0.9 MJ (-2.0;0.1), p=0.22), but the between-group difference was statistically insignificant (p=0.42). However, energy derived from added sugars decreased by 27% in the liraglutide arm compared with an increase of 14% in the placebo arm (p=0.004). Conclusions: Liraglutide lowered fat and lean body mass compared with placebo. Further, liraglutide reduced intake of added sugars. However, no significant difference in total daily energy intake was detected between liraglutide and placebo treated participants. This article is protected by copyright. All rights reserved.

Effects of liraglutide on visceral and ectopic fat in adults with overweight and obesity at high cardiovascular risk: a randomised, double-blind, placebo-controlled, clinical trial

Article

Aug 2021

Background Visceral and ectopic fat are key drivers of adverse cardiometabolic outcomes in obesity. We aimed to evaluate the effects of injectable liraglutide 3·0 mg daily on body fat distribution in adults with overweight or obesity without type 2 diabetes at high cardiovascular disease risk. Methods In this randomised, double-blind, placebo-controlled, phase 4, single centre trial, we enrolled community-dwelling adults, recruited from the University of Texas Southwestern Medical Center, with BMI of at least 30 kg/m² or BMI of at least 27 kg/m² with metabolic syndrome but without diabetes and randomly assigned them, in a 1:1 ratio, to 40 weeks of treatment with once-daily subcutaneous liraglutide 3·0 mg or placebo, in addition to a 500 kcal deficient diet and guideline-recommended physical activity counselling. The primary endpoint was percentage reduction in visceral adipose tissue (VAT) measured with MRI. All randomly assigned participants with a follow-up imaging assessment were included in efficacy analyses and all participants who received at least one dose of study drug were included in the safety analyses. The trial is registered on ClinicalTrials.gov: NCT03038620. Findings Between July 20, 2017 and Feb 21, 2020 from 235 participants assessed for eligibility, 185 participants were randomly assigned (n=92 liraglutide, n=93 placebo) and 128 (n=73 liraglutide, n=55 placebo) were included in the final analysis (92% female participants, 37% Black participants, 24% Hispanic participants, mean age 50·2 years (SD 9·4), mean BMI 37·7 kg/m²). Mean change in VAT over median 36·2 weeks was −12·49% (SD 9·3%) with liraglutide compared with −1·63% (SD 12·3%) with placebo, estimated treatment difference −10·86% (95% CI −6·97 to −14·75, p<0·0001). Effects seemed consistent across subgroups of age, sex, race–ethnicity, BMI, and baseline prediabetes. The most frequently reported adverse events were gastrointestinal-related (43 [47%] of 92 with liraglutide and 12 [13%] of 93 with placebo) and upper respiratory tract infections (10 [11%] of 92 with liraglutide and 14 [15%] of 93 with placebo). Interpretation In adults with overweight or obesity at high cardiovascular disease risk, once-daily liraglutide 3·0 mg plus lifestyle intervention significantly lowered visceral adipose tissue over 40 weeks of treatment. Visceral fat reduction may be one mechanism to explain the benefits seen on cardiovascular outcomes in previous trials with liraglutide among patients with type 2 diabetes. Funding NovoNordisk.

Two-year administration of sodium-glucose co-transporter 2 inhibitor brought about marked reduction of body fat independent of skeletal muscle amount or glycemic improvement in Japanese patients with type 2 diabetes

Article

May 2021

AimTo investigate long-term effects of sodium-glucose co-transporter 2 inhibitor (SGLT2i) on anthropometric and metabolic factors in Japanese patients with type 2 diabetes (T2DM).Patients and Methods This is a retrospective observation study. Forty-six outpatients with T2DM (32 men and 14 women, 51 ± 13 years old, BMI 27.9 ± 4.8, means ± S.D.) who had been treated by SGLT2i for 2 years were selected and their metabolic and anthropometric data were retrieved from medical records retrospectively. Regular instruction for diet and exercise had been performed throughout the administration of SGLT2i in outpatient clinic basis.ResultsBy the administration of SGLT2i for 2 years, body weight and body fat amount were significantly reduced (P < 0.0001) in spite of no change in skeletal muscle mass. HbA1c (P < 0.0001), liver function and lipid profile (P < 0.01) were ameliorated and eGFR was reduced significantly (P < 0.0001). It is of note that the reduction of body weight was strongly correlated to that of body fat (r = 0.951, P < 0.0001) with no correlation to the change of skeletal muscle mass. The reduction of HbA1c was strongly correlated to the baseline HbA1c (r = − 0.922, P < 0.0001) and modestly correlated to the baseline eGFR (r = − 0.449, P < 0.01). Multivariate analysis revealed a weak relationship between the amelioration of HbA1c and the reduction of body weight.ConclusionSGLT2i can effectively reduce body weight and body fat mass independent of the blood glucose improvement or the renal function. Under the periodical instruction for nutrition and exercise this oral hypoglycemic agent can be safely administered for a long term without a risk for sarcopenia.

Effects of liraglutide on the metabolism of triglyceride‐rich lipoproteins in type 2 diabetes

Article

Full-text available

Jan 2021

Aims: The postprandial increase in triglyceride-rich lipoproteins and their remnants often seen in type 2 diabetes (T2D) is a risk factor for cardiovascular disease. The glucagon-like peptide-1 receptor agonist liraglutide reduces postprandial lipemia but the underlying mechanism is unclear. Our aim was to elucidate the impact of liraglutide on the kinetics of apolipoprotein (apo)B48- and apoB100-containing triglyceride-rich lipoproteins in subjects with T2D after a single fat-rich meal. Materials and methods: Subjects with T2D were included in a study to investigate postprandial apoB48 and apoB100 metabolism before and after 16 weeks on l.8 mg/day liraglutide (n=14) or placebo (n=4). Stable isotope tracer and compartmental modelling techniques were used to determine the impact of liraglutide on chylomicron and very low-density lipoprotein (VLDL) production and clearance after a single fat-rich meal. Results: Liraglutide reduced apoB48 synthesis in chylomicrons by 60% (P<0.0001) and increased the triglyceride/apoB48 ratio (i.e., the size) of chylomicrons (P<0.001). Direct clearance of chylomicrons, a quantitatively significant pathway pre-treatment, fell by 90% on liraglutide (P<0.001). Liraglutide also reduced VLDL1 -triglyceride secretion (P=0.017) in parallel with reduced liver fat. Chylomicron-apoB48 production and particle size were related to insulin sensitivity (P=0.015 and P<0.001, respectively), but these associations were perturbed by liraglutide. Conclusion: In a physiologically relevant setting that mirrored regular feeding in subjects with T2D, liraglutide promoted potentially beneficial changes on postprandial apoB48 metabolism. Using our data in an integrated metabolic model, we describe how the action of liraglutide in T2D on chylomicron and VLDL kinetics could lead to decreased generation of remnant lipoproteins. This article is protected by copyright. All rights reserved.

Glucagon-Like Peptide 1 Receptor Agonists and Heart Failure: The Need for Further Evidence Generation and Practice Guidelines Optimization

Article

Sep 2020
CIRCULATION

With worsening epidemiological trends for both the incidence and prevalence of type 2 diabetes mellitus (T2DM) and heart failure (HF) worldwide, it is critical to implement optimal prevention and treatment strategies for patients with these comorbidities, either alone or concomitantly. Several guidelines and consensus statements have recommended glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter type 2 inhibitors as add-ons to lifestyle interventions with or without metformin in those at high atherosclerotic cardiovascular disease risk. However, these recommendations are either silent about HF or fail to differentiate between the prevention of HF in those at risk versus the treatment of individuals with manifest HF. Furthermore, these documents do not differentiate among those with different HF phenotypes. This distinction, even though important, may not be critical for sodium-glucose cotransporter type 2 inhibitors in view of the consistent data for benefit for both atherosclerotic cardiovascular disease- and HF-related outcomes that have emerged from the regulatory-mandated cardiovascular outcome trials for all sodium-glucose cotransporter type 2 inhibitors and the recent DAPA-HF trial (Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction)demonstrating the benefit of dapagliflozin on HF-related outcomes in patients with HF with reduced ejection fraction with or without T2DM. However, the distinction may be crucial for glucagon-like peptide-1 receptor agonists and other antihyperglycemic agents. Indeed, in several of the new statements, glucagon-like peptide-1 receptor agonists are suggested treatment not only for patients with T2DM and atherosclerotic cardiovascular disease, but also in those with manifest HF, despite a lack of evidence for the latter recommendation. Although glucagon-like peptide-1 receptor agonists may be appropriate to use in patients at risk for HF, mechanistic insights and observations from randomized trials suggest no clear benefit on HF-related outcomes and even uncertainty regarding the safety in those with HF with reduced ejection fraction. Conversely, theoretical rationales suggest that these agents may benefit patients with HF with preserved ejection fraction. Considering that millions of patients with T2DM have HF, these concerns have public health implications that necessitate the thoughtful use of these therapies. Achieving this aim will require dedicated trials with these drugs in both patients who have HF with reduced ejection fraction and HF with preserved ejection fraction with T2DM to assess their efficacy, safety, and risk-benefit profile.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the management of nonalcoholic fatty liver disease (NAFLD): A systematic review

Article

Full-text available

Jun 2020

There are no licensed drugs for nonalcoholic fatty liver disease (NAFLD), and there is a lack of consensus on the best outcome measures for controlled trials. This systematic review aimed to evaluate the efficacy of GLP‐1 RAs in the management of NAFLD, the degree of heterogeneity in trial design and the robustness of conclusions drawn from these clinical trials. We searched publication databases and clinical trial registries through 2 November 2019 for clinical trials with NAFLD. We evaluated improvements in histological findings, noninvasive markers of hepatic steatosis, inflammation, and fibrosis, insulin resistance and anthropometric measures. Our final analysis included 24 clinical trials, comprising 6313 participants with a mean duration of 37 weeks. Four clinical trials, including RCT (n = 1), single‐arm studies (n = 2) and case series studies (n = 1), used biopsy‐confirmed liver histological change as their end‐points. The remaining studies (n = 20) used surrogate end‐points. GLP‐1 RAs were effective for the improvement in hepatic inflammation, hepatic steatosis and fibrosis. More importantly, GLP‐1 RAs showed promise in improving the histological features of NASH. In addition, 8 ongoing trials were identified. In this systematic review of published and ongoing clinical trials of the efficacy of GLP‐1RAs for NAFLD, we found that GLP‐1 RAs are effective for hepatic steatosis and inflammation, with the potential to reverse fibrosis. Further prospective studies of sufficient duration using histological end‐points are needed to fully assess the efficacy of GLP‐1 RAs in the management of NAFLD.

