Historically, observational studies and meta-analyses have suggested an association between reduction of hyperglycemia with a reduction in microvascular and macrovascular complications in patients with type 2 diabetes 1–3. Moreover, previous studies have found that traditional oral diabetes medications, despite lowering blood glucose levels, generally do not improve cardiovascular outcomes. In contrast, several randomized trials have reported a reduction in microvascular events, primarily renal and retinal complications with the use of the new dipeptidyl peptidase IV (DPP-4) inhibitors 4. Recently, Patil et al.4 completed a meta-analysis of 18 randomized trials including 4998 patients treated with the new oral DPP-4 inhibitors compared with 3546 patients on other oral agents with a median follow-up of 46 weeks. They reported a 60% reduction in risk of nonfatal myocardial infarction (MI) or acute coronary syndrome (ACS) in diabetes patients treated with oral DPP-4 inhibitors [relative risk (RR) 0.40 (95% confidence interval (CI) 0.18–0.88)]. The RR of any adverse cardiovascular event with a DPP-4 inhibitor in this pooled analysis was 0.48 (95% CI 0.31–0.75), again in favor of DPP-4 agents. They concluded that the use of DPP-4 inhibitors was safe and resulted in a significant reduction in cardiovascular events. However, other recent large prospective trials found reduced microvascular complications but a higher incidence of hypoglycemia with intensive glycemic control without a reduction in macrovascular events 5. Lately, new concerns have emerged on the safety of DPP-4 inhibitors with the release of two large prospective trials, Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus (SAVOR) 6 and Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) 7. Newer oral DPP-4 inhibitors have also failed to show improvement in cardiovascular outcomes. In the SAVOR trial, there was an increase in heart failure hospitalizations but not an increase in mortality 6.
There have been encouraging results with the treatment of diabetes in the National Health Interview Survey, the National Hospital Discharge Survey, the US Renal Data System, and the US National Vital Statistics. A study compiling information from these databases showed that there is a significant reduction in the incidences of acute MI, stroke, lower-extremity amputation, end-stage renal disease, and death from hyperglycemic crisis between 1990 and 2010 8. Even though there is a marked reduction in ACS, there are still twice as many cardiovascular events in diabetes patients than in nondiabetic patients with an almost 10-fold increase in lower-extremity amputations in the diabetes subset. Unfortunately, with an escalating prevalence of obesity and diabetes, there still remains excess morbidity and mortality associated with this disease (Fig. 1).
The SAVOR trial 6 (TIMI-53) was a superiority trial. It was designed to evaluate the safety and efficacy of saxagliptin when added to existing type 2 diabetes treatments on cardiovascular outcomes in patients at risk for future cardiovascular events. In addition, a closed testing hierarchy was used to preserve the α-level and prespecified that a test for noninferiority for the primary composite endpoint should be completed first and a test for superiority performed afterwards. A total of 16 492 diabetes patients were prospectively randomized with a mean follow-up of 2.1 years. Patients were randomized to saxagliptin 5 mg daily (2.5 mg if glomerular filtration rate is below 50 ml/min) or placebo. The primary endpoint was a composite of cardiovascular death, MI, or ischemic stroke. The primary endpoint occurred in 613 patients in the saxagliptin group and in 609 patients in the placebo group (7.3 and 7.2%). The 2-year Kaplan–Meier estimates for superiority were not achieved; hazard ratio (HR) 1.00 (95% CI 0.89–1.12); however, noninferiority was significant at P less than 0.001. The major secondary endpoints included a composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure was 12.8% in the treatment arm and 12.4% in the placebo arm [2-year Kaplan–Meier estimates; HR 1.02 (95% CI 0.94–1.11)]. It also reduced the progression and development of microalbuminuria; however, it is unclear if it translates to decreased renal complications. Specifically, hospitalizations for heart failure were significantly increased in the saxagliptin arm by 27% [HR 1.27 (95% CI 1.07–1.51)]. The study result addressing whether the DPP-4 inhibitor saxagliptin can reduce cardiovascular events in diabetes patients was negative. However, the apparent off-target effect with increased hospitalizations for heart failure (best predicted by a history of heart failure) was not associated with an increase in mortality. This will remain a question for future trials (Figs 2 and 3, Tables 1 and 2).
