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Nonalcoholic fatty liver disease (NAFLD) is a global epidemic, affecting more than half of the people living with type 2 diabetes (T2D). The relationship between NAFLD and T2D is bidirectional and the presence of one perpetuates the other, which significantly increases the hepatic as well as extrahepatic complications. Until recently, there was no approved pharmacological treatment for NAFLD/ nonalcoholic steatohepatitits (NASH). However, there is evidence that drugs used for diabetes may have beneficial effects on NAFLD. Insulin sensitizers acting through peroxisome proliferator-activated receptor (PPAR) modulation act on multiple levels of NAFLD pathogenesis. Pioglitazone (PPARγ agonist) and saroglitazar (PPARα/γ agonist) are particularly beneficial and recommended by several authoritative bodies for treating NAFLD in T2D, although data on biopsy-proven NASH are lacking with the latter. Initial data on elafibanor (PPAR α/δ agonist) and Lanifibranor (pan PPAR agonist) are promising. On the other hand, incretin therapies based on glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RA) and dual- and triple-hormone receptor co-agonists reported impressive weight loss and may have anti-inflammatory and antifibrotic properties. GLP-1 RAs have shown beneficial effects on NAFLD/NASH and more studies on potential direct effects on liver function by dual- and triple-agonists are required. Furthermore, the long-term safety of these therapies in NAFLD needs to be established. Collaborative efforts among healthcare providers such as primary care doctors, hepatologists, and endocrinologists are warranted for selecting patients for the best possible management of NAFLD in T2D.

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AIM: To compare the efficacy of tirzepatide 10 and 15 mg with semaglutide 2.4 mg using an indirect treatment comparison. MATERIALS AND METHODS: Using SURMOUNT-1 and STEP 1 trial data, mean percentage change in body weight from baseline and odds ratio (OR) of achieving 5% or greater weight loss were compared between tirzepatide 10 and 15 mg at week 72 and semaglutide 2.4 mg at week 68 using matching-adjusted indirect comparison of the efficacy estimand. Sensitivity analyses were completed using different methods, including the Bucher method, also using different estimands and/or time points. RESULTS: Greater reductions in percentage change in body weight were observed with tirzepatide 10 and 15 mg versus semaglutide 2.4 mg (tirzepatide 10 mg mean difference: -4.67% [95% CI -5.91%, -3.43%]; tirzepatide 15 mg mean difference: -5.92% [95% CI -7.16%, -4.68%]; both P < .001). Similarly, more participants achieved 5% or greater weight loss with tirzepatide 10 mg (OR 2.61 [95% CI 1.48, 4.57]; P < .001) and 15 mg (OR 2.75 [95% CI 1.57, 4.81]; P < .001) compared with semaglutide 2.4 mg. All sensitivity analyses were consistent, except for an OR of achieving 5% or greater weight loss with tirzepatide 10 mg using the Bucher method to analyse the treatment regimen estimand (P = .074). CONCLUSIONS: Currently there are no direct comparisons of tirzepatide and semaglutide for weight management. Using the matching-adjusted indirect treatment comparison method to compare the efficacy of tirzepatide and semaglutide for chronic weight management, this analysis showed greater weight loss with tirzepatide 10 and 15 mg versus semaglutide 2.4 mg.

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Glucagon-like peptide (GLP)-1 receptor agonists are the cornerstone in the treatment of hyperglycemia in many people suffering from type 2 diabetes (T2D). These drugs have potent glucose-lowering actions and, additionally, lower body weight through satiety induction while reducing blood pressure and dyslipidemia. Partly through these actions, GLP-1 receptor agonism was shown to reduce cardiovascular disease (CVD) in people with T2D with previous CVD or at high-risk thereof. In these cardiovascular safety trials, in secondary or exploratory analyses, GLP-1 receptor agonists were also shown to reduce macro-albuminuria, an accepted surrogate marker for diabetic kidney disease (DKD), a condition that still represents a major unmet medical need. In this review we will discuss the evidence which suggests renoprotection induced by GLP-1 receptor agonists and the potential mechanisms that may be involved. These include mitigation of hyperglycemia, overweight and insulin resistance, systemic and glomerular hypertension, dyslipidemia, sodium retention, inflammation and renal hypoxia. The recently initiated large-sized FLOW trial investigating the effects of semaglutide on hard renal outcomes in patients with DKD will provide clarity whether GLP-1 receptor agonists may reduce the burden of DKD in addition to their other beneficial metabolic and cardiovascular effects.

