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A review of glucagon-like peptide-1 receptor agonists and their effects on lowering postprandial plasma glucose and cardiovascular outcomes in the treatment of type 2 diabetes mellitus.

ABSTRACT: Type 2 diabetes mellitus (T2DM) is an independent risk factor for cardiovascular (CV) comorbidities, with CV disease being the most common cause of death in adults with T2DM. Although glucocentric therapies may improve glycaemic control (as determined by glycated haemoglobin levels), evidence suggests that this approach alone has limited beneficial effects on CV outcomes relative to improvements in lipid and blood pressure control. This may be explained in part by the fact that current antidiabetic treatment regimens primarily address overall glycaemia and/or fasting plasma glucose, but not the postprandial plasma glucose (PPG) excursions that have a fundamental causative role in increasing CV risk. This literature review evaluates the relationship between PPG and the risk of CV disease, discusses the treatment of T2DM with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and examines the associated CV outcomes. The literature analysis suggests that exaggerated PPG excursions are a risk factor for CV disease because of their adverse pathophysiologic effects on the vasculature, resulting in increased all-cause and CV-related mortality. Although GLP-1 RAs are well established in the current T2DM treatment paradigm, a subgroup of these compounds has a particularly pronounced, persistent and short-lived effect on gastric emptying and, hence, lower PPG substantially. However, current long-term data on CV outcomes with GLP-1 RAs are contradictory, with both beneficial and adverse effects having been reported. This review explores the opportunity to direct treatment towards controlling PPG excursions, thereby improving not only overall glycaemic control but also CV outcomes.

SUBMITTER: Owens DR

PROVIDER: S-EPMC5697665 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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A review of glucagon-like peptide-1 receptor agonists and their effects on lowering postprandial plasma glucose and cardiovascular outcomes in the treatment of type 2 diabetes mellitus.

Owens David R DR Monnier Louis L Hanefeld Markolf M

Diabetes, obesity & metabolism 20170711 12

Type 2 diabetes mellitus (T2DM) is an independent risk factor for cardiovascular (CV) comorbidities, with CV disease being the most common cause of death in adults with T2DM. Although glucocentric therapies may improve glycaemic control (as determined by glycated haemoglobin levels), evidence suggests that this approach alone has limited beneficial effects on CV outcomes relative to improvements in lipid and blood pressure control. This may be explained in part by the fact that current antidiabe ...[more]

PMID: 28474401

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Project description:Glucagon-like Peptide-1 Receptor Agonists (GLP-1RAs) have demonstrated efficacy in improving mortality and cardiovascular (CV) outcomes. However, the impact of GLP-1RAs therapy on cardiorenal outcomes of diabetic patients at the commencement of dialysis remains unexplored. This study aimed to investigate the long-term benefits of GLP-1RAs in type 2 diabetic patients at dialysis commencement. A cohort of type 2 diabetic patients initializing dialysis was identified from the TriNetX global database. Patients treated with GLP-1RAs and those treated with long-acting insulin (LAI) were matched by propensity score. We focused on all-cause mortality, four-point major adverse cardiovascular events (4p-MACE), and major adverse kidney events (MAKE). Among 82,041 type 2 diabetic patients initializing dialysis, 2.1% (n = 1685) patients were GLP-1RAs users (mean ages 59.3 years; 55.4% male). 1682 patients were included in the propensity-matched group, treated either with GLP-1RAs or LAI. The main causes of acute dialysis in this study were ischemic heart disease (17.2%), followed by heart failure (13.6%) and sepsis (6.5%). Following a median follow-up of 1.4 years, GLP-1RAs uses at dialysis commencement was associated with a reduced risk of mortality (hazard ratio [HR] = 0.63, p < 0.001), 4p-MACE (HR = 0.65, p < 0.001), and MAKE (HR = 0.75, p < 0.001). This association was particularly notable in long-acting GLP-1RAs users, with higher BMI, lower HbA1c, and those with eGFR > 15 ml/min/1.73m2. GLP-1RAs' new use at dialysis commencement was significantly associated with a lower risk of MACE (p = 0.047) and MAKE (p = 0.004). Additionally, GLP-1RAs use among those who could discontinue from acute dialysis or long-term RAs users was associated with a lower risk of mortality, 4p-MACE, and MAKE. Given to the limitations of this observational study, use of GLP-1RAs at the onset of dialysis was associated with a decreased risk of MACE, MAKE, and all-cause mortality. These findings show the lack of harm associated with the use of GLP-1RAs in diabetic patients at the initiation of acute dialysis.

