Are Dipeptidyl Peptidase (DPP)-4 Inhibitors Safe in Patients with Heart Failure?

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Author: Kristin Watson, PharmD, BCPS-AQ Cardiology

The dipeptidyl peptidase-4 (DPP-4) inhibitors are a treatment option for patients with type 2 diabetes (Type 2 DM). The DPP-4 inhibitors approved for use in the United States at the time of this writing include: sitagliptin (Januvia®), saxagliptin (Onglyza®), linagliptin (Tradjenta®), and alogliptin (Nesina®).

According to the American Diabetes Association, DPP-4 inhibitor therapy is recommended as one of several possible “add-on” treatments if the hemoglobin A1C (A1C) goal is not met with metformin alone. The decision regarding which therapy to add to metformin is multi-factorial. Advantages of the DPP-4 inhibitors include their low hypoglycemic risk, relatively low adverse effect profile, and neutral effect on weight.¹ However, because these agents are fairly new, their cost relative to other therapies can be a disadvantage in many patients.

In 2008, the Food and Drug Administration (FDA) published recommendations regarding the evaluation of cardiovascular effects for new antihyperglycemic agents used in the treatment of Type 2 DM to ensure that “new therapy does not increase cardiovascular risk to an unacceptable extent”.² Although Type 2 DM confers an increased risk of cardiovascular events, most studies of antihyperglycemic medications focus primarily on change in A1C as their primary endpoint. While this endpoint is important to consider, the updated recommendation by the FDA enables clinicians to have additional data when selecting the most appropriate therapy.

The cardiovascular effects of saxagliptin were evaluated in the SAVOR-TIMI 53 trial, which enrolled patients with known cardiovascular disease or multiple cardiac risk factors. Participants were randomized to saxagliptin or placebo for a median of 2.1 years. No difference in the primary endpoint of cardiovascular death, myocardial infarction or ischemic stroke was observed. The risk of hospitalization for heart failure (HF) was increased in the treatment group 3.5% vs. 2.8%, (hazard ratio (HR), 1.27 (95% confidence interval (CI), 1.07-1.51; p = 0.007).³ The difference in rate of HF hospitalization was present at 12 months but did not persist thereafter. Risk was heightened among those with prior HF symptoms, elevated baseline N-terminal pro-brain natriuretic peptide (pro-BNP) concentrations, and an estimated glomerular filtration rate of 60 ml/min or less.⁴ The risk did not appear to change based on the degree of renal impairment.⁵ The mechanism for this adverse effect is unclear. Use of therapy did not lead to increases in pro-BNP nor was evidence of volume overload reported.

The effects of alogliptin on cardiovascular events was assessed in the EXAMINE trial, which randomized patients with an acute coronary syndrome within the past 15 to 90 days to alogliptin or placebo for a median duration of 18 months. No difference in the primary endpoint of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke was observed.⁶Based on the results of SAVOR-TIMI 53, the rate of HF hospitalization in the EXAMINE trial was evaluated in a post-hoc analysis. Alogliptin was not associated with an overall increased risk of hospitalization for HF (HR, 1.19 [95% CI, 0.90–1.58], p = 0.220). However, the use of alogliptin was associated with an increased risk of HF hospitalization in those without a history of HF (HR, 1.76 [95% CI, 1.07–2.90], p = 0.026) but not in those with pre-existing HF (HR, 1.00 [95% CI, 0.71–1.42], p = 0.996).⁷

The effects of sitagliptin were compared to placebo in patients with Type 2 DM and cardiovascular disease in the TECOS study. After a median follow-up period of 3 years, the rate of the primary endpoint (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and hospitalization for unstable angina) and hospitalization for HF were similar between groups.^8.9 In an observational trial of patients receiving sitagliptin, an increased risk of new onset HF was not observed.¹⁰ In retrospective cohort studies of patient receiving sitagliptin, an increased risk of HF hospitalization was observed in those with baseline HF (adjusted odds ratio, 1.84, 95% CI, 1.16 to 2.92) and among those on dialysis (adjusted HR, 1.52, 95% CI, 1.21–1.90).^11,12

Clinical trial data and a pooled analysis of trials with linagliptin suggest that its use is not associated with an increased risk of HF or cardiovascular events.^13,14 Linagliptin and its effect on cardiovascular outcomes is being compared to glimepiride in high-risk patients in the CAROLINA trial, which is expected to be completed in February 2019.¹⁵

Based on conflicting data among the DPP-4 inhibitors, several meta-analyses have been conducted to further evaluate the risk of HF hospitalization. Was the increased risk in SAVOR-TIMI 53 due to chance? Is the risk medication-specific or a class effect? In a retrospective, population-based cohort study published in the Annals of Internal Medicine, the association of HF hospitalization was similar between saxagliptin and sitagliptin as well as other medications for Type 2 DM (long-acting insulin, pioglitazone, and second-generation sulfonylureas).¹⁶ A systematic review in BMJ found a possible small but increased risk of HF hospitalization with DPP-4 inhibitor therapy, although it could not be determined whether this increased risk was due to saxagliptin alone or all DPP-4 inhibitors. The risk appeared higher in those with existing cardiovascular disease or multiple risk factors.¹⁷The median time to follow-up in both of these analyses was relatively short.

An additional observational study was unable to substantiate a risk of HF with DPP-4 inhibitors, and a meta-analysis of clinical trials found that the risk of HF was not a class effect.^{18, 19} That being said, in the latter analysis, saxagliptin alone was associated with a risk of HF in those 65 years of age or older and in those with diabetes for 10 or more years and a body mass index > 30 kg/m².¹⁹

Final Thoughts
Uncertainty remains regarding the association between DPP-4 inhibitors and risk of HF hospitalization. Until further data are available, we recommend clinicians consider the following:

Patient Presentation	Management Strategy
New or worsening HF symptoms after initiation of DPP-4 inhibitor therapy	Evaluate potential causes. Consider replacing DPP-4 inhibitor therapy with an alternative agent.
Current or prior HF symptoms and/or renal impairment	Avoid DPP-4 inhibitor therapy. Use an alternative agent.
Left ventricular dysfunction (i.e., left ventricular ejection fraction < 40%) without current/prior HF symptoms	Consider alternative agent. If a DPP-4 inhibitor is used, counsel patient on self-monitoring of HF symptoms (e.g., dyspnea on exertion, orthopnea, weight gain, edema) and to report any new or worsening symptoms immediately. Prescribers should evaluate the presence of signs (e.g., rales, elevated jugular venous pressure) and symptoms every 1 to 3 months during the first year of therapy.
Known cardiovascular disease or risk of heart failure	Consider risk vs. benefit. If used, counsel patient on self-monitoring of HF symptoms and evaluate for presence of signs/symptoms at each visit.

A summary of recommendations related to HF in the product labeling for each agent is shown below.

Agent	Product Labeling
Alogliptin²⁰	Consider risk and benefit prior to initiating in those at risk for developing HF. If HF develops, consider discontinuation of therapy. Manage HF according to standards of care.
Linagliptin²¹	No comments
Saxagliptin²²	Consider risk and benefit in those at risk for developing HF. Monitor for signs and symptoms of HF if therapy is initiated. Counsel patients on symptoms of HF; report immediately if they occur. If HF develops, consider discontinuation of therapy. Manage HF according to standards of care.
Sitagliptin²²	No comments