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

Article

Full-text available

Sep 1998

Background Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. Methods 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or. glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. in the conventional group, the aim was the best achievable FPG with diet atone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye,or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. Findings Over 10 years, haemoglobin A(1c) (HbA(1c)) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group-an 11% reduction. There was no difference in HbA(1c) among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). Interpretation Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes. None of the individual drugs had an adverse effect on cardiovascular outcomes. All intensive treatment increased the risk of hypoglycaemia.

LEAD-4 Met+TZD Study Efficacy and safety of the human GLP-1 analog liraglutide in combination with metformin and TZD in patients with type 2 diabetes mellitus (LEAD-4 Met+TZD)

Article

Full-text available

Jan 2009
DIABETES CARE

Effect of Excessive Weight Gain With Intensive Therapy of Type 1 Diabetes on Lipid Levels and Blood PressureResults From the DCCT

Article

Full-text available

Jul 1998

Context.— Intensive treatment of type 1 diabetes results in greater weight gain than conventional treatment.Objective.— To determine the effect of this weight gain on lipid levels and blood pressure.Design.— Randomized controlled trial; ancillary study of the Diabetes Control and Complications Trial (DCCT).Setting.— Twenty-one clinical centers.Participants.— The 1168 subjects enrolled in DCCT with type 1 diabetes who were aged 18 years or older at baseline.Intervention.— Randomized to receive either intensive (n=586) or conventional (n=582) diabetes treatment with a mean follow-up of 6.1 years.Main Outcome Measures.— Plasma lipid levels and blood pressure in each treatment group categorized by quartile of weight gain.Results. —With intensive treatment, subjects in the fourth quartile of weight gain had the highest body mass index (BMI) (a measure of weight adjusted for height), blood pressure, and levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B compared with the other weight gain quartiles with the greatest difference seen when compared with the first quartile (mean values for the highest and lowest quartiles: BMI, 31 vs 24 kg/m2; blood pressure, 120/77 mm Hg vs 113/73 mm Hg; triglyceride, 0.99 mmol/L vs 0.79 mmol/L [88 mg/dL vs 70 mg/dL]; LDL-C, 3.15 mmol/L vs 2.74 mmol/L [122 mg/dL vs 106 mg/dL]; and apolipoprotein B, 0.89 g/L vs 0.78 g/L; all P<.001). In addition, the fourth quartile group had a higher waist-to-hip ratio; more cholesterol in the very low density lipoprotein, intermediate dense lipoprotein, and dense LDL fractions; and lower high-density lipoprotein cholesterol and apolipoprotein A-I levels compared with the first quartile. Baseline characteristics were not different between the first and fourth quartiles of weight gain with intensive therapy except for a higher hemoglobin A1c in the fourth quartile. Weight gain with conventional therapy resulted in smaller increases in BMI, lipids, and systolic blood pressure.Conclusions.— The changes in lipid levels and blood pressure that occur with excessive weight gain with intensive therapy are similar to those seen in the insulin resistance syndrome and may increase the risk of coronary artery disease in this subset of subjects with time. Figures in this Article PATIENTS WITH type 1 diabetes characteristically gain weight with the institution of insulin therapy but may remain leaner than nondiabetic control subjects.1- 2 With intensification of diabetes therapy, continued weight gain correlates inversely with improvement in hemoglobin A1c levels.3- 4 After a mean follow-up of 6.5 years in the Diabetes Control and Complications Trial (DCCT), a study designed to determine the effect of intensive diabetes therapy on the microvascular complications of type 1 diabetes, the prevalence of obesity—which is determined when the body mass index (BMI), which was greater than 27.8 kg/m2for men and greater than 27.3 kg/m2for women—reached 33.1% in the intensively treated subjects compared with 19.1% in the conventionally treated subjects.5 Despite this weight gain, lipid levels for the intensively treated group as a whole improved, including lower levels of dense low-density lipoprotein (LDL) and lipoprotein(a) (Lp[a]) at follow-up, compared with the conventionally treated group.6- 7 Recent studies of adults with type 1 diabetes have highlighted, however, that a higher BMI or waist-to-hip ratio (WHR) is associated with adverse lipid levels similar to those of centrally obese subjects who do not have diabetes and those with type 2 diabetes, eg, higher triglyceride levels, normal or slightly higher low-density lipoprotein cholesterol (LDL-C) levels, and lower high-density lipoprotein cholesterol (HDL-C) levels.2,8- 9 Coronary artery disease (CAD) is a leading cause of mortality in adult patients with type 1 diabetes.10- 11 Because CAD prevalence in type 1 diabetes has recently been shown to be associated with a higher triglyceride level, lower HDL-C levels, a greater WHR in men, and a higher BMI in women,12 it is important to understand the effect of weight gain from intensive diabetes therapy on these risk factors.

Hypoglycaemia in Type 2 diabetes

Article

Full-text available

Apr 2008

The primary cause of hypoglycaemia in Type 2 diabetes is diabetes medication—in particular, those which raise insulin levels independently of blood glucose, such as sulphonylureas (SUs) and exogenous insulin. The risk of hypoglycaemia is increased in older patients, those with longer diabetes duration, lesser insulin reserve and perhaps in the drive for strict glycaemic control. Differing definitions, data collection methods, drug type/regimen and patient populations make comparing rates of hypoglycaemia difficult. It is clear that patients taking insulin have the highest rates of self-reported severe hypoglycaemia (25% in patients who have been taking insulin for > 5 years). SUs are associated with significantly lower rates of severe hypoglycaemia. However, large numbers of patients take SUs in the UK, and it is estimated that each year > 5000 patients will experience a severe event caused by their SU therapy which will require emergency intervention. Hypoglycaemia has substantial clinical impact, in terms of mortality, morbidity and quality of life. The cost implications of severe episodes—both direct hospital costs and indirect costs—are considerable: it is estimated that each hospital admission for severe hypoglycaemia costs around £1000. Hypoglycaemia and fear of hypoglycaemia limit the ability of current diabetes medications to achieve and maintain optimal levels of glycaemic control. Newer therapies, which focus on the incretin axis, may carry a lower risk of hypoglycaemia. Their use, and more prudent use of older therapies with low risk of hypoglycaemia, may help patients achieve improved glucose control for longer, and reduce the risk of diabetic complications. Diabet. Med. 25, 245–254 (2008)

Waist circumference and waist-to-hip ratio as predictors of cardiovascular events: Meta-regression analysis of prospective studies

Article

Full-text available

Apr 2007

The objectives of this study were to determine the association of waist circumference (WC) and waist-to-hip ratio (WHR) with the risk of incident cardiovascular disease (CVD) events and to determine whether the strength of association of WC and WHR with CVD risk is different. This meta-regression analysis used a search strategy of keywords and MeSH terms to identify prospective cohort studies and randomized clinical trials of CVD risk and abdominal obesity from the Medline, Embase, and Cochrane databases. Fifteen articles (n = 258 114 participants, 4355 CVD events) reporting CVD risk by categorical and continuous measures of WC and WHR were included. For a 1 cm increase in WC, the relative risk (RR) of a CVD event increased by 2% (95% CI: 1-3%) overall after adjusting for age, cohort year, or treatment. For a 0.01 U increase in WHR, the RR increased by 5% (95% CI: 4-7%). These results were consistent in men and women. Overall risk estimates comparing the extreme quantiles of each measure suggested that WHR was more strongly associated with CVD than that for WC (WHR: RR = 1.95, 95% CI: 1.55-2.44; WC: RR = 1.63, 95% CI: 1.31-2.04), although this difference was not significant. The strength of association for each measure was similar in men and women. WHR and WC are significantly associated with the risk of incident CVD events. These simple measures of abdominal obesity should be incorporated into CVD risk assessments.

Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): A randomised controlled trial

Article

Full-text available

Aug 2009
DIABETOLOGIA

Aims/hypothesis The aim of the study was to compare the efficacy and safety of liraglutide in type 2 diabetes mellitus vs placebo and insulin glargine (A21Gly,B31Arg,B32Arg human insulin), all in combination with metformin and glimepiride. Methods This randomised (using a telephone or web-based randomisation system), parallel-group, controlled 26 week trial of 581 patients with type 2 diabetes mellitus on prior monotherapy (HbA1c 7.5–10%) and combination therapy (7.0–10%) was conducted in 107 centres in 17 countries. The primary endpoint was HbA1c. Patients were randomised (2:1:2) to liraglutide 1.8 mg once daily (n = 232), liraglutide placebo (n = 115) and open-label insulin glargine (n = 234), all in combination with metformin (1 g twice daily) and glimepiride (4 mg once daily). Investigators, participants and study monitors were blinded to the treatment status of the liraglutide and placebo groups at all times. Results The number of patients analysed as intention to treat were: liraglutide n = 230, placebo n = 114, insulin glargine n = 232. Liraglutide reduced HbA1c significantly vs glargine (1.33% vs 1.09%; −0.24% difference, 95% CI 0.08, 0.39; p = 0.0015) and placebo (−1.09% difference, 95% CI 0.90, 1.28; p

LEAD-1 SU Study Group. Liraglutide, a once-daily human GLP-1 analogue, added to a sulfonylurea over 26 weeks produces greater improvements in glycemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU)

Article

Full-text available

Apr 2009
DIABETIC MED

To compare the effects of combining liraglutide (0.6, 1.2 or 1.8 mg/day) or rosiglitazone 4 mg/day (all n >or= 228) or placebo (n = 114) with glimepiride (2-4 mg/day) on glycaemic control, body weight and safety in Type 2 diabetes. In total, 1041 adults (mean +/- sd), age 56 +/- 10 years, weight 82 +/- 17 kg and glycated haemoglobin (HbA(1c)) 8.4 +/- 1.0% at 116 sites in 21 countries were stratified based on previous oral glucose-lowering mono : combination therapies (30 : 70%) to participate in a five-arm, 26-week, double-dummy, randomized study. Liraglutide (1.2 or 1.8 mg) produced greater reductions in HbA(1c) from baseline, (-1.1%, baseline 8.5%) compared with placebo (+0.2%, P < 0.0001, baseline 8.4%) or rosiglitazone (-0.4%, P < 0.0001, baseline 8.4%) when added to glimepiride. Liraglutide 0.6 mg was less effective (-0.6%, baseline 8.4%). Fasting plasma glucose decreased by week 2, with a 1.6 mmol/l decrease from baseline at week 26 with liraglutide 1.2 mg (baseline 9.8 mmol/l) or 1.8 mg (baseline 9.7 mmol/l) compared with a 0.9 mmol/l increase (placebo, P < 0.0001, baseline 9.5 mmol/l) or 1.0 mmol/l decrease (rosiglitazone, P < 0.006, baseline 9.9 mmol/l). Decreases in postprandial plasma glucose from baseline were greater with liraglutide 1.2 or 1.8 mg [-2.5 to -2.7 mmol/l (baseline 12.9 mmol/l for both)] compared with placebo (-0.4 mmol/l, P < 0.0001, baseline 12.7 mmol/l) or rosiglitazone (-1.8 mmol/l, P < 0.05, baseline 13.0 mmol/l). Changes in body weight with liraglutide 1.8 mg (-0.2 kg, baseline 83.0 kg), 1.2 mg (+0.3 kg, baseline 80.0 kg) or placebo (-0.1 kg, baseline 81.9 kg) were less than with rosiglitazone (+2.1 kg, P < 0.0001, baseline 80.6 kg). Main adverse events for all treatments were minor hypoglycaemia (< 10%), nausea (< 11%), vomiting (< 5%) and diarrhoea (< 8%). Liraglutide added to glimepiride was well tolerated and provided improved glycaemic control and favourable weight profile.

