CV Safety in Diabetes

Consulting Authors: Dr. Ronald Goldenberg and Dr. Jean-Marie Ekoé

Ronald Goldenberg, MD, FRCPC, FACE, is a consultant endocrinologist affiliated with North York General Hospital in Toronto and LMC Diabetes & Endocrinology in Thornhill. His major areas of interest include clinical care of diabetes, obesity, dyslipidemia, and thyroid disorders. He is a member of the Steering Committee for the 2013 CDA Clinical Practice Guidelines.

Jean-Marie Ekoé, MD, CSPQ, PD, is a Professor of Medicine, Endocrinology, Metabolism and Nutrition, as well as Chief of the Diabetes Foot Clinic, at the CHUM (Hôpital Hôtel-Dieu); Chairman of the Diabetes Quebec Professional Council; and Medical Director at the Université de Montréal nutrition clinic. His fields of expertise include general clinical endocrinology, and epidemiology of diabetes and its micro-macro-angiopathies.


New Data on CV Safety in Diabetes

Eagerly anticipated results from TECOS and ELIXA, two large cardiovascular (CV) safety trials of the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin and the glucagon-like peptide-1 receptor (GLP-1R) agonist lixisenatide, respectively, were a focal point of activities at the 75th Scientific Sessions of the American Diabetes Association (ADA), held in Boston in June 2015. "Tight" glucose control in diabetes remains critically important for patient welfare: elevated glucose levels are a strong risk factor for a wide range of serious health outcomes, and progressively higher A1C levels predict progressively greater risk of severe retinal or renal disease, cataracts, myocardial infarction (MI), heart failure, amputation, peripheral vascular disease, stroke, and death.1,2 Furthermore, compared with less intensive glucose control, more intensive glucose lowering in diabetes is associated with reductions in microvascular events such as eye disease, kidney disease, and neuropathy.3 More intensive glucose lowering is also associated with modest, but significant, macrovascular benefits, reflected in a reduction in major CV events such as strokes and MI4 that may become more evident the longer patients are followed.5

The past two decades have seen a proliferation of agents aimed at controlling glucose levels and enabling individualization of the care of patients with type 2 diabetes.6 For a variety of reasons, the CV safety of many relatively recently introduced and effective antihyperglycemic drugs, including the DPP-4 inhibitors and GLP-1R agonists, has been uncertain.7-11 A key question has been whether any of the newer antihyperglycemic agents have separate effects unrelated to glucose lowering that may be either beneficial or harmful for CV outcomes. In 2008, the U.S. FDA revised regulations for the approval of medications for type 2 diabetes mellitus (T2DM) and required all new antihyperglycemic therapies to demonstrate not only effective glucose lowering prior to approval, but also CV safety in the pre- and post-market approval setting.12-14 As a result of this change in the regulatory landscape, several large CV-outcome trials are ongoing or have recently been completed,14 including TECOS and ELIXA.

TECOS: Sitagliptin Does Not Increase Cardiovascular Risk;
"No Hint" of Increased Heart Failure

"TECOS should provide Canadian physicians with reassurance about the cardiovascular safety of sitagliptin. If you can prescribe a therapy that lowers glucose and does it safely without any cardiovascular harm, that's extremely reassuring."
- Dr. Ronald Goldenberg

The randomized, double-blind Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) evaluated the CV impact of sitagliptin compared with placebo when either was integrated into usual diabetes care at study centers worldwide.15,16 In this large, long-term, and rigorous trial in a high-risk population with CV disease, no CV safety concerns were documented. Of note, and in contrast to earlier studies of other DPP-4 inhibitors, sitagliptin in TECOS was not associated with any signal for heart failure. "It's unusual for a cardiologist to be at a diabetes meeting, and even more unusual for him to be excited," said Dr. Paul Armstrong, Professor of Medicine (Cardiology) at the University of Alberta, during a panel discussion that was broadcast live from the ADA mere hours after the TECOS results were first presented. "TECOS is the result of an eight-year gestation period, and the results are important, relevant, and exciting."