Project description:IntroductionThis study aimed to investigate the generalizability of the results of cardiovascular outcome trials (CVOTs) of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) to Chinese patients with type 2 diabetes mellitus (T2DM).MethodsThe 3B (Blood Glucose, Blood Pressure, and Blood Lipid) population, a nationally representative population of patients with T2DM in China (n = 25,411), was examined for eligibility of enrollment in four GLP-1 RAs CVOTs (Dulaglutide-REWIND, Exenatide-EXSCEL, Liraglutide-LEADER, and Semaglutide-SUSTAIN-6). We first estimated the proportion of 3B population who would meet the six inclusion and exclusion (I/E) criteria, namely age, hemoglobin A1c (HbA1c), body mass index (BMI), estimated glomerular filtration rate (eGFR), history of cardiovascular disease (CVD), and antidiabetic medication, in each CVOT. Then we compared 11 baseline characteristics, namely age, gender, duration of diabetes, HbA1c, BMI, eGFR, history of CVD, prior myocardial infarction (MI), low-density lipoprotein cholesterol (LDL-c), diastolic blood pressure (DBP), and systolic blood pressure, between the population in each CVOT and the 3B population. Lastly, we estimated the proportion of 3B population that matched the characteristics in each CVOT population.ResultsOn the basis of the I/E criteria, 31.1% of the 3B population would have been eligible for enrollment in REWIND, 15.0% for SUSTAIN-6, 12.9% for LEADER, and 11.3% for EXSCEL. On the basis of the baseline characteristics, REWIND most closely matched the 3B population on gender, duration of diabetes, HbA1c, DBP, LDL-c, history of CVD, and prior MI. The proportion of 3B population matching on at least eight or at least ten baseline characteristics with CVOT populations was highest for REWIND compared to other CVOTs.ConclusionAmong the four GLP-1 RA CVOTs, the REWIND trial using once-weekly dulaglutide is most generalizable to Chinese patients with T2DM.Trial registrationTrial registration: NCT01128205 ( www.clinicaltrials.gov ).

Project description:Due to their cardiovascular protective effect, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) represent breakthrough therapies for type 2 diabetes mellitus (T2DM). In this review article, we discuss the mechanistic and clinical synergies that make the combined use of GLP-1RAs and SGLT2is appealing in patients with T2DM. Overall, the presented cumulative evidence supports the benefits of GLP-1RA plus SGLT2i combination therapy on metabolic-cardiovascular-renal disease in patients with T2DM, with a low hypoglycemia risk. Accordingly, we encourage the adoption of GLP-1RA plus SGLT2i combination therapy in patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD (i.e., age ≥ 55 years, overweight/obesity, dyslipidemia, hypertension, current tobacco use, left ventricular hypertrophy, and/or proteinuria). Regarding renal effects, the evidence of SGLT2is in preventing kidney failure is more abundant than for GLP-1RAs, which showed a beneficial effect on albuminuria but not on hard kidney endpoints. Hence, in case of persistent albuminuria and/or uncontrolled metabolic risks (i.e., inadequate glycemic control, hypertension, overweight/obesity) on SGLT2i therapy, GLP-1RAs should be considered as the preferential add-on therapy in T2DM patients with chronic kidney disease. Despite the potential clinical benefits of GLP-1RA plus SGLT2i combination therapy in patients with T2DM, several factors may delay this combination to become a common practice soon, such as reimbursement and costs associated with polypharmacy. Altogether, when administering GLP-1RA plus SGLT2i combination therapy, it is important to adopt an individualized approach to therapy taking into account individual preferences, costs and coverage, toxicity profile, consideration of kidney function and glucose-lowering efficacy, desire for weight loss, and comorbidities.

Project description:BackgroundThe cardiovascular outcome trials (CVOTs) have shown that glucagon like peptide-1 receptor agonists (GLP1RAs) have varying degrees of cardiovascular (CV) safety in patients with type 2 diabetes mellitus (T2DM.) The lack of any head-to-head comparative trials among GLP1RAs urged the need for an indirect comparison of these agents. Therefore, this study was conducted to indirectly compare the CV safety and mortality effects among different GLP1RAs in patients with T2DM using network meta-analysis (NMA).MethodsMedline was searched to identify GLP1RA CVOTs to date. The outcomes of interest were CV death, myocardial infarction (IM), stroke, and death from any cause. An NMA with binomial likelihood logit link model was used for the binary outcomes. We conducted both fixed effects and random effects models for each outcome, and selected the best model based on the deviance information and the average posterior residual deviance. This NMA was reported in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA-NMA).ResultsA total of seven GLP1RA CVOTs were included having 56,004 patients. The NMA results showed that oral semaglutide was statistically better than exenatide (OR 0.47, 95% CI 0.21-0.99), dulaglutide (OR 0.46, 95% CI 0.20-0.97), albiglutide (OR 0.45, 95% CI 0.19-0.97), lixisenatide (OR 0.43, 95% CI 0.19-0.92) in reducing CV death events. No significant differences were detected between most of the treatments regarding reducing death from any cause, MI and stroke events. The ranking results showed that oral semaglutide had the highest probability to be ranked first (>?90%) in reducing CV death and death from any cause. Moreover, once weekly semaglutide had the highest probability to be ranked first in reducing MI and stroke events.ConclusionThe GLP1RAs have shown significant benefits in terms of CV safety. The indirect comparison and ranking probability results have shown that one weekly semaglutide and oral semaglutide seems to be the preferred option in patients with T2DM and established or at high risk of CVD. This result can aid health care providers, pharmacy and therapeutics committees in hospitals, and insurance companies when deciding which GLP1RA to start or add to their formulary.

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A review of glucagon-like peptide-1 receptor agonists and their effects on lowering postprandial plasma glucose and cardiovascular outcomes in the treatment of type 2 diabetes mellitus.

Publications

A review of glucagon-like peptide-1 receptor agonists and their effects on lowering postprandial plasma glucose and cardiovascular outcomes in the treatment of type 2 diabetes mellitus.

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