Cardiovascular effects of the incretin-based therapy: the good, the bad, or the ugly?

Incretin hormones are secreted from enteronendocrine cells mainly upon nutrient absorption from the gut lumen. So far, two genuine incretin hormones are identified: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Both GIP and GLP-1 enhances glucose-stimulated insulin secretion from pancreatic beta-cells via increase of intracellular cyclic adenosine monophosphate. Unlike GIP, GLP-1 suppresses glucagon secretion, decelerates gastric emptying, decreases appetite, and increases satiety. Both GIP and GLP-1 are rapidly degraded by enzymatic action of dipeptidyl peptidase-4 (DPP-4), which is abundantly expressed throughout the body including the blood compartment. To exploit the anti-diabetic properties of incretin hormones, GLP-1 receptor agonists and DPP-4 inhibitors have been developed and widely used in clinical practice. The benefits of GLP-1 receptor agonists and DPP-4 inhibitors in diabetes management are clear. However, scrutiny has been exercised over safety issues such as acute pancreatitis and increased susceptibility to certain infection. Because the most common cause of death of patients with type 2 diabetes is cardiovascular disease, it is critical that anti-diabetes agents at least should not increase the risk of cardiovascular events or related death. In this regard, enormous efforts have been put on the research on the cardiovascular effects of incretin-based therapy.

Incretin-based therapy has favorable effects on cardiovascular risk factors and/or surrogate markers of the progression of cardiovascular disease (for details, please refer to an excellent review1). Briefly, GLP-1 decreases body weight by decreasing appetite, increasing satiety, and increasing energy expenditure. GLP-1 increases natriuresis, which may contribute to its blood pressure lowering effect2. In animals, GLP-1 increases atrial natriuretic peptide secretion from atrial cardiomyocytes, which in turn increases renal sodium excretion3. Moreover, GLP-1 improves endothelial function1. In animal models of ischemic heart disease, GLP-1 decreased the extent of myocardial damage1. Furthermore, in an animal model of cerebral infarction, GLP-1 receptor activation decreased the infarct size4. In recently completed but not yet published the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) study, lixisenatide did not increase the risk of quadruple major adverse cardiovascular events (MACE: cardiovascular death, non-fatal myocardial infarction, unstable angina, and non-fatal stroke) or hospital admission for heart failure in type 2 diabetes patients with history of recent acute coronary syndrome. Because lixisenatide is a short-acting GLP-1 receptor agonist and may induce antibody development against the drug in some patients5, it might be unable to exert its full cardiovascular benefit. In this regard, the results of currently on-going cardiovascular outcome studies with long-acting GLP-1 receptor agonists such as liraglutide (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results [LEADER]), dulaglutide (Researching Cardiovascular Events with a Weekly Incretin in Diabetes [REWIND]), semaglutide (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes [SUSTAIN 6]), and exenatide once weekly (Exenatide Study of Cardiovascular Event Lowering Trial [EXSCEL]) are highly expecting.

DPP-4 inhibitors also showed favorable cardiovascular effects. Because there are many peptide substrates of DPP-4 other than GLP-1 (e.g., GIP and stromal cell-derived factor 1 [SDF-1]), the net cardiovascular effects of DPP-4 inhibitors cannot be explained by the action of GLP-1 alone1. For example, GIP not only increases glucose-dependent insulin secretion but also increases glucagon secretion, which may contribute to the decreased risk of hypoglycemia with DPP-4 inhibitors6. SDF-1 recruits endothelial progenitor cells to the ischemic tissue and may reduce ischemic injury1. In a meta-analysis with 70 studies, which were mostly short-term studies with mean duration of follow-up of 44.1 weeks, DPP-4 inhibitors exhibited a decreased risk of major cardiovascular events (odds ratio, 0.71; 95% CI, 0.59–0.86)7. The cardiovascular safety of DPP-4 inhibitors has been tested in the context of large, long-term, placebo-controlled trials. In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-TIMI 53 (SAVOR-TIMI 53) trial, saxagliptin did not increase the triple MACE (non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) compared to placebo in type 2 diabetes patients with high risk of cardiovascular disease for a median 2.1 years of follow-up (hazard ratio, 1.00; 95% CI, 0.89–1.12)8. In the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE) study with a median follow-up for 18 months, alogliptin did not increase the risk of the triple MACE compared to placebo (hazard ratio, 0.96; upper boundary of the one-sided repeated CI, 1.16) in type 2 diabetes patients who experienced recent acute coronary syndrome9. Very recently, the Trial to Evaluate Cardiovascular Outcomes After Treatment with Sitagliptin (TECOS) study with type 2 diabetes patients with established cardiovascular disease revealed that sitagliptin did not increase the risk of quadruple MACE compared to placebo (hazard ratio, 0.98; 95% CI, 0.88–1.09) during a median follow-up of 3.0 years10. Therefore, it can be concluded that DPP-4 inhibitors do not increase the risk of cardiovascular events in patients with type 2 diabetes. Currently, the Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus (CARMELINA) study is on-going to examine the cardiovascular and renal safety of linagliptin, another DPP-4 inhibitor, compared to placebo in type 2 diabetes patients with high cardiovascular risk. In addition, the Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients with Type 2 Diabetes (CAROLINA) study is testing cardiovascular safety of linagliptin compared to glimepiride, a sulfonylurea, in type 2 diabetes patients with increased risk of cardiovascular events. If linagliptin reveals superiority to glimepiride in terms of cardiovascular safety, the landscape of clinical practice in choosing oral anti-diabetes drugs will be significantly affected.