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BACKGROUND: To report the cardiovascular and renal effects of incretin-based therapies. METHODS: The studies of clinical trials on incretin-based therapy published in medical journals from the years 2010 to 2017 were comprehensively searched using MEDLINE and EMBASE with no language restriction. The studies were reviewed and the cardiovascular and renal risks reported were recorded. RESULTS: Incretin-based therapeutics represent novel and promising anti-diabetes drugs, the direct cardiovascular actions which may translate into demonstrable clinical benefits on cardiovascular outcomes. Furthermore, incretin-based therapies do not adversely affect renal function.

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As a new class of antidiabetic drug, incretin-based therapies, which include dipeptidyl peptidase-4 inhibitors (DPP-4Is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have raised concerns about symptoms of withdrawal in patients with type 2 diabetes mellitus (T2DM), such as dizziness and headache. To systematically evaluate whether incretin-based therapies may lead to dizziness and headache in patients with T2DM compared to other traditional antidiabetic drugs or placebo. We searched Medline, Embase, the Cochrane library, and clinicaltrials.gov from inception through June 23, 2017, to identify randomized controlled trials of the safety of DPP-4Is or GLP-1 RAs versus placebo or other antidiabetic drugs in T2DM patients. We used the network meta-analysis under the frequentist framework to compare the association between multiple antidiabetic drugs and dizziness and headache. A total of 233 clinical trials with nine treatments and 147,710 patients were included: two incretin-based therapies, one placebo, and six traditional antidiabetic drugs (metformin, insulin, sulfonylurea, thiazolidinediones, alpha-glucosidase inhibitor, and sodium-glucose co-transporter 2). Compared to insulin, thiazolidinediones, or placebo, GLP-1 RAs statistically significantly increased the risk of dizziness (odds ratios [ORs]: 1.92, 1.57, and 1.40, respectively) and headache (ORs: 1.34, 1.41, and 1.18, respectively). DPP-4Is increased the risk of headache (OR: 1.22, 95% confidence interval [CI]: 1.02 to 1.46; moderate quality) and dizziness (OR: 1.46, 95% CI: 1.05 to 2.03; moderate quality) compared to insulin. Of the incretin-based therapies, DPP-4Is had a lower risk of dizziness than GLP-1 RAs (OR: 0.76, 95% CI: 0.67 to 0.87; high quality). Ranking probability analysis indicated that GLP-1 RAs may have the greatest risk of both dizziness and headache among the nine treatments (22.5% and 23.4%, respectively), whereas DPP-4Is were in the middle (46.2% and 45.0%, respectively). Incretin-based therapies increase the risk of dizziness and headache compared to insulin, thiazolidinediones, and placebo.

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Diabetic kidney disease (DKD) remains the main cause for chronic kidney disease (CKD) and end-stage kidney disease (ESKD) worldwide. Both CKD and ESKD lead to major increases in risk of cardiovascular disease and death in people with diabetes. Despite optimal management of lifestyle, glucose levels and hypertension, residual risk remains high, indicating that additional therapies to mitigate the burden of the disease are desired. In past decades, new treatment options for the management of diabetes have emerged, of which some have showed promising renoprotective potential. This review discusses current understanding of the renal effects of glucagon-like peptide receptor agonists and their potential use in prevention and treatment of DKD.

