Efficacy and safety of high-dose glucagon-like peptide-1, glucagon-like peptide-1/glucose-dependent insulinotropic peptide,and glucagon-like peptide-1/glucagon receptor agonists in type 2 diabetes

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become agents of choice for people with type 2 diabetes (T2D) with established cardiovascular disease or in high-risk individuals. With currently available GLP-1 RAs, 51%-79% of subjects achieve an HbA1c target of less than 7.0% and 4%-27% lose 10% of body weight, illustrating the need for more potent agents. Three databases (PubMed, Cochrane, Web of Science) were searched using the MESH terms ‘glucagon-like peptide-1 receptor agonist’, ‘glucagon receptor agonist’, ‘glucose-dependent insulinotropic peptide’, ‘dual or co-agonist’, and ‘tirzepatide’. Quality of papers was scored using PRISMA guidelines. Risk of bias was evaluated using the Cochrane assessment tool. An HbA1c target of less than 7.0% was attained by up to 80% with high-dose GLP-1 RAs and up to 97% with tirzepatide, with even up to 62% of people with T2D reaching an HbA1c of less than 5.7%. A body weight loss of 10% or greater was obtained by up to 50% and up to 69% with high-dose GLP-1 RAs or tirzepatide, respectively. The glucose- and weight-lowering effects of the GLP-1/glucagon RA cotadutide equal those of liraglutide 1.8 mg. Gastrointestinal side effects of high-dose GLP-1 RAs and co-agonists occurred in 30%-70% of patients, mostly arising within the first 2 weeks of the first dose, being mild or moderate in severity, and transient. The development of high-dose GLP-1 RAs and the dual GLP-1/glucose-dependent insulinotropic peptide RA tirzepatide resulted in increasing numbers of people reaching HbA1c and body weight targets, with up to 62% attaining normoglycaemia with 15-mg tirzepatide. Whether this will also translate to better cardiovascular outcomes and affect treatment guidelines remains to be studied.     

All-cause mortality and cardiovascular outcomes with sodium-glucose Co-transporter 2 inhibitors,glucagon-like peptide-1 receptor agonists and with combination therapy in people with type 2 diabetes

Aim

To assess the relationship of sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor analogues (GLP-1RA) and their combination (SGLT2i + GLP-1RA) with 5-year risk of all-cause mortality, hospitalization and cardiovascular/macrovascular disease in people with type 2 diabetes.

Materials and Methods

Retrospective cohort analysis of 2.2 million people with type 2 diabetes receiving insulin across 85 health care organizations using a global federated health research network. Three intervention cohorts (SGLT2i, GLP-1RA and SGLT2i + GLP-1RA) were compared against a control cohort (no SGLT2i/GLP-1RA). Propensity score matching for age, ischaemic heart disease, sex, hypertension, chronic kidney disease, heart failure and glycated haemoglobin was used to balance cohorts 1:1 (SGLT2i, n = 143 600; GLP-1RA, n = 186 841; SGLT-2i + GLP-1RA, n = 108 504). A sub-analysis comparing combination and monotherapy cohorts was also performed.

Results

The intervention cohorts showed a reduced hazard ratio (HR, 95% confidence interval) over 5 years compared with the control cohort for all-cause mortality (SGLT2i 0.49, 0.48-0.50; GLP-1RA 0.47, 0.46-0.48; combination 0.25, 0.24-0.26), hospitalization (0.73, 0.72-0.74; 0.69, 0.68-0.69; 0.60, 0.59-0.61) and acute myocardial infarct (0.75, 0.72-0.78; 0.70, 0.68-0.73; 0.63, 0.60-0.66), respectively. All other outcomes showed a significant risk reduction in favour of the intervention cohorts. The sub-analysis showed a significant risk reduction in all-cause mortality for combination therapy versus SGLT2i (0.53, 0.50-0.55) and GLP-1RA (0.56, 0.54-0.59).

Conclusions

SGLT2i, GLP-1RAs or combination therapy confers mortality and cardiovascular protection in people with type 2 diabetes over 5 years. Combination therapy was associated with the greatest risk reduction in all-cause mortality versus a propensity matched control cohort. In addition, combination therapy offers a reduction in 5-year all-cause mortality when compared directly against either monotherapy.     

