Nasser Mikhail

Effects of incretin-based therapy in patients with heart failure and myocardial infarction

Studies designed to evaluate the short-term effects of incretin-related drugs in subjects with cardiac disease are still preliminary. In patients with heart failure, two of five studies showed that glucagon-like peptide-1 (GLP-1) infusion was associated with an absolute increase in left ventricular ejection fraction (LVEF) by 6–10xa0%, whereas no significant benefit was observed in the remaining three studies. In patients with coronary artery disease, single infusion of the GLP-1 receptor analog, exenatide, did not increase LVEF, but this drug may decrease infarct size in patients with myocardial infarction presenting with short duration of ischemic symptoms. Single dose of GLP-1 and the dipeptidyl-peptidase-IV (DPP-IV) inhibitor, sitagliptin, may improve left ventricular function, predominantly in ischemic segments, and attenuate post-ischemic stunning. Nausea, vomiting and hypoglycemia were the most common adverse effects associated with GLP-1 and exenatide administration. Increased heart rate was also observed with exenatide in patients with heart failure. Large randomized trials including diabetic patients with preexisting heart failure and myocardial infarction showed that chronic therapy with the DPP-IV inhibitors saxagliptin and alogliptin did not reduce cardiovascular events or mortality. Moreover, saxagliptin use was associated with significant increase in frequency of heart failure requiring hospitalization, hypoglycemia and angioedema. Overall, short-term preliminary data suggest potential cardioprotective effects of exenatide and sitagliptin in patients with heart failure and myocardial infarction. Meanwhile, long-term randomized trials suggest no benefit of alogliptin, and increased harm associated with the use of saxagliptin.

Cardiovascular Effects of Liraglutide

BACKGROUNDnLiraglutide is a glucagon-like 1 (GLP-1) agonist approved for treatment of type 2 diabetes and obesity.nnnOBJECTIVEnTo review the cardiovascular effects of liraglutide including macrovascular and microvascular events, its use in heart failure, and its effects on heart rate and blood pressure.nnnRESULTSnThe impact of liraglutide on cardiovascular outcomes was examined in a large welldesigned study published in 2016, the LEADER trial. This study included 9,340 patients with advanced type 2 diabetes and high baseline cardiovascular risk. The primary outcome was the first occurrence of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 3.8 years, patients randomized to liraglutide had significant reduction in the composite primary outcome compared to patients randomized to placebo, hazard ratio (HR) 0.87; 95% CI 0.78-0.97. Death from cardiovascular causes was significantly reduced with liraglutide therapy (HR, 0.78; 95% CI 0.66-0.93), as well as death from any cause (HR, 0.85; 95% CI 0.74-0.97). In 2017, the LEADER investigators reported that nephropathy events were significantly lower after liraglutide therapy than placebo (HR 0.78; 95% CI 0.67-0.92), but there was no significant difference in retinopathy events. Meanwhile, other studies suggested that the use of liraglutide may be harmful in patients with severe heart failure, in part due to increase in heart rate.nnnCONCLUSIONnLiraglutide is a useful therapy in patients with advanced type 2 diabetes complicated by cardiovascular disease, except patients with severe heart failure. Further studies are needed to evaluate the long-term effects of liraglutide, and to see whether its beneficial effects extend to patients with type 2 diabetes and low cardiac risk.

Who would really benefit from DPP-4 inhibitors?

Since the introduction of DPP-4 inhibitors in 2006, this class of drugs has increasingly become a strong competitor of sulfonylureas (SU) as second-line therapy in patients with type 2 diabetes uncontrolled on metformin. The use of DPP-4 inhibitors is associated with neutral effect on body weight and low risk of hypoglycemia except when used in conjunction with SU or insulin. These two advantages make DPP-4 inhibitors as convenient therapeutic option in patients who are overweight and subjects susceptible for hypoglycemia. The third advantage is the possibility of using these agents in diabetic patients with chronic kidney disease and those on hemodialysis [1]. They can be used, therefore, as alternative to metformin in patients with various stages of kidney disease. However, it is still unclear whether there exist patients’ clinical and biochemical characteristics that may influence the efficacy of DPP-4 inhibitors. In this issue of Endocrine, Esposito et al. [2] performed a meta-regression analysis of 20,053 patients exposed to various DPP-4 inhibitors in 78 randomized trials that lasted 12 weeks or longer. The authors found that higher values of HbA1c and lower fasting hyperglycemia at baseline were the most two important predictors of greater reductions in HbA1c values, whereas age did not modify the efficacy of DPP-4 inhibitors [2]. The analysis of Esposito et al. [2] included the largest available database used to study determinants of efficacy of all available DPP-4 inhibitors. Clearly, the results of this metaanalysis represent a step forward for better understanding of this area of medicine characterized by scanty and sometimes inconsistent investigations. However, the study had some limitations besides those already mentioned by the authors. First, no attempts were undertaken to include unpublished studies to minimize publication bias. Second, the exclusion of 11 trials of initial combination of DPP-4 inhibitors with other oral agents and insulin may not be necessary because the use of these combinations in clinical practice is not uncommon, and their inclusion would have increased the study’s statistical power. Surprisingly, the authors did not mention an earlier meta-analysis designed for the same purpose by the group of Manomi and co-workers [3] including 44 trials of 21-week duration or longer. In the latter study, the authors also reported a greater efficacy of DPP-4 inhibitors in patients with lower fasting plasma glucose concentrations [3]. Yet, unlike the study of Esposito and co-workers [2], Monami et al. [3] found that older age and unexpectedly lower HbA1c values at baseline predicted a greater therapeutic response to DPP-4 inhibitors. Moreover, diabetes duration, an important clinical parameter that was not analyzed as covariate in the study of Esposito et al. [2], did not affect the efficacy of DPP-4 inhibitors in the meta-analysis performed by Monami and his colleagues [3]. Other investigators explored several possible determinants of DPP-4 efficacy. In one nonrandomized study (n = 109), Fadini et al. [4] observed that the presence of the metabolic syndrome, irrespective of its definition, predicted lesser HbA1c reduction in response to sitagliptin and vildagliptin. In the same study, neither age nor diabetes duration modified the efficacy of these two DPP-4 inhibitors [4]. Biochemical markers such as plasma DPP-4 activity may virtually serve as predictor of efficacy of DPP-4 inhibitors. In another nonrandomized study (n = 52), Aso et al. [5] found that high serum levels of soluble CD26 (sCD26) were associated with poor efficacy N. Mikhail (&) Endocrinology Division, Olive-View UCLA Medical Center, David-Geffen School of Medicine, 14445 Olive View Dr, Sylmar, CA 91342, USA e-mail: nmikhail@dhs.lacounty.gov