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The advent of incretin mimetics such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) has enriched the armamentarium for diabetes management owing to their glycaemic as well as extra-glycaemic benefits. The approval status and availability of this class of drugs vary widely across the globe. Being a relatively newer class of drug with numerous benefits, several national and international guidelines are working towards addressing clinical questions pertaining to the optimal use of GLP-1 RAs for the management of diabetes. Although the newer class of drugs are associated with significant benefits such as patient-centric approach, these drugs demand the providers to be vigilant and knowledgeable about the medication. The South Asian population is at higher risk of type 2 diabetes mellitus (T2DM) because of their genetic predisposition and lifestyle changes. Hence, prevention and management of T2DM and its associated complications in this population are of paramount importance. The current report aims to present an overview of current knowledge on GLP-1 RAs based on pragmatic review of the available clinical evidence. In addition, this report is a consensus of expert endocrinologists representing South Asian countries including India, Pakistan, Bangladesh, Nepal, Sri Lanka, Afghanistan and the Maldives on essential recommendations related to the use of GLP-1 RAs in a real-world scenario.

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AIM: To evaluate the comparative effects of incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4Is), on ß-cell function and insulin resistance in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Medline, Embase, the Cochrane Library and www.clinicaltrials.gov were searched for randomized controlled trials (RCTs) with a duration of at least 4 weeks. Network meta-analysis was performed, followed by subgroup analysis and meta-regression. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to assess the quality of evidence. Outcomes of interest include homeostasis model assessment for ß cell function (HOMA-ß) and insulin resistance (HOMA-IR), fasting C-peptide and fasting plasma glucose (FPG). Weighted mean difference (WMD) with 95% confidence interval (CI) was calculated as the measure of effect size. RESULTS: A total of 360 RCTs (74% at least double-blinded) with 157 696 patients were included. Incretin-based therapies were compared with six other classes of glucose-lowering drugs or with placebo. Compared with placebo, a significant increase in HOMA-ß and fasting C-peptide was detected for GLP-1RAs (WMD = 20.31 [95% CI, 16.34-24.39] with low quality; WMD = 0.16 ng/mL [95% CI, 0.03-0.29] with low quality) and for DPP-4Is (WMD = 9.90 [95% CI, 8.27-11.61] with moderate quality; WMD = 0.09 ng/mL [95% CI, 0.04-0.14] with moderate quality) separately, while a significant reduction in HOMA-IR and FPG were found in favour of GLP-1RAs (WMD = -0.67 [95% CI, -1.08 to -0.27] with low quality; WMD = -1.04 mmol/L [95% CI, -1.26 to -0.83] with moderate quality) and DPP-4Is (WMD = -0.23 [95% CI, -0.38 to -0.08] with low quality; WMD = -0.77 mmol/L [95% CI, -0.98 to -0.57] with moderate quality), respectively. CONCLUSIONS: Incretin-based therapies not only show an increase in HOMA-ß and fasting C-peptide level, but also achieve a reduction in HOMA-IR and FPG in comparison with placebo. Although GRADE scores indicate low to moderate for most comparisons, incretin-based therapies seem to be an advisable option for long-term treatment to preserve ß-cell function.

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OBJECTIVE: To evaluate the comparative cardiovascular safety of incretin-based therapies in patients with type 2 diabetes mellitus (T2DM). METHODS: Medline, Embase, the Cochrane Library and www.clinicaltrials.gov were searched for randomized controlled trials (RCTs) with duration≥12 weeks. Network meta-analysis was performed, followed by subgroup analysis and meta-regression. The Grading of Recommendations Assessment, Development and Evaluation system was used to assess the quality of evidence. The outcome of interest was a composite of cardiovascular death, myocardial infarction, stroke and heart failure. Odds ratio (OR) with 95% confidence interval (CI) was calculated as the measure of effect size. RESULTS: 281 RCTs (76.9% double-blinded) with 180,000 patients were included, comparing incretin-based therapies with other six classes of anti-diabetic drugs or placebo. A statistically significant reduction in the risk of cardiovascular events was found in favour of GLP-1RAs when compared with placebo (OR 0.89, 95%CI: 0.80-0.99) and sulfonylurea (OR 0.76, 95%CI: 0.59-0.99), whereas DPP-4 inhibitors showed a neutral effect compared with placebo (OR 0.92, 95%CI: 0.83-1.01). CONCLUSIONS: Incretin-based therapies show similar cardiovascular risk in comparison with metformin, insulin, thiazolidinediones, alpha-glucosidase inhibitor and sodium-glucose co-transporter 2. GLP-1RA could decrease the risk compared with sulfonylurea or placebo, while DPP-4I appears to have neutral effect on cardiovascular risk.