Efficacy and Safety of the Human Glucagon-Like Peptide-1 Analog Liraglutide in Combination With Metformin and Thiazolidinedione in Patients With Type 2 Diabetes (LEAD-4 Met+TZD)

Article

Full-text available

Apr 2009

To determine the efficacy and safety of liraglutide (a glucagon-like peptide-1 receptor agonist) when added to metformin and rosiglitazone in type 2 diabetes. This 26-week, double-blind, placebo-controlled, parallel-group trial randomized 533 subjects (1:1:1) to once-daily liraglutide (1.2 or 1.8 mg) or liraglutide placebo in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily). Subjects had type 2 diabetes, A1C 7-11% (previous oral antidiabetes drug [OAD] monotherapy >or=3 months) or 7-10% (previous OAD combination therapy >or=3 months), and BMI <or=45 kg/m(2). Mean A1C values decreased significantly more in the liraglutide groups versus placebo (mean +/- SE -1.5 +/- 0.1% for both 1.2 and 1.8 mg liraglutide and -0.5 +/- 0.1% for placebo). Fasting plasma glucose decreased by 40, 44, and 8 mg/dl for 1.2 and 1.8 mg and placebo, respectively, and 90-min postprandial glucose decreased by 47, 49, and 14 mg/dl, respectively (P < 0.001 for all liraglutide groups vs. placebo). Dose-dependent weight loss occurred with 1.2 and 1.8 mg liraglutide (1.0 +/- 0.3 and 2.0 +/- 0.3 kg, respectively) (P < 0.0001) compared with weight gain with placebo (0.6 +/- 0.3 kg). Systolic blood pressure decreased by 6.7, 5.6, and 1.1 mmHg with 1.2 and 1.8 mg liraglutide and placebo, respectively. Significant increases in C-peptide and homeostasis model assessment of beta-cell function and significant decreases in the proinsulin-to-insulin ratio occurred with liraglutide versus placebo. Minor hypoglycemia occurred more frequently with liraglutide, but there was no major hypoglycemia. Gastrointestinal adverse events were more common with liraglutide, but most occurred early and were transient. Liraglutide combined with metformin and a thiazolidinedione is a well-tolerated combination therapy for type 2 diabetes, providing significant improvements in glycemic control.

Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, in Type 2 Diabetes The LEAD (Liraglutide Effect and Action in Diabetes)-2 study

Article

Full-text available

Oct 2008

The efficacy and safety of adding liraglutide (a glucagon-like peptide-1 receptor agonist) to metformin were compared with addition of placebo or glimepiride to metformin in subjects previously treated with oral antidiabetes (OAD) therapy. In this 26-week, double-blind, double-dummy, placebo- and active-controlled, parallel-group trial, 1,091 subjects were randomly assigned (2:2:2:1:2) to once-daily liraglutide (either 0.6, 1.2, or 1.8 mg/day injected subcutaneously), to placebo, or to glimepiride (4 mg once daily). All treatments were in combination therapy with metformin (1g twice daily). Enrolled subjects (aged 25-79 years) had type 2 diabetes, A1C of 7-11% (previous OAD monotherapy for > or =3 months) or 7-10% (previous OAD combination therapy for > or =3 months), and BMI < or =40 kg/m(2). A1C values were significantly reduced in all liraglutide groups versus the placebo group (P < 0.0001) with mean decreases of 1.0% for 1.8 mg liraglutide, 1.2 mg liraglutide, and glimepiride and 0.7% for 0.6 mg liraglutide and an increase of 0.1% for placebo. Body weight decreased in all liraglutide groups (1.8-2.8 kg) compared with an increase in the glimepiride group (1.0 kg; P < 0.0001). The incidence of minor hypoglycemia with liraglutide ( approximately 3%) was comparable to that with placebo but less than that with glimepiride (17%; P < 0.001). Nausea was reported by 11-19% of the liraglutide-treated subjects versus 3-4% in the placebo and glimepiride groups. The incidence of nausea declined over time. In subjects with type 2 diabetes, once-daily liraglutide induced similar glycemic control, reduced body weight, and lowered the occurrence of hypoglycemia compared with glimepiride, when both had background therapy of metformin.

Flint, A. , Raben, A. l. , Astrup, A. & Holst, J. J. Glucagon-like peptide I promotes satiety and suppresses energy intake in humans. J. Clin. Invest. 101, 515-520

Article

Full-text available

Feb 1998

We examined the effect of intravenously infused glucagon-like peptide 1 (GLP-1) on subjective appetite sensations after an energy-fixed breakfast, and on spontaneous energy intake at an ad libitum lunch. 20 young, healthy, normal-weight men participated in a placebo-controlled, randomized, blinded, crossover study. Infusion (GLP-1, 50 pmol/ kg.h or saline) was started simultaneously with initiation of the test meals. Visual analogue scales were used to assess appetite sensations throughout the experiment and the palatability of the test meals. Blood was sampled throughout the day for analysis of plasma hormone and substrate levels. After the energy-fixed breakfast, GLP-1 infusion enhanced satiety and fullness compared with placebo (treatment effect: P < 0.03). Furthermore, spontaneous energy intake at the ad libitum lunch was reduced by 12% by GLP-1 infusion compared with saline (P = 0.002). Plasma GLP-1, insulin, glucagon, and blood glucose profiles were affected significantly by the treatment (P < 0.002). In conclusion, the results show that GLP-1 enhanced satiety and reduced energy intake and thus may play a physiological regulatory role in controlling appetite and energy intake in humans.

Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT. Diabetes Control and Complications Trial

Article

Full-text available

Aug 1998

Intensive treatment of type 1 diabetes results in greater weight gain than conventional treatment. To determine the effect of this weight gain on lipid levels and blood pressure. Randomized controlled trial; ancillary study of the Diabetes Control and Complications Trial (DCCT). Twenty-one clinical centers. The 1168 subjects enrolled in DCCT with type 1 diabetes who were aged 18 years or older at baseline. Randomized to receive either intensive (n = 586) or conventional (n = 582) diabetes treatment with a mean follow-up of 6.1 years. Plasma lipid levels and blood pressure in each treatment group categorized by quartile of weight gain. With intensive treatment, subjects in the fourth quartile of weight gain had the highest body mass index (BMI) (a measure of weight adjusted for height), blood pressure, and levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B compared with the other weight gain quartiles with the greatest difference seen when compared with the first quartile (mean values for the highest and lowest quartiles: BMI, 31 vs 24 kg/m2; blood pressure, 120/77 mm Hg vs 113/73 mm Hg; triglyceride, 0.99 mmol/L vs 0.79 mmol/L [88 mg/dL vs 70 mg/dL]; LDL-C, 3.15 mmol/L vs 2.74 mmol/L [122 mg/dL vs 106 mg/dL]; and apolipoprotein B, 0.89 g/L vs 0.78 g/L; all P<.001). In addition, the fourth quartile group had a higher waist-to-hip ratio; more cholesterol in the very low density lipoprotein, intermediate dense lipoprotein, and dense LDL fractions; and lower high-density lipoprotein cholesterol and apolipoprotein A-I levels compared with the first quartile. Baseline characteristics were not different between the first and fourth quartiles of weight gain with intensive therapy except for a higher hemoglobin A1c in the fourth quartile. Weight gain with conventional therapy resulted in smaller increases in BMI, lipids, and systolic blood pressure. The changes in lipid levels and blood pressure that occur with excessive weight gain with intensive therapy are similar to those seen in the insulin resistance syndrome and may increase the risk of coronary artery disease in this subset of subjects with time.

A Meta-Analysis of the Effect of Glucagon-Like Peptide-1 (7–36) Amide on Ad Libitum Energy Intake in Humans

Article

Full-text available

Oct 2001

Seven studies have now been published pertaining to the acute effect of iv administration of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake. In four of these studies energy intake was significantly reduced following the glucagon-like peptide-1 infusion compared with saline. In the remaining studies, no significant effect of glucagon-like peptide-1 could be shown. Lack of statistical power or low glucagon-like peptide-1 infusion rate may explain these conflicting results. Our aim was to examine the effect of glucagon-like peptide-1 on subsequent energy intake using a data set composed of subject data from previous studies and from two as yet unpublished studies. Secondly, we investigated whether the effect on energy intake is dose dependent and differs between lean and overweight subjects. Raw subject data on body mass index and ad libitum energy intake were collected into a common data set (n = 115), together with study characteristics such as infusion rate, duration of infusion, etc. From four studies with comparable protocol the following subject data were included if available: plasma concentrations of glucagon-like peptide-1, subjective appetite measures, well-being, and gastric emptying rate of a meal served at the start of the glucagon-like peptide-1 infusion. Energy intake was reduced by 727 kJ (95% confidence interval, 548-908 kJ) or 11.7% during glucagon-like peptide-1 infusion. Although the absolute reduction in energy intake was higher in lean (863 kJ) (634-1091 kJ) compared with overweight subjects (487 kJ) (209-764 kJ) (P = 0.05), the relative reduction did not differ between the two groups (13.2% and 9.3%, respectively). Stepwise regression analysis showed that the glucagon-like peptide-1 infusion rate was the only independent predictor of the reduction in energy intake during glucagon-like peptide-1 (7-36) amide infusion (r = 0.4, P < 0.001). Differences in mean plasma glucagon-like peptide-1 concentration on the glucagon-like peptide-1 and placebo day (n = 43) were related to differences in feelings of prospective consumption (r = 0.40, P < 0.01), fullness (r = 0.38, P < 0.05), and hunger (r = 0.26, P = 0.09), but not to differences in ad libitum energy intake. Gastric emptying rate was significantly lower during glucagon-like peptide-1 infusion compared with saline. Finally, well-being was not influenced by the glucagon-like peptide-1 infusion. Glucagon-like peptide-1 infusion reduces energy intake dose dependently in both lean and overweight subjects. A reduced gastric emptying rate may contribute to the increased satiety induced by glucagon-like peptide-1.