The EXAMINE trial 7 was a double-blind noninferiority trial. It evaluated the impact of adding alogliptin to standard diabetes therapy on major cardiovascular events in patients with type 2 diabetes with ACS within 15–90 days before randomization. The primary cardiovascular endpoint was a composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke. A total of 5380 patients underwent randomization and were followed for up to 40 months (median 18 months). The primary endpoint was achieved in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) [HR 0.96 (P<0.32)] at 36-month follow-up. Figure 3 and Table 2 shows the components of the primary endpoint in addition to the exploratory adjudicated components. The EXAMINE trial did not find increased hospitalizations for heart failure. The principal secondary endpoint of death from cardiovascular causes, nonfatal MI, nonfatal stroke, or urgent revascularization due to unstable angina found no significant difference between placebo (n=359, 13.4%) versus alogliptin (n=344, 12.7%), P less than 0.26. Hospitalization for heart failure in the alogliptin treatment arm was 106/2701 events versus 89/2679 which was not significant [odds ratio 1.19 (95% CI 0.89–1.58)] (Figs 4 and 5).
Diabetes and heart failure considerations
Over the past three decades, we have seen a marked increase in prevalence of type 2 diabetes. What are the potential etiologies of this increase? Are they dietary or food density changes, changes in exercise, increased obesity, microbiome changes, or epigenetic changes 12? It is apparent that the vascular bed is clearly centered in the insulin-resistant complex. Unfortunately, cardiovascular disease continues to cause death in over 50% of type 2 diabetes patients. In addition, heart failure syndrome with preserved left ventricular function accounts for almost 50% of diabetes patient developing heart failure 13. At a more basic level, translational information in diabetes finds microRNAs as important regulators of hypoxia and growth factor pathways 14. Abnormalities of increased oxidative stress in diabetes, advanced glycosylation end products, reduced stem cells, vascular endothelial growth factor, and metabolic inflexibility at a cardiomyocyte level are among the targets for future research 15.
Heart failure in diabetes patients with preserved left ventricular function is complex 16. It is important to recognize that over 80% of the patients in SAVOR-TIMI and EXAMINE trials had hypertension, which itself is associated with increased left ventricular matrix changes that reduce ventricular compliance. Clinical conditions associated with diastolic dysfunction include left ventricular hypertrophy by echocardiography or ECG, enlarged left atrium, and a fourth heart sound. Type 2 diabetes patients have insulin resistance that can shift the metabolic pathways away from glucose as the major energy source, thus leading to an increased loss of ATPs (Fig. 6). The combination of both matrix changes and reduced energy production decreases power in the insulin-resistant heart and together increases the potential risk for heart failure. Moreover, the insulin-resistant heart is comprised of molecular and cellular disharmony. Translational research and prospective trials will be required to answer many of these questions.
In summary, both trials of the new DPP-4 inhibitors have failed to show a reduction in cardiovascular events in type 2 diabetes patients. There was a significant increase in hospitalization for heart failure with saxagliptin but not alogliptin, a paradigm previously observed with the thiazolidinedione class of drugs. The reasons for increased heart failure admissions with DPP-4 inhibitors remain unclear. Could this be a play of chance or actually be an increase in heart failure due to DPP-4 inhibitor? Consideration of translational findings in animals have ranged from improvement in cardiac function 17 to a possible increased circulating blood volume from increased neuropeptide Y due to vasoconstriction of microcirculation 18. Further studies are needed to determine whether this is a problem with the drug characteristics or the drug class. Various studies on oral diabetes agents have similarly failed to consistently show a decrease in macrovascular outcomes. Current research studies in animals have not demonstrated structural cardiovascular harm, and neither the SAVOR nor EXAMINE trials showed an increase in cardiac mortality. Early diagnosis and initiation of treatment for type 2 diabetes patients may be a better strategy for reducing cardiovascular outcomes.
Conflicts of interest
There are no conflicts of interest.
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