What are the key results and clinical implications of
the TECOS study, and what have the study's results added to our understanding of CV safety in T2DM treatment?

The primary objective of TECOS was to demonstrate non-inferiority of the long-term CV safety of adding sitagliptin to usual diabetes care, as compared to usual care alone (while secondary objectives enabled an assessment for superiority of sitagliptin in this respect). On-study glycemic management was designed to inform an understanding of the non-glycemic contribution of sitagliptin to CV outcomes, and thus a goal of the trial was to minimize A1C differences between study groups, thereby eliminating any glucose-lowering-related bias in favor of sitagliptin. Open-label use of antihyperglycemic therapy was encouraged as required, with the aim of reaching individually appropriate glycemic targets in all patients.

In total, 14,671 patients were randomized to receive either sitagliptin or placebo in addition to their existing therapy. Eligible patients were aged ≥ 50 years with T2DM and an A1C ≥ 6.5% and ≤ 8.0%. All patients were receiving either stable monotherapy for glucose control; dual combination therapy with metformin, pioglitazone, or sulfonylurea; or (following a protocol amendment during the trial) a stable dose of insulin with or without metformin. Additional eligibility criteria ensured that all patients had established CV disease, defined as either a history of MI; prior coronary revascularization; coronary angiography with at least one
≥ 50% stenosis; history of ischemic stroke; carotid arterial disease with ≥ 50% cartoid stenosis; or peripheral arterial disease with objective evidence.

Baseline characteristics, including demographics and the use of antihyperglycemic agents and secondary CV-prevention medications, were well balanced between study arms. The TECOS population was predominantly white (68%) and male (70%), with a mean age of 65.5 years. On average, the duration of diabetes in both groups was 11.6 years, and average baseline A1C levels were 7.2% in both arms. At baseline, the majority of patients (~80% in each group) were taking metformin and slightly less than half (~45%) of all patients were taking a sulfonylurea.

Median follow-up during the trial was three years, and glycemic control in both groups was excellent: A1C levels showed a slight increase early in the trial in the placebo group, while the sitagliptin group experienced a slight decrease (Figure 1). Over time, however, the difference between groups was minimized, and the overall least-squares mean difference for the entire follow-up was relatively small at -0.29% (p < 0.0001). Although TECOS was not designed to investigate the anti-hyperglycemic efficacy of sitagliptin, the utility of this drug as a glucose-lowering agent was demonstrated, as treatment with sitagliptin was associated with a 28% reduced risk of initiating an additional antihyperglycemic agent during the study (21.7% of patients in the sitagliptin group vs. 27.9% in the placebo group; Intent-to-Treat [ITT] Hazard Ratio [HR] 0.72; 95% confidence interval [CI] 0.68 to 0.77;
< 0.001), as well as a 30% reduced risk of initiating chronic insulin therapy during the study (9.7% sitagliptin group vs. 13.2% placebo group; ITT HR 0.70; 95% CI 0.63 to 0.79; p < 0.001).

Figure01In TECOS, sitagliptin use had a neutral effect on all CV outcomes: per-protocol analyses demonstrated that sitagliptin therapy was statistically non-inferior to placebo in terms of the primary CV endpoint (a composite of time to the first confirmed event of CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina; HR 0.98; 95% CI 0.88 to 1.09; p < 0.001). Planned ITT analyses of the same composite outcome for superiority were not significant
(Figure 2; HR 0.98; 95% CI 0.89 to 1.08; p = 0.645). Indeed, as noted by Dr. Rury Holman, Professor of Diabetic Medicine at the University of Oxford in the U.K. and joint chairman of the TECOS Executive Committee, the Kaplan-Meier plots for the cumulative numbers of patients with an event in each arm "are virtually identical."