The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men

Article

Full-text available

Mar 2002

Glucagon-like peptide-1 (GLP-1), a polypeptide hormone secreted by the l-cells in the gastrointestinal tract, has shown promising effects as a new treatment modality for patients with Type II (non-insulin-dependent) diabetes mellitus. However, the pharmacokinetic profile of native GLP-1 with a rapid elimination has limited its therapeutic potential. NN2211 is a fatty acid derivative of GLP-1, which pre-clinically has shown a protracted pharmacokinetic profile, while maintaining its biological activity. This study aimed to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of NN2211 in healthy male subjects following seven days treatment. In a double-blind, randomized, dose escalation, placebo controlled study, healthy male subjects were enrolled at five consecutive dose levels of NN2211 (1.25, 5.0, 7.5, 10.0, 12.5 microg/kg). Six subjects were allocated at random at each dose level to active or placebo treatment with a ratio of 2:1. Dosing with NN2211 was performed on day 1, and days 5-11. The 84-h pharmacokinetics and 24-h glucose and insulin profiles were assessed on day 1 and day 11. Following s. c. administration the half-life of NN2211 was found to be 12.6 +/- 1.1 h, with a subsequent accumulation index after a daily dose for seven days of 1.4-1.5. There were dose-proportional increases in exposure (AUC and C(max)) with increasing doses. Overall, there were no statistically significant differences from placebo in the 24-h glucose and insulin profiles. In subjects treated with NN2211 rather than placebo, there was a higher incidence of adverse events, most notably dizziness and adverse events related to the gastrointestinal system. There were no serious adverse events but three subjects were nonetheless withdrawn because of dizziness, fever and nausea. There were no clinically relevant changes in vital signs, ECG parameters, physical examination or safety laboratory parameters. A significantly lower diuresis was observed in the actively treated subjects, without a clinically relevant change in packed cell volume. This study shows NN2211 has a pharmacokinetic profile supporting a daily dose in human beings, but also that subjects treated with NN2211 rather than placebo, had a higher incidence of adverse events, most notably dizziness and adverse events related to the gastrointestinal system.

Total-body skeletal muscle mass: Estimation by a new dual-energy X-ray absorptiometry method

Article

Full-text available

Aug 2002

Skeletal muscle (SM) is an important body-composition component that remains difficult and impractical to quantify by most investigators outside of specialized research centers. A large proportion of total-body SM is found in the extremities, and a large proportion of extremity lean soft tissue is SM. A strong link should thus exist between appendicular lean soft tissue (ALST) mass and total-body SM mass. The objective was to develop prediction models linking ALST estimated by dual-energy X-ray absorptiometry (DXA) with total-body SM quantified by multislice magnetic resonance imaging in healthy adults. ALST and total-body SM were evaluated with a cross-sectional design in adults [body mass index (in kg/m(2)) < 35] with an SM-prediction model developed and validated in model-development and model-validation groups, respectively. The model-development and model-validation groups included 321 and 93 ethnically diverse adults, respectively. ALST alone was highly correlated with total-body SM (model 1: R(2) = 0.96, SEE = 1.63 kg, P < 0.001), although multiple regression analyses showed 2 additional predictor variables: age (model 2: 2-variable combined R(2) = 0.96, SEE = 1.58 kg, P < 0.001) and sex (model 3: 3-variable combined R(2) = 0.96, SEE = 1.58 kg, P < 0.001). All 3 models performed well in the validation group. An SM-prediction model based on the SM-ALST ratio was also developed, although this model had limitations when it was applied across all subjects. Total-body SM can be accurately predicted from DXA-estimated ALST, thus affording a practical means of quantifying the large and clinically important SM compartment.

Effect of Rosiglitazone on Insulin Sensitivity and Body Composition in Type 2 Diabetic Patients

Article

Full-text available

Oct 2002

To investigate the effects of rosiglitazone (RSG) on insulin sensitivity and regional adiposity (including intrahepatic fat) in patients with type 2 diabetes. We examined the effect of RSG (8 mg/day, 2 divided doses) compared with placebo on insulin sensitivity and body composition in 33 type 2 diabetic patients. Measurements of insulin sensitivity (euglycemic hyperinsulinemic clamp), body fat (abdominal magnetic resonance imaging and DXA), and liver fat (magnetic resonance spectroscopy) were taken at baseline and repeated after 16 weeks of treatment. There was a significant improvement in glycemic control (glycosylated hemoglobin -0.7 +/- 0.7%, p < or = 0.05) and an 86% increase in insulin sensitivity in the RSG group (glucose-disposal rate change from baseline: 17.5 +/- 14.5 micro mol glucose/min/kg free fat mass, p < 0.05), but no significant change in the placebo group compared with baseline. Total body weight and fat mass increased (p < or = 0.05) with RSG (2.1 +/- 2.0 kg and 1.4 +/- 1.6 kg, respectively) with 95% of the increase in adiposity occurring in nonabdominal regions. In the abdominal region, RSG increased subcutaneous fat area by 8% (25.0 +/- 28.7 cm(2), p = 0.02), did not alter intra-abdominal fat area, and reduced intrahepatic fat levels by 45% (-6.7 +/- 9.7%, concentration relative to water). Our data indicate that RSG greatly improves insulin sensitivity in patients with type 2 diabetes and is associated with an increase in adiposity in subcutaneous but not visceral body regions.

Interindividual variation in abdominal subcutaneous and visceral adipose tissue: Influence of measurement site

Article

Full-text available

Oct 2004

We evaluated the influence of measurement site on the ranking (low to high) of abdominal subcutaneous (SAT) and visceral (VAT) adipose tissue. We also determined the influence of measurement site on the prediction of abdominal SAT and VAT mass. The subjects included 100 men with computed tomography (CT) measurements at L4-L5 and L3-L4 levels and 100 men with magnetic resonance imaging (MRI) measurements at L4-L5 and 5 cm above L4-L5 (L4-L5 +5 cm). Corresponding mass values were determined by using multiple-image protocols. For SAT, 90 and 92 of the 100 subjects for CT and MRI, respectively, had a difference in rank position at the two levels. The change in rank position exceeded the error or measurement for approximately 75% of the subjects for both methods. For VAT, 91 and 95 of the 100 subjects for CT and MRI, respectively, had a difference in rank position at the two levels. The change in rank position exceeded the error of measurement for 36% of the subjects for CT and for 8% of the subjects for MRI. For both imaging modalities, the variance explained in SAT and VAT mass (kg) was comparable for L4-L5, L4-L5 +5 cm, and L3-L4 levels. In conclusion, the ranking of subjects for abdominal SAT and VAT quantity is influenced by measurement location. However, the ability to predict SAT and VAT mass by using single images obtained at the L4-L5, L4-L5 +5 cm, or L3-L4 levels is comparable.

Effect of pioglitazone on body composition and energy expenditure: A randomized controlled trial

Article

Full-text available

Feb 2005
METABOLISM

Several clinical studies have demonstrated that body weight increases after treatment with thiazolidinediones (TZDs). Prior studies have demonstrated an increase in insulin-stimulated lipid storage in adipose tissue. Some, but not all, studies demonstrate reductions in visceral adipose tissue. Changes in body weight are the result of changes in energy intake, energy expenditure, or both. Based on these findings, the primary aim of this study was to evaluate the effect of TZDs on visceral, subcutaneous, and total body fat. Secondary aims were to determine the effects of pioglitazone on (a) energy expenditure, (b) hunger and satiety, (c) blood lipids, and (d) the role of insulinemia/sulfonylurea usage on weight gain in patients with type 2 diabetes. We performed a randomized, double-blind, placebo-controlled trial in 48 men and women with type 2 diabetes who had not previously received treatment with TZDs. Patients were treated for 24 weeks with 45 mg/d of pioglitazone or a matching placebo. Body composition was measured by dual-energy x-ray absorptiometry. Visceral and subcutaneous fat were measured by computed tomography. Resting metabolic rate and thermogenic response to a test meal were measured by indirect calorimetry before and after a standardized meal. Hunger and satiety were measured with visual analog scales before and after the same test meal. Blood was collected for the measurement of fasting glucose and insulin levels, hemoglobin A 1c levels, and lipid content. Pioglitazone treatment resulted in a decrease in hemoglobin A(1c) level by 0.96 +/- 1.1% vs 0.11 +/- 0.8% in the placebo group (P < .005). Body weight and fat increased steadily in the patients treated with pioglitazone during the 6 months of the study (+3.9 +/- 3.1 kg at 6 months in pioglitazone-treated patients vs -0.8 +/- 3.4 kg in the placebo-treated patients). Subcutaneous fat in the trunk, arms, and legs were all increased in the pioglitazone-treated group. Visceral fat did not change significantly in either group. Neither resting metabolic rate nor the thermogenic responses to a meal were altered by pioglitazone. Subjective measures of hunger (visual analog scale) did not change with pioglitazone treatment. Triglycerides fell in the pioglitazone-treated group (-58.5 +/- 124 mg/dL, P < .003). Neither the prior use of sulfonylureas nor the level of insulinemia before treatment was a predictor of weight or fat change. Pioglitazone increased subcutaneous body fat, but not visceral fat. There was no measurable effect on energy expenditure or hunger/satiety. In contrast to the placebo-treated patient with diabetes, weight gain occurs in the face of falling hemoglobin A(1c) and triglyceride levels.

Non-alcoholic fatty liver disease and metabolic syndrome: What we know and what we don't know

Article

Full-text available

Feb 2006

NAFLD is a very common asymptomatic liver condition that may progress to cirrhosis and hepatocellular carcinoma, and a relation to the different components of the metabolic syndrome has been found. In this review we highlight some of the epidemiological aspects of the two disorders and discuss some of the possible mechanisms and questions to be answered concerning the risk factors for the progression of this condition, as well as the need for more studies to focus on possible modalities of treatment.