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BACKGROUND: Early reperfusion of the blocked vessel is critical to restore the blood flow to the ischemic myocardium to salvage myocardial tissue and improve clinical outcome. This reperfusion strategy after a period of ischemia, however, may elicit further myocardial damage named myocardial reperfusion injury. The manifestations of reperfusion injury include arrhythmias, myocardial stunning and micro-vascular dysfunction, in addition to significant cardiomyocyte death. It is suggested that an overproduction of reactive oxygen species, intracellular calcium overload and inflammatory cell infiltration are the most important features of myocardial ischemia-reperfusion injury. OBJECTIVE: In this review, various pharmacological interventions to treat myocardial reperfusion injury including the antioxidant flavonols, hydrogen sulfide, adenosine, opioids, incretin-based therapies and cyclosporin A which targets the mitochondrial permeability transition pore are discussed. CONCLUSION: The processes involved in reperfusion injury might provide targets for improved outcomes after myocardial infarction but thus far that aim has not been met in the clinic.

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There is a relative lack of long-term data for individual glucose-lowering therapies for the treatment of type 2 diabetes mellitus. A systematic search of published literature reporting data of approximately ≥3 years of follow-up from randomized controlled trials and their extensions was conducted. Trials to evaluate the efficacy and/or safety of glucose-lowering drugs currently approved for the treatment of adults with type 2 diabetes were included. Search results included long-term published data for traditional oral glucose-lowering drugs, insulin, α-glucosidase inhibitors, and incretin-based therapies. In general, results indicated that the short-term risk/benefit profile of these therapies is in line with longer-term evaluations. Individual results from these trials are reviewed in this report. These findings support the use of approved drug classes for longer-term treatment of type 2 diabetes.

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BACKGROUND: Pancreatic safety remains a concern for diabetic patients using incretin-based medications. We aimed to determine if there was an association between incretin-based therapy and an increased risk for acute pancreatitis and pancreatic cancer in patients with type 2 diabetes mellitus (DM). METHODS: This retrospective population-based cohort study analyzed data from the Taiwan National Health Insurance Research Database. A total of 13 171 eligible type 2 DM patients who had received incretin-based treatment for a minimum of two months were matched 1:1 for age, gender, diabetes complications severity index, and inception date with DM patients who never used this pharmacotherapy. The cohorts were compared for occurrence of acute pancreatitis and pancreatic cancer. The association between incretin-based therapy and acute pancreatitis was assessed using a Cox proportional hazard model and stratified analyses. RESULTS: Acute pancreatitis occurred in 71 (0.54%) incretin users and 66 (0.50%) non-users, respectively (P = 0.67). The association remained insignificant (adjusted hazard ratio [HR], 1.06; 95% confidence interval [CI] = 0.72-1.55) after adjustment for cholelithiasis (adjusted HR, 2.76; 95% CI = 1.32-5.75) and alcohol-related disease (adjusted HR 9.14, 95% CI = 2.08-40.14) in the Cox model. Stratified analyses affirmed no association between incretin-based therapy and pancreatitis in any subgroup. Pancreatic cancer occurred in 6 (0.05%) and 10 (0.08%) patients in the user and non-user cohort, respectively (P = 0.32). CONCLUSION: Incretin-based therapy is not associated with acute pancreatitis and short-term pancreatic cancer risk among ethnic Chinese patients with diabetes. This study supports the pancreatic safety of incretin-based pharmacotherapy.