Cardiovascular and mortality outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: A meta-analysis with the FREEDOM cardiovascular outcomes trial

Background and aimsFREEDOM, a cardiovascular outcome trial with a GLP-1 receptor agonist, testing a continuous subcutaneous infusion of exenatide (ITCA 650), recently reported its findings.MethodsWe meta-analysed its results with eight prior GLP-1 receptor agonists trials.ResultsGLP-1 receptor agonists reduced MACE by 13% (HR 0.87 [95% CI 0.81–0.94]; p = 0.00065) and all-cause mortality by 11% (HR 0.89 [0.83–0.95]; p = 0.00084). However, FREEDOM results appear dissimilar to prior GLP-1 receptor agonist trials.ConclusionFREEDOM results should not influence current considerations about the benefits or harms of approved formulations of GLP-1 receptor agonists. There is also an ongoing debate about the safety of ITCA 650.     

Severe acute renal failure in patients treated with glucagon-like peptide-1 receptor agonists

We report two patients with diabetes in whom acute renal failure requiring hemodialysis occurred while on treatment with glucagon-like peptide-1 receptor agonists. We discuss the mechanisms of this complication and the potential for its prevention.     

Effects of glucagon-like peptide-1 receptor agonists on major coronary events in patients with type 2 diabetes

Aims

To perform a meta-analysis to assess the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on major coronary events, including myocardial infarction (MI), unstable angina and coronary revascularization, in patients with type 2 diabetes mellitus (T2DM).

Materials and methods

We systematically searched the PubMed, CENTRAL, EMBASE and clinicaltrial.gov databases to seek eligible studies with a cardiovascular endpoint comparing GLP-1RAs with a placebo in T2DM patients. Odds ratio (ORs) and 95% confidence intervals (CIs) were calculated for the outcomes.

Results

Nine studies, with a total of 64 236 patients, were included. GLP-1RA treatment reduced fatal and nonfatal MI by 8% (OR 0.92, 95% CI 0.86–0.99; P = 0.02, I² = 39%). The reduction reached 15% in human-based GLP-1RA-treated patients. Similarly, once-weekly GLP-1RA treatment reduced the risk of MI by 13%. In contrast, GLP-1RA treatment did not reduce the risk of hospitalization for unstable angina (OR 1.11, 95% CI 0.97–1.28; P = 0.13, I² = 21%). GLP-1RAs exhibited a tendency to lower the risk of coronary revascularization (OR 0.95, 95% CI 0.89–1.02; P = 0.15, I² = 22%), but without statistical significance. Human-based GLP-1RAs decreased the risk by 11%.

Conclusions

In high-risk patients with T2DM, GLP-1RAs were associated with a decrease in MI, especially the human-based and once-weekly GLP-1RAs. No benefit was seen for hospitalization for unstable angina or coronary revascularization. Further research is urgently needed to ascertain improvements in coronary events.     

Cardioprotective properties of glucagon-like peptide-1 receptor agonists in type 2 diabetes mellitus patients: A systematic review

Background and aimsCardiovascular disease is one of the main contributors for the mortality in type 2 diabetes mellitus (T2DM) patients. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) had shown cardiovascular benefits which may be advantageous to reduce mortality in T2DM patients. This systematic review focused on analyzing the effects of GLP-1 RAs on cardiovascular outcomes.MethodsWe conducted an extensive search through JSTOR, PubMed, Scopus, EBSCohost, and CENTRAL. All related studies assessing the use of GLP-1 RAs in T2DM patients from inception up to October 2020 were screened. Any cardioprotective properties as the outcomes were obtained.ResultsA total of six studies (4 randomized, 2 observational) with a total of 182.205 patients were included in this review. The GLP-1 RAs used were either liraglutide or exenatide in combination with antihypertensive or antilipidemic drugs. All studies showed that GLP-1 RA significantly caused weight loss and improved cardiac functional capacity by increasing left ventricular ejection fraction and reducing end-systolic and end-diastolic left ventricle volume. GLP-1 RA also improved myocardial blood flow without affecting myocardial glucose uptake. However, GLP-1 RA failed to show its effect in reducing blood pressure and improving lipid profiles.ConclusionsDespite the limited number of studies, consistent data showed that GLP-1 RA has several cardioprotective properties.     