Antiobesity action of peripheral exenatide (exendin-4) in rodents: Effects on food intake, body weight, metabolic status and side-effect measures

Article

Full-text available

Sep 2006

Exenatide (exendin-4) is an incretin mimetic currently marketed as an antidiabetic agent for patients with type 2 diabetes. In preclinical models, a reduction in body weight has also been shown in low-fat-fed, leptin receptor-deficient rodents. To more closely model the polygenic and environmental state of human obesity, we characterized the effect of exenatide on food intake and body weight in high-fat-fed, normal (those with an intact leptin signaling system) rodents. As glucagon-like peptide-1 receptor agonism has been found to elicit behaviors associated with visceral illness in rodents, we also examined the effect of peripheral exenatide on kaolin consumption and locomotor activity. High-fat-fed C57BL/6 mice and Sprague-Dawley rats were treated with exenatide (3, 10 and 30 microg/kg/day) for 4 weeks via subcutaneously implanted osmotic pumps. Food intake and body weight were assessed weekly. At 4 weeks, body composition and plasma metabolic profiles were measured. Kaolin consumption and locomotor activity were measured in fasted Sprague-Dawley rats following a single intraperitoneal injection of exenatide (0.1-10 microg/kg). Exenatide treatment in mice and rats dose-dependently decreased food intake and body weight; significant reductions in body weight gain were observed throughout treatment at 10 and 30 microg/kg/day (P<0.05). Decreased body weight gain was associated with a significant decrease in fat mass (P<0.05) with sparing of lean tissue. Plasma cholesterol, triglycerides and insulin were also significantly reduced (P<0.05). Exenatide at 10 microg/kg significantly reduced food intake (P<0.05) but failed to induce kaolin intake. In general, locomotor activity was reduced at doses of exenatide that decreased food intake, although a slightly higher dose was required to produce significant changes in activity. Systemic exenatide reduces body weight gain in normal, high-fat-fed rodents, a model that parallels human genetic variation and food consumption patterns, and may play a role in metabolic pathways mediating food intake.

Liraglutide, a Long-Acting Glucagon-Like Peptide-1 Analog, Reduces Body Weight and Food Intake in Obese Candy-Fed Rats, Whereas a Dipeptidyl Peptidase-IV Inhibitor, Vildagliptin, Does Not

Article

Full-text available

Feb 2007
DIABETES

Metabolic effects of the glucagon-like peptide-1 analog liraglutide and the dipeptidyl peptidase-IV inhibitor vildagliptin were compared in rats made obese by supplementary candy feeding. Female Sprague-Dawley rats were randomized to 12-week diets of chow or chow plus candy. The latter were randomized for 12 further weeks to continue their diet while receiving 0.2 mg/kg liraglutide twice daily subcutaneously, 10 mg/kg vildagliptin twice daily orally, or vehicle or to revert to chow-only diet. Energy expenditure was measured, and oral glucose tolerance tests (OGTTs) were performed. Body composition was determined by dual-energy X-ray absorptiometry scanning, and pancreatic beta-cell mass was determined by histology. Candy feeding increased weight, fat mass, and feeding-associated energy expenditure. Liraglutide or reversal to chow diet fully reversed weight and fat gains. Liraglutide was associated with decreased calorie intake and shifted food preference (increased chow/decreased candy consumption). Despite weight loss, liraglutide-treated rats did not decrease energy expenditure compared with candy-fed controls. Vildagliptin affected neither weight, food intake, nor energy expenditure. OGTTs, histology, and blood analyses indirectly suggested that both drugs increased insulin sensitivity. Liraglutide and vildagliptin inhibited obesity-associated increases in beta-cell mass. This was associated with weight and fat mass normalization with liraglutide, but not vildagliptin, where the ratio of beta-cell to body mass was low.

Incretin Receptors for Glucagon-Like Peptide 1 and Glucose-Dependent Insulinotropic Polypeptide Are Essential for the Sustained Metabolic Actions of Vildagliptin in Mice

Article

Full-text available

Jan 2008

Dipeptidyl peptidase-4 (DPP4) inhibitors lower blood glucose in diabetic subjects; however, the mechanism of action through which these agents improve glucose homeostasis remains incompletely understood. Although glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) represent important targets for DPP4 activity, whether additional substrates are important for the glucose-lowering actions of DPP4 inhibitors remains uncertain. We examined the efficacy of continuous vildagliptin administration in wild-type (WT) and dual incretin receptor knockout (DIRKO) mice after 8 weeks of a high-fat diet. Vildagliptin had no significant effect on food intake, energy expenditure, body composition, body weight gain, or insulin sensitivity in WT or DIRKO mice. However, glycemic excursion after oral glucose challenge was significantly reduced in WT but not in DIRKO mice after vildagliptin treatment. Moreover, vildagliptin increased levels of glucose-stimulated plasma insulin and reduced levels of cholesterol and triglycerides in WT but not in DIRKO mice. Vildagliptin treatment reduced the hepatic expression of genes important for cholesterol synthesis and fatty acid oxidation, including phospho-mevalonate kinase (Mvk), acyl-coenzyme dehydrogenase medium chain (Acadm), mevalonate (diphospho)decarboxylase (Mvd), and Acyl-CoA synthetase (Acsl1), in WT but not in DIRKO mice. However, vildagliptin also reduced levels of hepatic mRNA transcripts for farnesyl di-phosphate transferase (Fdft1), acetyl coenzyme A acyltransferase 1 (Acaa1), and carnitine palmitoyl transferase 1 (Cpt 1) in DIRKO mice. No direct effect of GLP-1 receptor agonists was detected on cholesterol or triglyceride synthesis and secretion in WT hepatocytes. These findings illustrate that although GLP-1 and GIP receptors represent the dominant molecular mechanisms for transducing the glucoregulatory actions of DPP4 inhibitors, prolonged DPP4 inhibition modulates the expression of genes important for lipid metabolism independent of incretin receptor action in vivo.

Is the reduction of lower-body subcutaneous adipose tissue associated with elevations in risk factors for diabetes and cardiovascular disease?

Article

Full-text available

Jul 2008

Since the accumulation of lower-body subcutaneous adipose tissue (LBSAT) is associated with decreased cardiometabolic risk, we evaluated whether reductions in LBSAT independent of changes in visceral AT (VAT) and abdominal SAT are associated with elevations in diabetes and cardiovascular disease risk factors. Overweight and obese men (n = 58) and premenopausal women (n = 49) with elevated cardiometabolic risk underwent 3 months of diet and/or exercise induced weight-loss treatment; regional body composition assessment by magnetic resonance imaging (MRI); and cardiometabolic risk assessment, including an OGTT. After control for potential confounders, reductions in VAT, abdominal SAT and LBSAT were all associated with improvements in selective cardiometabolic risk factors, including fasting glucose levels, lipid status and OGTT glucose and insulin. Independent of changes in the other AT depots, reductions in VAT and abdominal SAT, but not LBSAT, remained associated with improvement in fasting glucose levels, glucose tolerance and lipid status. Among overweight and obese adults with increased cardiometabolic risk, the selective reduction of LBSAT is not associated with elevations in risk factors for diabetes and cardiovascular disease. Thus, the reduction of excess AT conveys health benefit regardless of origin.

Meta-analysis demonstrates that liraglutide, a once daily human GLP-1 analogue significantly reduces lipids and other markers of cardiovascular risk in T2DM

Article

Jan 2009
DIABETOLOGIA

Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure (vol 280, pg 140, 1998)

Article

Nov 1998

JQ Purnell

Long-term efficacy and safety comparison of liraglutide, glimepiride and placebo, all in combination with metformin in type 2 diabetes: 2-year results from the LEAD-2 study

Article

Sep 2012
DIABETES OBES METAB

Aims: To investigate efficacy and safety of dual therapy with liraglutide and metformin in comparison to glimepiride and metformin, and metformin monotherapy over 2 years in patients with type 2 diabetes. Methods: In the 26-week the Liraglutide Effect and Action in Diabetes (LEAD)-2 core trial, patients (n = 1091) were randomized (2 : 2 : 2 : 1: 2) to liraglutide (0.6, 1.2 or 1.8 mg once-daily), placebo or glimepiride; all with metformin. Patients were enrolled if they were 18-80 years old with HbA1c 7.0-11.0% (previous monotherapy ≥3 months), or 7.0-10.0% (previous combination therapy ≥3 months), and body mass index ≤40 kg/m(2) . Patients completing the 26-week double-blinded phase could enter an 18-month open-label extension. Results: HbA1c decreased significantly with liraglutide (0.4% with 0.6 mg, 0.6% with 1.2 and 1.8 mg) versus 0.3% increase with metformin monotherapy (p < 0.0001). HbA1c decrease with liraglutide was non-inferior versus 0.5% decrease with glimepiride. Liraglutide groups experienced significant weight loss (2.1, 3.0 and 2.9 kg with 0.6, 1.2 and 1.8 mg, respectively) compared to weight gain (0.7 kg) with glimepiride (p < 0.0001). Weight loss with liraglutide 1.2 and 1.8 mg was significantly greater than with metformin monotherapy (1.8 kg; p = 0.0185 and p = 0.0378 for 1.2 and 1.8 mg, respectively). The occurrence of minor hypoglycaemia was <5.0% in all liraglutide groups, significantly less than with glimepiride (24.0%; p < 0.0001). Liraglutide was well tolerated overall: gastrointestinal events were more common than with glimepiride or metformin monotherapy, but occurrence decreased with time. Conclusions: Liraglutide provided sustained glycaemic control over 2 years comparable to that provided by glimepiride. Liraglutide was well tolerated, and was associated with weight loss and a low rate of hypoglycaemia.

Incretin-Based Therapies in Type 2 Diabetes Mellitus

Article

Oct 2008

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide are incretins secreted from enteroendocrine cells postprandially in part to regulate glucose homeostasis. Dysregulation of these hormones is evident in type 2 diabetes mellitus (T2DM). Two new drugs, exenatide (GLP-1 mimetic) and sitagliptin [dipeptidyl peptidase (DPP) 4 inhibitor], have been approved by regulatory agencies for treating T2DM. Liraglutide (GLP-1 mimetic) and vildagliptin (DPP 4 inhibitor) are expected to arrive on the market soon. The background of incretin-based therapy and selected clinical trials of these four drugs are reviewed. A MEDLINE search was conducted for published articles using the key words incretin, glucose-dependent insulinotropic polypeptide, GLP-1, exendin-4, exenatide, DPP 4, liraglutide, sitagliptin, and vildagliptin. Exenatide and liraglutide are injection based. Three-year follow-up data on exenatide showed a sustained weight loss and glycosylated hemoglobin (HbA(1c)) reduction of 1%. Nausea and vomiting are common. Results from phase 3 studies are pending on liraglutide. Sitagliptin and vildagliptin are orally active. In 24-wk studies, sitagliptin reduces HbA(1c) by 0.6-0.8% as monotherapy, 1.8% as initial combination therapy with metformin, and 0.7% as add-on therapy to metformin. Vildagliptin monotherapy lowered HbA(1c) by 1.0-1.4% after 24 wk. Their major side effects are urinary tract and nasopharyngeal infections and headaches. Exenatide and liraglutide cause weight loss, whereas sitagliptin and vildagliptin do not. The availability of GLP-1 mimetics and DPP 4 inhibitors has increased our armamentarium for treating T2DM. Unresolved issues such as the effects of GLP-1 mimetics and DPP 4 inhibitors on beta-cell mass, the mechanism by which GLP-1 mimetics lowers glucagon levels, and exactly how DPP 4 inhibitors lead to a decline in plasma glucose levels without an increase in insulin secretion, need further research.