Figure02Analyses of a secondary composite CV endpoint—time to the first confirmed event of CV death, nonfatal MI, or nonfatal stroke—revealed a similar pattern of results, with sitagliptin therapy non-inferior to placebo for this endpoint, but not superior (per-protocol analysis HR 0.99; 95% CI 0.89 to 1.11; p < 0.001 for non-inferiority; ITT analysis HR 0.99; 95% CI 0.89 to 1.10; p = 0.84 for superiority). Other secondary endpoints reinforced sitagliptin's essential "neutrality" in terms of CV events, with placebo-like rates of all major secondary CV outcomes and overall mortality reported in the sitagliptin arm of the study (Table 1).

Table01The CV safety of sitagliptin in TECOS was demonstrated within the context of very good overall safety. For example, the incidence of severe hypoglycemia (one of several events of interest in this trial) did not differ between the sitagliptin and placebo arms (Table 2). Similarly, the incidence of overall malignancies did not significantly differ between the sitagliptin and placebo arms. Confirmed events of acute pancreatitis were uncommon overall, but numerically more frequent in the sitagliptin group. Confirmed events of pancreatic cancer, meanwhile, were also uncommon but were numerically more frequent in the placebo group.Table02

What were the strengths and weaknesses of the
TECOS study design?

TECOS in Context: Heart Failure Across Large
CV Safety Trials of Oral Antihyperglycemic Agents

Perhaps the most noteworthy and differentiating finding to emerge from TECOS was the complete absence of any signal for heart failure in association with the use of sitagliptin. As summarized by Dr. Holman during his TECOS presentation, "We didn't detect any hint of risk in relation to heart failure for the TECOS population." Specifically, rates of hospitalization for heart failure did not differ between the two study arms (Figure 3; HR 1.00; 95% CI 0.83 to 1.20; p = 0.98). TECOS is seen as a particularly robust trial in which to demonstrate this safety profile. As conveyed by Dr. Jean-Marie Ekoé, a consulting author for this report, "The main strengths [of TECOS] include the fact that we had many subjects involved—about 14,000 people—and long-term follow-up which was on average three years. There was a total absence of cardiovascular signals and we demonstrated that, over a long period of time, it was feasible to administer a medication that could lower A1C without having a safety signal that could increase the cardiovascular risk that we already know exists in diabetic patients." This safety profile, and in particular sitagliptin's lack of impact on heart failure, contrasts with the outcomes noted in two previous CV trials of DPP-4 inhibitors, SAVOR and EXAMINE.Figure03


The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus—Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study17 and the Examination of Cardiovascular Outcomes with Alogliptin vs. Standard of Care (EXAMINE) study18 both focused on the CV safety of DPP-4 inhibitors. In SAVOR-TIMI 53, saxagliptin treatment compared to placebo did not increase nor decrease the rate of CV events captured in the composite primary endpoint, including CV death, nonfatal MI, and nonfatal stroke. Similarly, in the EXAMINE trial, alogliptin did not differ from placebo in terms of this same composite primary endpoint.

However, in aggregate, SAVOR and EXAMINE raised concerns about heart failure risks with DPP-4 inhibitors. Unexpectedly, saxagliptin-treated subjects in SAVOR-TIMI 53 had significantly higher rates of heart failure hospitalization compared to placebo: 3.5% (n = 289) vs. 2.8% (n = 228) over 2.1 years of follow up (HR 1.27; 95% CI 1.07 to 1.51; p = 0.007), despite comparable primary-endpoint rates in the trial. Post-hoc analyses of the EXAMINE trial showed that, over a relatively short follow-up of 1.5 years, hospitalization for heart failure occurred in numerically more patients receiving alogliptin than placebo (3.9% [n = 106] vs. 3.3% [n = 89]; HR 1.19; 95% CI 0.90 to 1.58; p = 0.22). Heterogeneity between these two trials limits the conclusions that may be drawn by combining data, but a recent meta-analysis suggests the results of SAVOR and EXAMINE reflect a 25% increase in the risk of hospitalization for heart failure across the two trials (HR = 1.25; 95% CI 1.08 to 1.45).19

What were the strengths and weaknesses of the SAVOR and EXAMINE studies, and what did these studies' results tell us about CV safety with DPP-4 inhibitors?