Determinants of response to the glucagon-like peptide-1 receptor agonists in a type 2 diabetes population in the real-world

AimsTo identify clinical predictors associated with a response in terms of glycemic control and weight loss in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs).MethodsA retrospective observational study was performed with real-world databases in primary care. Patients with type 2 diabetes-initiated treatment with GLP-1RAs during the study period, and response to GLP-1RAs were determined six months from treatment initiation. An optimal glycated hemoglobin (HbA1c) or weight response was defined as a reduction of ≥ 1% or ≥ 3%, respectively. A “great” response was defined as both an optimal HbA1c and weight response. Bivariate and multivariate analyses with intention-to-treat were performed.ResultsA sample of 2944 patients with type 2 diabetes was recruited. Higher HbA1c at baseline was the main clinical predictor of an optimal HbA1c response (odds ratio [OR]: 2.30, 95% confidence interval [CI]: 1.96–2.71 in men and OR: 2.03, 95% CI: 1.76–2.33 in women). Treatment without insulin at baseline was associated with a greater weight reduction in men (OR: 2.50, 95% CI: 1.41–4.44). Older age and a higher weight at baseline were related with this in women (OR: 1.02, 95% CI: 1.00–1.05 and OR: 1.01, 95% CI: 1.00–1.02, respectively).ConclusionsA high HbA1c at baseline and previous non-insulin therapy were the main predictors of a greater response (optimal HbA1c and weight response) to GLP1ra in both men and women. This may aid in treatment decision-making before initiating treatment with GLP-1RAs.     

Efficacy and adherence of glucagon-like peptide-1 receptor agonist treatment in patients with type 2 diabetes mellitus in real-life settings

Despite the availability of a large number of therapeutic options throughout the world, rates of optimal glycaemic control in adult patients with type 2 diabetes mellitus remain low. Delays in treatment intensification to insulin and low adherence to insulin regimes, which are well-documented contributors to poor glycaemic control, are in many cases driven by fear of hypoglycaemic events, weight gain and injections. Over the last 10 years, injectable glucagon-like peptide-1 receptor agonists (GLP1-RAs) have emerged as alternatives to basal insulin for treatment intensification in patients inadequately controlled with oral antidiabetic drugs. As a class, GLP1-RAs are associated with weight loss and fewer hypoglycaemic events than insulin. In addition, some of them are available in once-a-week formulations and therefore require fewer injections. However, as randomized controlled trials are not representative of everyday practice, physicians should consider the results of real-life studies to guide their treatment decisions. In this review, while significant variations in efficacy, tolerability and adherence data were noted from one study to another, rates of glycaemic control overall were low. Indeed, our present analysis has suggested that regular re-evaluations of treatment, including response, tolerability, adherence, cost and quality of life, are necessary.     

Heart failure outcomes and glucagon-like peptide-1 receptor agonists: A systematic review of observational studies

Aim/objectiveRecently, the glucagon-like peptide-1 receptor agonists (GLP-1RA) class showed a significant reduction in heart failure (HF) hospitalization in several meta-analyses of cardiovascular outcome trials (CVOTs). The objective of this systematic review is to summarize the real-world evidence regarding HF outcomes of GLP-1RAs.MethodsWe searched the PubMed and EMBASE databases for observational studies that investigated HF outcomes of GLP-1RAs.ResultsOur search yielded 10 observational studies. Of those, 7 were cohort studies, and 3 were nested case-control studies. The risk of HF was the outcome in four cohort studies. One study that compared exenatide and exenatide combined with insulin to insulin showed a reduction in HF risk in the exenatide and exenatide plus insulin groups (HR 0.34, 95% CI 0.22−0.52, p-value <0.001 and HR 0.40, 95% CI 0.32−0.50, p-value <0.001, respectively). The other three cohort studies did not show a statistically significant result. In the three cohort studies that investigated HF hospitalization as an outcome, two showed a lower rate of HF hospitalization [48 (16.7%) vs. 76 (28%), p-value <0.05 and HR 0.51, 95% CI 0.34−0.77, p = 0.002] in the GLP-1RA groups. Conversely, the remaining study showed a reduction of 14% in HF hospitalization in the dipeptidyl peptidase-4 inhibitors (DPP-4i) group compared to the GLP-1RA group (HR 0.86, 95% CI 0.83−0.90). In contrast to the cohort studies, the three nested case-control studies showed similar results of no association of GLP-1RA use and HF hospitalization with OR 0.67 (95% CI 0.32–1.42), HR 0.95 (95% CI 0.83–1.10), and OR 0.84 (95% CI 0.48–1.47), respectively.ConclusionThe real-world evidence regarding the reduction in HF risk and hospitalization in GLP-1RA users is conflicting. Further well-designed, large multicenter, observational studies are needed to show clearer evidence.     