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We aimed to investigate the association between incretin-based therapies and 1-year change in depressive symptoms in a cohort of 1735 patients with newly diagnosed type 2 diabetes. The incretin group experienced significant reduction in depressive symptoms compared to controls. This was independent of HbA1c and may be mediated by an anti-inflammatory mechanism.

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Incretin-based therapies have revolutionized the medical management of type 2 diabetes mellitus (T2DM) in the 21(st) century. Glucagon-like peptide-1 (GLP-1) suppresses appetite and gastric motility, and has trophic effects on pancreas, cardio-protective and renal effects. GLP-1 analogues and dipeptidyl peptidase-4 inhibitors form the incretin-based therapies. Significant reduction of hemoglobin A1c when used as monotherapy and in combination regimens, favorable effects on body weight, and low risk of hypoglycemia are their unique therapeutic benefits. Their safety and tolerability are comparable to other anti-diabetic medications. Concern about elevated risk of pancreatitis has been discarded by two recent meta-analyses. This article discusses the therapeutic manipulation of incretin system for the management of T2DM.

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Dipeptidyl-peptidase-IV (DPP-4) inhibitors are oral antidiabetic agents that can be administered as monotherapy in patients with contraindications to metformin or metformin intolerance, and in combination with other oral compounds and/or insulin. DPP-4 inhibitors act in a glucose-dependent manner and only increase insulin secretion and inhibit glucagon secretion under hyperglycemic conditions. Renal impairment is frequent in type 2 diabetes as a result of microvascular complications and diabetes treatment, and options in these patients are limited. Linagliptin is a DPP-4 inhibitor with a hepatobiliary route of elimination. In comparative studies, it was noninferior to metformin and sulfonylureas in lowering glycated hemoglobin (HbA1c) and improving glycemic parameters. It can be used throughout all stages of renal impairment without dose adjustments. This review gives an overview of linagliptin in various stages of chronic kidney disease and has a focus on efficacy and safety parameters from clinical studies in patients with impaired renal function. These data are interpreted in the context of type 2 diabetes therapy in general.

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AIM: To investigate the real-world incidence of acute pancreatitis (AP) associated with incretin-based therapy (IBT). METHODS: We carried out a systematic review and meta-analysis of observational studies using Medline, PubMed, Embase, the Cochrane Database, ClinicalTrials.gov and conference proceedings. We included: those studies in which AP was a pre-defined clinical outcome; longitudinal studies (case-control, cohort); studies that adjusted for confounders; studies that reported on a population exposed to IBT; studies in which non-IBT users or past users (who received IBTs >90 days before the index date) were used as the control group; studies that reported risk estimates [relative risks, odds ratios (ORs) or hazard ratios] with 95% confidence intervals (CIs) for AP event with IBT use, or that reported sufficient data to estimate these; and publications in the English language. Data were extracted by two independent investigators, and a consensus was reached with involvement of a third. Study-specific ORs from seven cohort studies and two case-control studies were meta-analysed using random-effects models. Associations were tested in subgroups representing different patient characteristics and study quality. RESULTS: A total of nine studies that included 1,324,515 patients and 5195 cases of AP were included in our meta-analysis. The summary estimate of OR for an association between IBT and AP was 1.03 (95% CI 0.87-1.20). CONCLUSIONS: The present meta-analysis of real-world data does not suggest that IBT is associated with AP. Although we should continue to remain vigilant, IBTs should be regarded as reasonable options to consider adding to the regimen of a patient with type 2 diabetes.