A fourth major CV safety trial was also reported at ADA this year: the Lixisenatide in Acute Coronary Syndrome (ELIXA) study of the GLP-1R agonist, lixisenatide.20 ELIXA is the first study to report on the CV safety of this class of agents. Results indicated that, in post-acute coronary syndrome (ACS) patients with T2DM and average A1C of 7.7%, lixisenatide over the course of two years had a neutral effect on CV outcomes. For the primary outcome of time to first confirmed event of CV death, MI, stroke, or hospitalization for unstable angina, lixisenatide added to usual care was statistically non-inferior to placebo added to usual care. Incidence rates for the primary endpoint were 13.4% in the lixisenatide arm and 13.2% in the placebo arm (HR 1.02; 95% CI 0.89 to 1.17; p < 0.001). This pattern of placebo-like CV risk in association with lixisenatide was repeated throughout a number of secondary CV endpoints including, reassuringly for this agent, hospitalization for heart failure which occurred in 4.0% of lixisenatide subjects and 4.2% of placebo subjects (HR 0.96; 95% CI 0.75 to 1.23).

What have the ELIXA results added to our
understanding of CV safety in T2DM treatment?

CV Safety and Heart Failure in Aggregate:
Incretin-Related Agents

As a whole, the TECOS, ELIXA, SAVOR, and EXAMINE studies have demonstrated the overall CV safety of incretin agents (DDP-4 inhibitors and a GLP-1R agonist) in high-CV-risk patients with T2DM. Still, among the DPP-4 inhibitors, the available data suggest possible differences in terms of associated risk for heart-failure hospitalization. Although differences in outcome measures may reflect differences in trial design, patient population, or other study-specific parameters or definitions (Table 3), they also may reflect differences in pharmacologic effect between the DPP-4 inhibitors; sitagliptin is the only DPP-4 inhibitor to be associated with no signal for heart failure in a large, CV-oriented safety trial. "An absolute strength of the TECOS study," said Dr. Ekoé, "and a great and positive surprise, was being able to demonstrate for the first time that there was neutrality [of an active treatment, sitagliptin], which was not the case before with the two previous studies. The implication in everyday practice is that we will have a certain level of assurance in prescribing sitagliptin without worrying that there will be an increase in cardiovascular risk; we can even administer sitagliptin to patients who already have cardiovascular complications, without any concerns." Table03

Summary and Conclusions

The implication [of the TECOS results] in everyday practice is that we will have a certain level of assurance in prescribing sitagliptin without worrying that there will be an increase in cardiovascular risk; we can even administer sitagliptin to patients who already have cardiovascular complications, without any concerns."
- Dr. Jean-Marie Ekoé

TECOS provides robust and powerful evidence of the CV and overall safety of sitagliptin. Not only did this study reveal no overall CV safety concerns, it also demonstrated that sitagliptin is not associated with an increase in heart failure. As summarized by Dr. Eric Peterson, a cardiologist and executive director of the Duke Clinical Research Institute, as well as joint chair of the TECOS study, "Based upon TECOS, sitagliptin appears to be an excellent and well-tolerated choice for antihyperglycemic therapy in those with CV disease."

"TECOS should provide Canadian physicians with reassurance about the cardiovascular safety of sitagliptin," said Dr. Ronald Goldenberg, also a consulting author of this report. "I think we have to remember, as healthcare providers, that the reason we treat diabetes is largely to reduce the microvascular complications of the disease, and if you can prescribe a therapy that lowers glucose and does it safely without any cardiovascular harm, that's extremely reassuring for both the healthcare provider and the patients taking these drugs."


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