Liraglutide once a day versus exenatide twice a day for type 2 diabetes: A 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6)

Article

Jun 2009
LANCET

Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the efficacy and safety of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist. Adults with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both, were stratified by previous oral antidiabetic therapy and randomly assigned to receive additional liraglutide 1.8 mg once a day (n=233) or exenatide 10 microg twice a day (n=231) in a 26-week open-label, parallel-group, multinational (15 countries) study. The primary outcome was change in glycosylated haemoglobin (HbA(1c)). Efficacy analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00518882. Mean baseline HbA(1c) for the study population was 8.2%. Liraglutide reduced mean HbA(1c) significantly more than did exenatide (-1.12% [SE 0.08] vs -0.79% [0.08]; estimated treatment difference -0.33; 95% CI -0.47 to -0.18; p<0.0001) and more patients achieved a HbA(1c) value of less than 7% (54%vs 43%, respectively; odds ratio 2.02; 95% CI 1.31 to 3.11; p=0.0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (-1.61 mmol/L [SE 0.20] vs -0.60 mmol/L [0.20]; estimated treatment difference -1.01 mmol/L; 95% CI -1.37 to -0.65; p<0.0001) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide -3.24 kg vs exenatide -2.87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0.448, p<0.0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1.93 vs 2.60 events per patient per year; rate ratio 0.55; 95% CI 0.34 to 0.88; p=0.0131; 25.5%vs 33.6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode. Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations. Novo Nordisk A/S.

Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): A randomised, 52-week, phase III, double-blind, parallel-treatment trial

Article

Oct 2008
LANCET

New treatments for type 2 diabetes mellitus are needed to retain insulin-glucose coupling and lower the risk of weight gain and hypoglycaemia. We aimed to investigate the safety and efficacy of liraglutide as monotherapy for this disorder. In a double-blind, double-dummy, active-control, parallel-group study, 746 patients with early type 2 diabetes were randomly assigned to once daily liraglutide (1.2 mg [n=251] or 1.8 mg [n=247]) or glimepiride 8 mg (n=248) for 52 weeks. The primary outcome was change in proportion of glycosylated haemoglobin (HbA(1c)). Analysis was done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NTC00294723. At 52 weeks, HbA(1c) decreased by 0.51% (SD 1.20%) with glimepiride, compared with 0.84% (1.23%) with liraglutide 1.2 mg (difference -0.33%; 95% CI -0.53 to -0.13, p=0.0014) and 1.14% (1.24%) with liraglutide 1.8 mg (-0.62; -0.83 to -0.42, p<0.0001). Five patients in the liraglutide 1.2 mg, and one in 1.8 mg groups discontinued treatment because of vomiting, whereas none in the glimepiride group did so. Liraglutide is safe and effective as initial pharmacological therapy for type 2 diabetes mellitus and leads to greater reductions in HbA(1c), weight, hypoglycaemia, and blood pressure than does glimepiride.

Relationship between lactate dehydrogenase and mycloperoxidase levels in human gingival Crevicular fluid and clinical and microbial measurements

Article

Mar 1988

The present study was designed to determine, in a cross-sectional study, whether there was any relationship between levels of lactate dehydrogenase (LDH) and myeloperoxidase (MPO) in gingival crevicular fluid (GCF) and clinical periodontal status or microbial parameters. Another objective was to determine, in a longitudinal study, the effect of a single session of root planning on GCF levels of LDH and MPO and the relation to changes in clinical and microbial measurements. 15 and 12 test subjects with moderate to severe periodontal disease were seen in the cross-sectional and longitudinal study, respectively. 1 healthy and 2 diseased sites were evaluated in each subject. Higher LDH and MPO levels in GCF were closely associated with higher clinical and microbial signs of periodontal disease. Root planing was effective in reducing these enzymes in GCF, with an accompanying decrease in clinical and microbial signs associated with disease. The return of LDH to baseline levels at 3 months after instrumentation, without a corresponding return of clinical signs of disease, may serve as a marker for subclinical periodontal pathology.

The Role of Fat Depletion in the Biological Benefits of Caloric Restriction

Article

Apr 2001

One of the most robust observations in the biology of aging is that caloric restriction (CR) extends life in a variety of species. Although CR results in substantial decrease in fat mass, the role of fat in life extension was considered minimal. Indeed, in the fields of obesity and diabetes, the amount of fat has been directly implicated in the metabolic consequences. Since it became apparent that fat is a massive endocrine tissue, some of its roles have been recently revised. Many of the systemic effects of CR can now be explained by the chronic effects related to decreased plasma levels of peptides, cytokines, complement factors and substrates that are produced in fat. Most of the benefits of CR on the neuroendocrine system and those related to the improvement in glucose homeostasis can be attributed to a decrease in adipose cells and their products. If all or most of the life-extending benefits of CR can be attributed to decreased fat stores, the expression of specific candidate substrates and proteins may be explored and manipulated in searching for the most powerful adipose-dependent signals that modulate life expectancy.

Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and ??-cell function in type 2 diabetes: A parallel-group study

Article

Mar 2002

Glucagon-like peptide 1 (GLP-1) has been proposed as a treatment for type 2 diabetes. We have investigated the long-term effects of continuous administration of this peptide hormone in a 6-week pilot study. 20 patients with type 2 diabetes were alternately assigned continuous subcutaneous infusion of GLP-1 (n=10) or saline (n=10) for 6 weeks. Before (week 0) and at weeks 1 and 6, they underwent beta-cell function tests (hyperglycaemic clamps), 8 h profiles of plasma glucose, insulin, C-peptide, glucagon, and free fatty acids, and appetite and side-effect ratings on 100 mm visual analogue scales; at weeks 0 and 6 they also underwent dexascanning, measurement of insulin sensitivity (hyperinsulinaemic euglycaemic clamps), haemoglobin A(1c), and fructosamine. The primary endpoints were haemoglobin A(1c) concentration, 8-h profile of glucose concentration in plasma, and beta-cell function (defined as the first-phase response to glucose and the maximum insulin secretory capacity of the cell). Analyses were per protocol. One patient assigned saline was excluded because no veins were accessible. In the remaining nine patients in that group, no significant changes were observed except an increase in fructosamine concentration (p=0.0004). In the GLP-1 group, fasting and 8 h mean plasma glucose decreased by 4.3 mmol/L and 5.5 mmol/L (p<0.0001). Haemoglobin A(1c) decreased by 1.3% (p=0.003) and fructosamine fell to normal values (p=0.0002). Fasting and 8 h mean concentrations of free fatty acids decreased by 30% and 23% (p=0.0005 and 0.01, respectively). Gastric emptying was inhibited, bodyweight decreased by 1.9 kg, and appetite was reduced. Both insulin sensitivity and beta-cell function improved (p=0.003 and p=0.003, respectively). No important side-effects were seen. GLP-1 could be a new treatment for type 2 diabetes, though further investigation of the long-term effects of GLP-1 is needed.

The Effect of Liraglutide, a Long-Acting Glucagon-Like Peptide 1 Derivative, on Glycemic Control, Body Composition, and 24-h Energy Expenditure in Patients With Type 2 Diabetes

Article

Sep 2004
DIABETES CARE

Glucagon-like peptide (GLP)-1 is a gut hormone that exerts incretin effects and suppresses food intake in humans, but its therapeutic use is limited due to its short half-life. This was a randomized, double-blind, parallel-group, placebo-controlled trial investigating the effect of the long-acting GLP-1 derivative liraglutide (NN2211) on glycemic control, body weight, body composition, and 24-h energy expenditure in obese subjects with type 2 diabetes. Thirty-three patients (mean +/- SD) aged 60.0 +/- 9.5 years, with HbA(1c) 7.5 +/- 1.2% and BMI 36.6 +/- 4.1 kg/m(2), were randomized to treatment with a single daily subcutaneous dose of 0.6 mg liraglutide (n = 21) or placebo (n = 12) for 8 weeks. In addition to weight and glycemic parameters, body composition was assessed by dual-energy X-ray absorptiometry (DEXA) scanning and 24-h energy expenditure in a respiratory chamber. After 8 weeks, liraglutide reduced fasting serum glucose (liraglutide, -1.90 mmol/l, and placebo, 0.27 mmol/l; P = 0.002) and HbA(1c) (liraglutide, -0.33%, and placebo, 0.47%; P = 0.028) compared with placebo. No change in body weight was detected (liraglutide, -0.7 kg, and placebo, -0.9 kg; P = 0.756). There was a nonsignificant trend toward a decrease in total fat mass (liraglutide, -0.98%, and placebo, -0.12%; P = 0.088) and toward an increase in lean body mass (liraglutide, 1.02%, and placebo, 0.23%; P = 0.118) in the liraglutide group compared with the placebo group. Twenty-four-hour energy expenditure was unaffected by the treatment (liraglutide, -12.6 kJ/h, and placebo, -13.7 kJ/h; P = 0.799). Eight weeks of 0.6-mg liraglutide treatment significantly improved glycemic control without increasing weight in subjects with type 2 diabetes compared with those on placebo. No influence on 24-h energy expenditure was detected.

Effects of metformin on the body composition in subjects with risk factors for type 2 diabetes

Article

Mar 2005

To measure the effect of metformin on the body composition, insulin resistance and sensitivity in subjects with risk factors for type 2 diabetes mellitus (type 2 DM). Design: Placebo-controlled clinical trial. Twenty-three subjects with risk factors for type 2 DM were randomly assigned to receive 850 mg of metformin or a placebo twice a day for 2 months. Before and after the treatment, the body mass index and waist/hip ratio were calculated, the body composition was measured through bioelectric impedance and the fasting levels of blood glucose, insulin, triglycerides and cholesterol were measured. The level of insulin resistance was calculated by the homeostatic model and the level of sensitivity by the quantitative insulin sensitivity check index method. The Wilcoxon rank test was used. Twenty-one subjects completed the study, 12 of the metformin group and nine of the placebo group. In the metformin group, there was a decrease in fat weight from 25.9 +/- 9.4 to 20.8 +/- 9.2 kg, p < 0.01, an increase in lean weight from 57.05 +/- 13.6 to 61.9 +/- 16.5 kg, p < 0.01, an increase in basal metabolism from 1735 +/- 413 to 1878 +/- 505 calories/day, p < 0.05 and an increase in body water, p < 0.05. There was no significant decrease in insulin resistance. In the placebo group, the blood glucose increased from 84.7 +/- 13 to 96.7 +/- 16 mg/dl, p < 0.05. There were no significant modifications in lipids. The administration of metformin for 2 months improves the parameters of body composition and insulin dynamics in subjects with risk factors for type 2 DM.