Long-term effects of GLP-1 receptor agonists in type 2 diabetic patients: A retrospective real-life study in 131 patients

AimWe evaluate retrospectively long-term effects of GLP-1 receptor agonists in type 2 diabetic patients treated between 2008 and 2016.Methods131 patients treated by GLP-1 receptor agonists (GLP-1RAs) were included. The objective was to evaluate the evolution of glycated hemoglobin (HbA_1c) during a period up to 4 years. The secondary objectives consisted of analysing the long-term effects of treatment on body mass index (BMI), blood pressure and lipids; reporting the proportion of patients who reached HbA_1c objectives; estimating the time before treatment failure and determining predictive factors of failure. We also compared twice-daily exenatide to once-daily liraglutide on the major parameters.ResultsHbA_1c improved significantly, mostly during the first year of treatment (−1.2%), and this effect was maintained after 4 years (−1.4% vs. baseline). At 1 year, 26% and 47% of subjects achieved HbA_1c levels <7.0% and 7.5%, respectively. Treatment failure was observed in 51% of patients after a mean duration of GLP-1RA treatment of 50 months. Half of patients had failed after 42 months. Baseline HbA_1c greater than 9.0% and male gender were predictive factors of treatment failure. BMI also decreased: −0.9 kg/m² the first year, −1.9 kg/m² after 4 years. No significant difference was found between patients treated with exenatide and liragutide over time.ConclusionsThe beneficial effects of GLP-1RAs on HbA_1c reached a plateau after the first year of treatment and are maintained at 4 years only in one third of patients. Failure occurred predominantly in men with a baseline HbA_1c greater than 9%.     

Effects of the long-acting human glucagon-like peptide-1 analog liraglutide on plasma omentin-1 levels in patients with type 2 diabetes mellitus

Objective

Omentin is a protein expressed and secreted from visceral but not subcutaneous adipose tissue, which increases insulin sensitivity in human adipocytes. However, its pathophysiologic role in humans remains largely unknown. The objective of this study is to assess plasma omentin-1 levels in patients with type 2 diabetes mellitus (T2DM) and matched control subjects and to investigate the effects of liraglutide on plasma omentin-1 levels in patients with T2DM.

Patients and methods

Thirty T2DM patients with poor glycemic control after more than 3 months of treatment with one or two OHA(s) (T2DM), and 30 matched normal glycaemic controls (NGT) participated in the study. The T2DM group was given an injection of liraglutide once-daily for 16 weeks. Plasma omentin-1 levels were measured by enzyme-linked immunosorbent assay and the relationship between plasma omentin-1 levels and metabolic parameters was also analyzed.

Results

Plasma omentin-1 levels were lower in T2DM than in the control (19.3 ± 4.0 μg/L vs. 26.4 ± 6.0 μg/L, P < 0.01). Plasma omentin-1 levels increased significantly in T2DM patients after treatment with liraglutide compared with pre-treatment (19.3 ± 4.0 μg/L vs. 21.2 ± 3.9 μg/L, P < 0.01). In all diabetic patients, multiple regression analysis showed that FINS and HOMA-IR were independently associated with plasma omentin-1 levels.

Conclusions

In T2DM patients, plasma omentin-1 levels decreased, but significantly increased after the treatment with liraglutide and metformin. These data suggest that liraglutide may play a role in increasing omentin-1 levels in T2DM patients.     

Cardiovascular effectiveness of glucagon-like peptide 1 receptor agonists versus dipeptidyl peptidase-4 inhibitors in type 2 diabetes: A meta-analysis based on propensity score-matched studies