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The most commonly used oral drug in treating type 2 diabetes (T2DM) after metformin are sufonylureas (SUs) based on the confidence gained over the several decades and because of its cheaper cost. Unfortunately, SUs are associated with secondary failure and sometimes associated with therapy related severe hypoglycaemia limiting its compliance and wider utility in current clinical practice. Although large randomised trials could not associate SUs with any obvious increase in cardiovascular (CV) mortality, some recent larger databases showing divergent results suggesting increasingly CV signals and this might put SUs in difficulty given the availability of other safer alternatives. In recent years, incretin-based therapies like dipeptidyl peptidase-4 inhibitors (DPP-4I) and glucagon-like peptide-1 (GLP-1) agonist (GLP-1A) are gaining popularity primarily because of their advantage of weight reduction/neutrality and minimal hypoglycemia along with the perception of possible pleiotropic CV benefit mainly derived from pooled CV data of their trials. Sodium glucose transporter 2 inhibitors (SGLT-2I) are another new promising molecule currently looking for its space in the management of T2DM. Insulin could be utilized at any place when required and in this regard outcomes reduction with an initial glargine intervention (ORIGIN) study also suggested that basal insulin glargine could be safely used even in early stage. This review will discuss what could be possibly be the best option as a second line oral agent, once metformin monotherapy becomes ineffective.

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The biguanide, metformin, is considered first-line treatment for type 2 diabetes. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor acts through the incretin pathway and has a glucose dependent mode of action. The complementary hypoglycemic properties of these drugs make fixed dose combination treatment an attractive prospect. Evidence from recent clinical trials suggests a beneficial effect of the combination on efficacy, demonstrated by significant improvement of hemoglobin A1c (HbA1c), fasting and postprandial glucose levels. The fixed dose combination is likely to have greater patient tolerability compared with monotherapy with either agent because of low rates of hypoglycemia, weight neutrality, and lower rates of side effects. High acquisition cost and paucity of long-term safety data are, however, potential barriers to their wider use. An overview of the pharmacology and clinical outcomes from recent trials of the metformin-sitagliptin combination and how the combination could fit into the type 2 diabetes treatment algorithm is presented in this review.

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Glucagon-like peptide-1 (GLP-1) is one of the hormones responsible for the incretin effect, a term that refers to the observation that orally administered glucose results in a larger increase in plasma insulin levels and insulin-dependent decrease in blood glucose concentration when compared to the same amount of glucose given intravenously. GLP-1 is secreted mainly by gut endocrine L-cells and is released under the control of carbohydrates, proteins and lipids. Upon secretion, GLP-1 targets different cell types and exerts a wide variety of actions such as potentiation of glucose-stimulated insulin secretion, reduction of appetite, delay of gastric emptying and increase in ß-cell mass. These beneficial effects have resulted in the application of GLP-1-based therapies in patients with type 2 diabetes, but also exploitation of its effects in type 1 diabetes is being envisaged. In this review, we focus on the different, short- and long-term action mechanisms of GLP-1 with specific emphasis on its role as a modulator of ß-cell function and survival.

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Dipeptidyl-peptidase-IV (DPP-4) inhibitors have become an important orally active drug class for the treatment of type 2 diabetes as second-line therapy after metformin failure or as monotherapy or combination therapy with other drugs when metformin is not tolerated or contraindicated. DPP-4 inhibitors act mainly by increasing endogenous incretin hormone concentrations. They stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner with a significantly lower risk for hypoglycaemia than sulfonylureas. Furthermore, DPP-4 inhibitors are weight neutral. Linagliptin is a DPP-4 inhibitor that is eliminated by a hepatobiliary route, whereas the other DPP-4 inhibitors available today show a renal elimination. Therefore, it can be used in normal kidney function as well as in all stages of chronic kidney disease to stage 5 (glomerular filtration rate <15 ml/min/1.73 m(2)) without dose adjustments. Linagliptin was noninferior to metformin and sulfonylureas in clinical studies. In recent studies, it showed a superior safety profile over sulfonylurea treatment regarding hypoglycaemia and weight gain. More patients reached an HbA1c <7% without hypoglycaemia and weight gain with linagliptin compared with glimepiride. The safety profile with respect to a composite cardiovascular endpoint and stroke was also favourable for linagliptin, most likely due to a higher incidence of hypoglycaemia associated with glimepiride therapy and titration. This review gives an overview on the efficacy and safety of linagliptin in comparison with other antidiabetic drugs in type 2 diabetes patients with renal and cardiovascular risk factors as well as an outlook on the perspective for linagliptin in this patient population in the future.