In Vivo Biological Activity of Exendin (1–30)

Article

Jul 2005

Activation of the glucagon-like peptide-1 (GLP-1) receptor on pancreatic beta cells by GLP-1 and exendin-4 (a more potent and stable agonist of the GLP-1 receptor than GLP-1) increases insulin secretion. Exendin-4 is 39 amino acids long, unlike GLP-1 which has 30 amino acids. Because of its non-mammalian (lizard) origin and unique C-terminal sequence, exendin-4 may be immunogenic in humans. We showed previously that the C terminally truncated exendin peptide exendin (1–30) has a reduced affinity for the GLP-1 receptor and a diminished ability to increase intracellular cAMP in insulinoma cells. Here we show that daily intraperitoneal injection of exendin (1–30) (1 nmol/kg) for 20 d followed by 31 d twice daily to Lepr db/Leprdb (db/db) mice significantly reduced the amount of visceral fat relative to saline-treated controls and improved HbA1C (control 9.5±0.2% vs treated 7.9±0.2%, p=0.001) but was not as effective as exendin-4. To examine the ability of exendin (1–30) to stimulate beta-cell growth, we injected one group of 3-mo-old Fisher rats with exendin (1–30) (1 nmol/kg) and another group with saline for 8 d. We observed no change in beta-cell area, but did see a change in the number of islets with nuclei positive for BrdU [10.7±1.8% exendin (1–30) vs 6.5±0.5% control].

Point: Visceral Adiposity Is Causally Related to Insulin Resistance

Article

Oct 2005
DIABETES CARE

The relationship between obesity and insulin resistance, while well recognized for many years, has nonetheless been confusing since not all obese individuals have insulin resistance (1) and because insulin resistance occurs in individuals who have BMIs that are within the normal or mildly overweight categories (2). Early attempts to understand the relationships between obesity, type 2 diabetes, and cardiovascular disease focused on the waist-to-hip ratio as a means of distinguishing those individuals who were at increased risk from those who were not (3,4). A high waist-to-hip ratio is a surrogate for masculine distribution of obesity (central obesity). Cross-sectional studies by Kissebah et al. (5) and Krotkiewski et al. (6) in the 1980s demonstrated that hypertension, hypertriglyceridemia, hyperinsulinemia, and glucose intolerance were increased in subjects with a high waist-to-hip ratio. Long-term longitudinal population-based studies of men (13.5 years) and women (12 years) in Gothenburg, Sweden, showed that the waist-to-hip ratio was a predictor of the future development of diabetes, myocardial infarction, angina pectoris, stroke, and death independent of BMI (3,4). Technology developed in the 1990s, including computer tomography scans and MRI, made it possible to precisely measure specific adipose tissue depots such as total body adipose tissue mass, abdominal subcutaneous adipose tissue mass, visceral adipose tissue mass, and hepatic and intramuscular triglyceride content (7,8). Utilizing those techniques, many studies have examined the relationship between total adipose tissue, abdominal subcutaneous adipose tissue, and visceral adipose tissue mass and insulin resistance, the components of the metabolic syndrome, and the development of type 2 diabetes or clinical cardiovascular events (9–21). Despite the much smaller size of the visceral adipose tissue depot compared with the total subcutaneous adipose tissue depot or total adiposity, many investigations demonstrated that the visceral adipose tissue mass and not …

Computed Tomography Features of Nonalcoholic Steatohepatitis With Histopathologic Correlation

Article

Jan 2006

This study was conducted to describe the computed tomography (CT) features of nonalcoholic steatohepatitis (NASH) and to evaluate if the CT features could be used to diagnose and stage NASH. From 1994 until 2004, pathology records revealed 68 patients with NASH. Of these, 12 patients underwent CT scans before (n=6), on the same day as (n=3), or after (n=3) a liver biopsy. Using the same database, 9 patients with steatosis alone evaluated with a CT scan before (n=2), on the same day as (n=3), or after (n=4) the liver biopsy were selected as a control group. Two radiologists measured liver attenuation (compared with spleen) and assessed the pattern of steatosis, craniocaudal liver span, caudate-to-right lobe ratio, preportal space distance, and presence of porta hepatis lymph nodes and ascites. Biopsy specimens were assessed by a pathologist, and the degree of necroinflammatory activity, steatosis, and fibrosis was determined. Histopathologic and CT findings were compared between patients with NASH and patients with steatosis alone using the Mann-Whitney U test and Fisher exact test. In patients with NASH, the mean liver-to-spleen attenuation ratio was 0.66 (range: 0.1-1.1). Steatosis was diffuse (n=9), geographic or nonlobar (n=2), or diffuse with an area of focal sparing (n=1). The liver craniocaudal span varied from 17.5 to 25.5 cm (mean=21.4 cm), and hepatomegaly was present in 11 (91.7%) patients. The caudate-to-right-lobe ratio (mean=0.43) and preportal space (mean=4.5 mm) were normal in all cases. Porta hepatis lymph nodes were present in 7 (58.3%) patients; their mean dimensions were 16 mmx11 mm. Ascites was absent in all patients. On histopathology, the degree of necroinflammatory activity was mild (n=9), moderate (n=1), or severe (n=2). The degree of steatosis was 33% to 66% (n=5) or >67% (n=7). All but 3 patients had fibrosis; 6 had focal nonbridging fibrosis, 1 had multifocal nonbridging fibrosis, and 2 had bridging fibrosis. There was a significant correlation between the degree of steatosis on pathologic examination and the liver-to-spleen attenuation ratio on CT (P=0.048). The severity of inflammation and stage of fibrosis on pathologic examination did not correlate with the CT features. Among patients with steatosis alone, the mean liver-to-spleen attenuation ratio was 0.80 (range: 0.3-1.2); the craniocaudal liver span varied from 12 to 20 cm (mean=16 cm); hepatomegaly was present in 2 (22.2%) patients; the caudate-to-right lobe ratio was normal in all patients, with a mean of 0.36 (range: 0.22-0.47); the preportal space distance was enlarged in 2 cases (mean=7.5 mm, range: 1-16 mm); porta hepatis lymph nodes were present in 7 (77.8%) patients, and their mean dimensions were 11 mmx8 mm (large axis range: 6-19 mm, short axis range: 4-14 mm); and no patient had ascites. There was a significant difference in the craniocaudal liver span between patients with NASH (mean=21 cm) and patients with steatosis (mean=16 cm) (P<0.05). The caudate-to-right-lobe ratio was also significantly different between patients with NASH (mean=0.43) and patients with steatosis (mean=0.36) (P<0.05). There were no significant differences in liver-to-spleen attenuation ratios, measurements of preportal space, or the presence of porta hepatic lymph nodes. The CT features of NASH include steatosis, hepatomegaly, and porta hepatis lymph nodes, and the liver-to-spleen attenuation ratio correlated with the degree of steatosis on histopathology. Patients with NASH had a greater liver span and increased caudate-to-right-lobe-ratio compared with patients with steatosis alone.

Ding, XK, Saxena, NK, Lin, SB, Gupta, N and Anania, FA. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology 43: 173-181

Article

Jan 2006

Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning problem in hepatology, and is associated with insulin resistance. Exendin-4 is a peptide agonist of the glucagon-like peptide (GLP) receptor that promotes insulin secretion. The aim of this study was to determine whether administration of Exendin-4 would reverse hepatic steatosis in ob/ob mice. Ob/ob mice, or their lean littermates, were treated with Exendin-4 [10 microg/kg or 20 microg/kg] for 60 days. Serum was collected for measurement of insulin, adiponectin, fasting glucose, lipids, and aminotransferase concentrations. Liver tissue was procured for histological examination, real-time RT-PCR analysis and assay for oxidative stress. Rat hepatocytes were isolated and treated with GLP-1. Ob/ob mice sustained a reduction in the net weight gained during Exendin-4 treatment. Serum glucose and hepatic steatosis was significantly reduced in Exendin-4 treated ob/ob mice. Exendin-4 improved insulin sensitivity in ob/ob mice, as calculated by the homeostasis model assessment. The measurement of thiobarbituric reactive substances as a marker of oxidative stress was significantly reduced in ob/ob-treated mice with Exendin-4. Finally, GLP-1-treated hepatocytes resulted in a significant increase in cAMP production as well as reduction in mRNA expression of stearoyl-CoA desaturase 1 and genes associated with fatty acid synthesis; the converse was true for genes associated with fatty acid oxidation. In conclusion, Exendin-4 appears to effectively reverse hepatic steatosis in ob/ob mice by improving insulin sensitivity. Our data suggest that GLP-1 proteins in liver have a novel direct effect on hepatocyte fat metabolism.

Dispelling Myths and Removing Barriers About Insulin in Type 2 Diabetes

Article

Jan 2006

Jerry Meece

Effects of Pioglitazone Versus Glipizide on Body Fat Distribution, Body Water Content, and Hemodynamics in Type 2 Diabetes

Article

Apr 2006
DIABETES CARE

Pioglitazone, a peroxisome proliferator-activated receptor agonist and glipizide, an insulin secretagogue, are commonly used to treat type 2 diabetes. Our study was designed to examine the effects of pioglitazone versus glipizide on body water, body composition, and hemodynamic parameters in the presence of comparable glycemic control between groups. We studied 19 diabetic subjects randomly assigned to either 45 mg pioglitazone (n = 8) or 10 mg (median dose) glipizide (n = 11) for 12 weeks. Body water content was measured with deuterated water, body composition by dual-energy X-ray absorptiometry and computed tomography, and cardiac output and systemic vascular resistance by acetylene rebreathing technique both before and after therapy. Pioglitazone increased (P < 0.001 from baseline) total body water (+2.4 +/- 0.5 l) accounting for 75% of the total weight gain (+3.1 +/- 2.0 kg) but did not alter vascular endothelial growth factor concentrations. Total abdominal (-32.2 +/- 19 cm(2)) and visceral fat area (-16.1 +/- 8 cm(2)) tended to decrease with pioglitazone but increased (P < 0.02 for differences between groups) with glipizide (+38.4 +/- 17 cm(2) abdominal; +19.1 +/- 9 cm(2) visceral). Pioglitazone tended to reduce (P = 0.05) diastolic (-8.4 +/- 4 mmHg) and mean (-9.5 +/- 5 mmHg; P = 0.08) blood pressure and reduced (P < 0.001) systemic vascular resistance (2,785 +/- 336 vs. 2,227 +/- 136 dynes/s per m(2)), while there were no differences in these parameters with glipizide. Neither therapy altered circulating catecholamine concentrations. When pioglitazone and glipizide are given in doses sufficient to achieve equivalent glycemic control in people with type 2 diabetes, pioglitazone increases total body water, thereby accounting for the majority of weight gain, tended to decrease visceral and abdominal fat content and blood pressure, and reduces systemic vascular resistance.