Glucagon-like peptide 1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) are two novel classes of hypoglycemic agents. The relative cardiovascular effectiveness between these two drug classes in patients with type 2 diabetes (T2D) is unestablished due to the absence of large cardiovascular outcome trials directly comparing DPP-4i with GLP-1RA. We aimed to incorporate large propensity score-matched cohort studies to conduct a meta-analysis, to determine the relative effectiveness of GLP-1RA versus DPP-4i on cardiovascular endpoints in T2D patients. Compared to DPP-4i, GLP-1RA was associated with the significantly lower risks of major adverse cardiovascular events [MACE] (HR 0.76, 95% CI 0.63?0.92), cardiovascular mortality (HR 0.59, 95% CI 0.37?0.95), myocardial infarction (HR 0.89, 95% CI 0.80?0.98), stroke (HR 0.86, 95% CI 0.76?0.96), and all-cause mortality (HR 0.63, 95% CI 0.42?0.96) in T2D patients; whereas these two drug classes had the similar risk of hospitalization for heart failure [HHF] (HR 0.95, 95% CI 0.77–1.16). Meta-regression analyses showed that six factors (i.e., mean age, female proportion, cardiovascular disease proportion, heart failure proportion, and the proportions of receiving metformin and insulin at baseline) did not significantly affect the effects of GLP-1RA on MACE and HHF (P ≥ 0.076). This meta-analysis provides the direct evidence regarding the relative cardiovascular effectiveness of GLP-1RA versus DPP-4i from real-world studies, and its findings suggest that among T2D patients GLP-1RA should be considered in preference to DPP-4i as for preventing atherosclerotic cardiovascular events and death in clinical practice.     

Cardiovascular effects of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: The P value and beyond

Despite growing awareness of the dangers of a dichotomous interpretation of trial results based on the ‘statistical significance’ of a treatment effect, the uptake of new approaches has been slow in diabetes medicine. We showcase a number of ways to interpret the evidence for a treatment effect applied to the cardiovascular outcome trials of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT-2is): the P value function (or confidence curves), which depicts the treatment effect across the whole spectrum of confidence levels; the counternull value, which is the hazard ratio (i.e. treatment effect size) supported by the same amount of evidence as the null value (i.e. no treatment effect); and the S value, which quantifies the strength of the evidence against the null hypothesis in terms of the number of coin tosses yielding the same side. We show how this approach identifies potential treatment effects, highlights similarities among trials straddling the threshold of statistical significance, and quantifies differences in the strength of the evidence from trials reporting statistically significant results. For example, while REWIND, CANVAS and CREDENCE failed to reach statistical significance at the .05 level for all-cause mortality, their counternull values indicate that reduced death rates by 19%, 24% and 31%, respectively, are supported by the same amount of evidence as that indicating no treatment effect. Moreover, similarities among results emerge in trials of GLP-1RAs (REWIND, EXSCEL and LEADER) lying closely around the threshold of ‘statistical significance’. Lastly, several S values, such as for the primary outcome in HARMONY Outcomes (S value 10.9) and all-cause death in EMPAREG-OUTCOME (S value 15.0), stand out compared with values for other outcomes and other trials, suggesting much larger differences in the evidence between these studies and several others that cluster around the .05 significance threshold. P value functions, counternull values and S values should complement the standard reporting of the treatment effect to help interpret clinical trials and make decisions among competing glucose-lowering medications.     

All-cause mortality in a population-based type 1 diabetes cohort in the U.S. Virgin Islands

Objective

Type 1 diabetes remains a significant source of premature mortality; however, its burden has not been assessed in the U.S. Virgin Islands (USVI). As such, the objective of this study was to estimate type 1 diabetes mortality in a population-based registry sample in the USVI.

Research design and methods

We report overall and 20-year mortality in the USVI Childhood (<19 years old) Diabetes Registry Cohort diagnosed 1979–2005. Recent data for non-Hispanic blacks from the Allegheny County, PA population-based type 1 diabetes registry were used to compare mortality in the USVI to the contiguous U.S.

Results

As of December 31, 2010, the vital status of 94 of 103 total cases was confirmed (91.3%) with mean diabetes duration 16.8 ± 7.0 years. No deaths were observed in the 2000–2005 cohort. The overall mortality rates for those diagnosed 1979–1989 and 1990–1999 were 1852 and 782 per 100,000 person-years, respectively. Overall cumulative survival for USVI was 98% (95% CI: 97–99) at 10 years, 92% (95% CI: 89–95) at 15 years and 73% (95% CI: 66–80) at 20 years. The overall SMR for non-Hispanic blacks in the USVI was 5.8 (95% CI: 2.7–8.8). Overall mortality and cumulative survival for non-Hispanic blacks did not differ between the USVI and Allegheny County, PA.

Conclusions

This study, as the first type 1 diabetes mortality follow-up in the USVI, confirmed previous findings of poor disease outcomes in racial/ethnic minorities with type 1 diabetes.