Overall, the cardiovascular safety has been demonstrated with DPP-4 inhibitors. However, the issue related to the risk of hospital admission due to heart failure has not yet been settled. In preclinical studies, GLP-1 improved left ventricular function in a rapid pacing-induced cardiomyopathy model1. Substrates of DPP-4, such as substance P or neuropeptide Y might have roles in relation to heart failure by modulating sympathetically mediated vasoconstriction11. Treatment-related hypoglycemia, although it is not common with DPP-4 inhibitors if only those agents are used in the absence of sulfonylurea and/or insulin, might aggravate left ventricular dysfunction by increasing sympathetic tone and stimulating renin-angiotensin-aldosterone system11. Although heart failure has not been dealt as a primary outcome in recently completed cardiovascular outcome trials8–10, inconsistent results related to this issue have been reported. Sitaglipitin did not increase the risk of admission for heart failure in the TECOS study10. Alogliptin also did not increase the risk of hospital admission for heart failure in the EXAMINE study12. However, when the data was reanalyzed according to the history of heart failure, alogliptin increased the risk of heart failure admission in patients without the history of previous heart failure whereas it did not increase the risk in patients with the history of previous heart failure12. However, the interaction between the therapy and the history of previous heart failure was not statistically significant12. In the SAVOR-TIMI 53 study, saxagliptin significantly increased the risk of hospital admission for heart failure8, particularly in patients with high baseline pro-B-type natriuretic peptide levels, impaired renal function, and prior history of heart failure13. Whether the increased risk of heart failure is specific for a certain DPP-4 inhibitor or merely a chance finding is not clear by now. The inconsistent effect on the risk of heart failure among studies with different DPP-4 inhibitors, the existence of clinical difference among DPP-4 inhibitors is now in question. In this regard, a study to examine the risk of heart failure according to different DPP-4 inhibitors needs to be performed. Meanwhile, a real world experience study will be of help to guide anti-diabetes therapy. A study using a U.S. claims database revealed that the risk of heart failure admission was not different between sitagliptin and saxagliptin, which were prescribed before the publication of the SAVOR-TIMI 53 trial14.

Type 2 diabetes greatly increases the risk of cardiovascular disease just like a steep cline as depicted in Fig1. However, the effect size of intensive glycemic control is only modest. Therefore, control for other cardiovascular risk factors within the frame of the current standards of care (e.g., anti-platelets, anti-hypertensives, statins and other lipid managements, and lifestyle measures) have to be emphasized. It is needless to say that cardiovascular safety is of paramount importance as anti-diabetes drugs. As newer forms of anti-diabetes drugs are introduced to clinical practice, keen interest is being paid whether they have protective, neutral, or detrimental effects in terms of cardiovascular safety. If an anti-diabetes drug also has the cardioprotective property it will be an ideal anti-diabetes drug and will be positioned as the second choice after metformin failure or as the first choice replacing the current position of metformin. Some anti-diabetes drugs may have off-target effects that may contribute to the increased risk of triple or quadruple MACE. In this case, the remedy is worse than the evil and should be withdrawn from the market. As discussed in this editorial, incretin-based therapy could be a sort of “fixes-that-backfire”, which may increase the risk of unexpected side effects such as pancreatitis, pancreatic cancer, and heart failure. Although cardiovascular safety in terms of triple or quadruple MACE is confirmed with incretin-based therapy, scrutiny and vigilance for other safety issues are still indispensable.

Figure 1

Patients with type 2 diabetes on a slippery slope of cardiovascular disease. Glucose-lowering therapy may decrease (ideal drugs) or increase (the remedy worse than the evil) or may have neutral effect on the risk of cardiovascular events such as myocardial infarction, unstable angina, stroke, and cardiovascular death. In a different scenario, an anti-diabetes drug may push the patient towards a deadly cliff of increased risk of unexpected adverse effects like fixes-that-backfire. In this regard, pancreatic safety issues and hospital admission for heart failure which might be potentially related to the incretin-based therapy require scrutiny and vigilance. For detailed explanation, please refer to the text. AE, adverse event; CV, cardiovascular; CVD, cardiovascular disease; HF, heart failure; MI, myocardial infarction; UA, unstable angina.

Disclosure

YMC received a lecture fee or consultation fee from Astra-Zeneca, Boeringer-Ingelheim, MSD, LG Life Sciences, and Hanmi.