Is all fat the same? The role of fat in the pathogenesis of the metabolic syndrome and type 2 diabetes mellitus

Article

Jul 2006
SURGERY

The incretin system: Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes

Article

Dec 2006
LANCET

Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone that stimulates insulin and suppresses glucagon secretion, inhibits gastric emptying, and reduces appetite and food intake. Therapeutic approaches for enhancing incretin action include degradation-resistant GLP-1 receptor agonists (incretin mimetics), and inhibitors of dipeptidyl peptidase-4 (DPP-4) activity (incretin enhancers). Clinical trials with the incretin mimetic exenatide (two injections per day or long-acting release form once weekly) and liraglutide (one injection per day) show reductions in fasting and postprandial glucose concentrations, and haemoglobin A1c (HbA1c) (1-2%), associated with weight loss (2-5 kg). The most common adverse event associated with GLP-1 receptor agonists is mild nausea, which lessens over time. Orally administered DPP-4 inhibitors, such as sitagliptin and vildagliptin, reduce HbA1c by 0.5-1.0%, with few adverse events and no weight gain. These new classes of antidiabetic agents, and incretin mimetics and enhancers, also expand beta-cell mass in preclinical studies. However, long-term clinical studies are needed to determine the benefits of targeting the incretin axis for the treatment of type 2 diabetes.

Insulin-associated weight gain in diabetes – causes, effects and coping strategies

Article

Dec 2007

Insulin therapy or intensification of insulin therapy commonly results in weight gain in both type 1 and type 2 diabetes. This weight gain can be excessive, adversely affecting cardiovascular risk profile. The spectre of weight gain can increase diabetic morbidity and mortality when it acts as a psychological barrier to the initiation or intensification of insulin, or affects adherence with prescribed regimens. Insulin-associated weight gain may result from a reduction of blood glucose to levels below the renal threshold without a compensatory reduction in calorie intake, a defensive or unconscious increase in calorie intake caused by the fear or experience of hypoglycaemia, or the 'unphysiological' pharmacokinetic and metabolic profiles that follow subcutaneous administration. There is, however, scope for limiting insulin-associated weight gain. Strategies include limiting dose by increasing insulin sensitivity through diet and exercise or by using adjunctive anorectic or insulin-sparing pharmacotherapies such as pramlintide or metformin. Insulin replacement regimens that attempt to mimic physiological norms should also enable insulin to be dosed with maximum efficiency. The novel acylated analogue, insulin detemir, appears to lack the usual propensity for causing weight gain. Elucidation of the pharmacological mechanisms underlying this property might help clarify the mechanisms linking insulin with weight regulation.

Bodyweight Changes Associated with Antihyperglycaemic Agents in Type 2 Diabetes Mellitus

Article

Feb 2007

The majority of patients with type 2 diabetes mellitus are overweight or obese at the time of diagnosis, and obesity is a recognised risk factor for type 2 diabetes and coronary heart disease (CHD). Conversely, weight loss has been shown to improve glycaemic control in patients with type 2 diabetes, as well as to lower the risk of CHD. The traditional pharmacotherapies for type 2 diabetes can further increase weight and this may undermine the benefits of improved glycaemic control. Furthermore, patients’ desire to avoid weight gain may jeopardise compliance with treatment, thereby limiting treatment success and indirectly increasing the risk of long-term complications. This review evaluates the influences of established and emerging therapies on bodyweight in type 2 diabetes.

Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years*

Article

Jan 2008
CURR MED RES OPIN

Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A(1c) (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of > or = 3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety. Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5 mug exenatide, or 10 mug exenatide for 30 weeks, followed by 5 mug exenatide BID for 4 weeks, then 10 mug exenatide BID for > or = 3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas. 217 patients (64% male, age 58 +/- 10 years, weight 99 +/- 18 kg, BMI 34 +/- 5 kg/m(2), A1C 8.2 +/- 1.0% [mean +/- SD]) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (-1.1 +/- 0.1% [mean +/- SEM]) were sustained to 3 years (-1.0 +/- 0.1%; p < 0.0001), with 46% achieving A1C < or = 7%. Exenatide progressively reduced body weight from baseline (-5.3 +/- 0.4 kg at 3 years; p < 0.0001). Patients with elevated serum alanine aminotransferase (ALT) at baseline (n = 116) had reduced ALT (-10.4 +/- 1.5 IU/L; p < 0.0001) and 41% achieved normal ALT. Patients with elevated ALT at baseline tended to lose more weight than patients with normal ALT at baseline (-6.1 +/- 0.6 kg vs. -4.4 +/- 0.5 kg; p = 0.03), however weight change was minimally correlated with baseline ALT (r = -0.01) or ALT change (r = 0.31). Homeostasis Model Assessment B (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n = 151). Triglycerides decreased 12% (p = 0.0003), total cholesterol decreased 5% (p = 0.0007), LDL-C decreased 6% (p < 0.0001), and HDL-C increased 24% (p < 0.0001). Exenatide was generally well tolerated. The most frequent adverse event was mild-to-moderate nausea. The main limitation of this study is the open-label, uncontrolled nature of the study design which does not provide a placebo group for comparison. Adjunctive exenatide treatment for > or = 3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.

Disruptions in Energy Balance: Does Nature overcome Nurture?

Article

May 2008
PHYSIOL BEHAV

Fat accumulation, in general, is the result of a breakdown in the homeostatic regulation of energy balance. Although, the specific factors influencing the disruption of energy balance and why these factors affect individuals differently are not completely understood, numerous studies have identified multiple contributors. Environmental components influence food acquisition, eating, and lifestyle habits. However, the variability in obesity-related outcomes observed among individuals placed in similar controlled environments supports the notion that genetic components also wield some control. Multiple genetic regions have been associated with measures related to energy balance; however, the replication of these genetic contributors to energy intake and energy expenditure in humans is relatively small perhaps because of the heterogeneity of human populations. Genetic tools such as genetic admixture account for individual's genetic background in gene association studies, reducing the confounding effect of population stratification, and promise to be a relevant tool on the identification of genetic contributions to energy balance, particularly among individuals of diverse racial/ethnic backgrounds. Although it has been recognized that genes are expressed according to environmental influences, the search toward the understanding of nature and nurture in obesity will require the detailed study of the effect of genes under diverse physiologic and behavioral environments. It is evident that more research is needed to elucidate the methodological and statistical issues that underlie the interactions between genes and environments in obesity and its related comorbidities.

Overview of Adipose Tissue and Its Role in Obesity and Metabolic Disorders

Article

Feb 2008
Meth Mol Biol

Gema Frühbeck

As the result of its apparent structural and histological simplicity, adipose tissue (AT) functions initially were limited to energy storage, insulation, and thermoregulation. Only decades later was the extraordinarily dynamic role of AT recognized, revealing its participation in a broad range of physiological processes, including reproduction, apoptosis, inflammation, angiogenesis, blood pressure, atherogenesis, coagulation, fibrinolysis, immunity and vascular homeostasis with either direct or indirect implications in the regulation of proliferation. The functional pleiotropism of AT relies on its ability to synthesize and, in some cases,secrete a large number of enzymes, hormones, growth factors, cytokines, complement factors, and matrix and membrane proteins, collectively termed adipokines. At the same time, white AT expresses receptors for most of these factors, warranting a wide cross-talk at both local and systemic levels in response to metabolic changes or other external stimuli. In this chapter, mounting evidence on the specific characteristics of AT from different depots is outlined in relation to fat distribution and comorbidity development. The current knowledge in this field is reviewed with a broad perspective ranging from classification, structure, and distribution to the key functional roles of AT with a particular focus on the role of adipokines and their involvement in the metabolic disorders accompanying obesity.

How strong is the association between abdominal obesity and the incidence of type 2 diabetes?

Article

Jun 2008
INT J CLIN PRACT

Quantitative evidence on the strength of the association between abdominal obesity and the incidence of type 2 diabetes was assessed. Systematic review of longitudinal studies assessing the relationship between measures reflecting abdominal obesity and the incidence of type 2 diabetes. There was a strong association between measures reflecting abdominal obesity and the incidence of type 2 diabetes, the pooled odds ratio was 2.14 (95% CI: 1.70-2.71; p < 0.0001). Waist circumference (WC) was at least as good as other measures in predicting outcome. There is a strong association between measures reflecting abdominal obesity and the development of type 2 diabetes. Reducing WC may reduce the risk of developing type 2 diabetes.

Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin in type 2 diabetes

Nauck MA
Frid A
Hermansen K
Nauck MA
Frid A
Hermansen K

Previous treatment: OHA monotherapy, n OHA combination

Jan 2008
91-15410

(54)/17 (55) 151 (62)/27 (77) 73 (60)/15 (75) 140 (57)/26 (70) 121 (49)/10 (50) 117 (47)/12 (52) 133 (54)/6 (33) Age, years 57 (9)/58 (9) 57 (9)/59 (8) 56 (11)/58 (10) 56 (9)/56 (10) 57 (9)/56 (9) 52 (11)/54 (9) 54 (11)/55 (11) 53 (11)/54 (13) Weight, kg 88 (16)/91 (15) 88 (19)/86 (15) 88 (17)/93 (12) 91 (17)/94 (16) 89 (17)/97 (12) 93 (21)/94 (14) 93 (19)/94 (15) 93 (19)/88 (14) Previous treatment: OHA monotherapy, n OHA combination, n 83 (34)/14 (38) 159 (66)/23 (62) 91 (38)/10 (32) 150 (62)/21 (68) 81 (34)/12 (34) 161 (67)/23 (66) 41 (34)/7 (35) 81 (66)/13 (65) 89 (37)/15 (41) 156 (64)/22 (60) 87 (35)/9 (45) 160 (65)/11 (55) 91 (36)/11 (48) 160 (64)/12 (52) 94 (38)/8 (44) 154 (62)/10 (56) Data are mean (s.d.) or n (%). OHA, oral hypoglycaemic agents References 1 Fernández JR, Casazza K, Divers J, L ´ opez-AlarcónAlarc´Alarcón M. Disruptions in energy balance: does nature overcome nurture? Physiol Behav 2008; 94: 105–112.

OA Liraglutide induces fat tissue loss

J Jendle

OA Liraglutide induces fat tissue loss J. Jendle et al.

Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monotherapy or added to metformin, is primarily as a result of a reduction in fat tissue

Abstract

No full-text available

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