Analyses of Results From Cardiovascular Safety Trials With DPP-4 Inhibitors: Cardiovascular Outcomes, Predefined Safety Outcomes, and Pooled Analysis and Meta-analysis

Abstract

The U.S. Food and Drug Administration requires that the cardiovascular (CV) safety of all new drugs for diabetes be demonstrated through pooled analyses of phase III studies or specifically designed trials. This requirement prompted several placebo-controlled, noninferiority CV safety trials in high-risk patients; to date, all completed trials showed that dipeptidyl peptidase (DPP)-4 inhibitors do not increase or reduce the risk of major CV events. These results apparently contrast with those of pooled analyses and meta-analyses of previous, smaller trials with metabolic end points, which had suggested a reduction of risk. However, the design of CV trials, which were required to demonstrate safety, is not adequate (for duration, management of concurrent therapies, etc.) for the assessment of potential therapeutic benefits. In addition, CV safety trials enroll patients at high risk of CV events, who are different from those included in earlier trials with metabolic end points. Differences in characteristics of patients enrolled probably account for most of the discrepancy in CV outcomes between CV safety studies and earlier trials. The availability of several large-scale trials with longer duration provides the unique opportunity for assessment of the safety of DPP-4 inhibitors not only with respect to major CV events but also with reference to other safety issues. For example, CV safety trials can be a source of information for pancreatitis, cancer, or hypoglycemia.In December 2008, the U.S. Food and Drug Administration (FDA) published guidance prompting pooled analyses and meta-analyses of cardiovascular (CV) events (sometimes with post hoc adjudication) observed in trials with metabolic outcomes (1). A shift of emphasis occurred from short-term, HbA 1c -centered phase II-III trials in "healthy" patients with type 2 diabetes to CV safety studies in a more vulnerable population (2). Results from the first trials according to the FDA guidance were

Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low‐grade inflammation the neglected component?

“…Thus, despite the large number of clinical variables measured in these trials, specific inflammatory parameters such as circulating cytokines or CRP are not present in the list of dosed markers. This is conceivably explained by the high cost required to complete this kind of trial; at least 611 CV events must be recorded to provide significant data . However, data from animal models have suggested a strong anti‐inflammatory effect of SGLT2 inhibitors.…”

“…This is conceivably explained by the high cost required to complete this kind of trial; at least 611 CV events must be recorded to provide significant data. 3,4 However, data from animal models have suggested a strong anti-inflammatory effect of SGLT2 inhibitors. For instance, diabetic rats treated with empagliflozin showed decreased inflammation, as evidenced by MCP-1 downregulation in the rat aorta.…”

“…Similar results were later obtained for other members of this class of drugs (eg, canagliflozin) . Other trials with different glucose‐lowering drugs, such as DPP‐4 inhibitors, in a comparable population of patients did not achieve this success, despite a similar reduction in glycated haemoglobin (HbA1c), suggesting that SGLT2 inhibitors are characterized by additional protective mechanisms against CV disease . These results of SGLT2 inhibitor clinical trials initially pointed out a marked protective effect on heart failure, while the rate of myocardial infarction and strokes was not significantly different .…”

Cardiovascular outcome trials of glucose-lowering medications: an update

“…Indeed, composite exposure to albiglutide and placebo at phase 2/3 was not very different from that in Harmony Outcome [37]. However, the number of people with MACE events was just 105 (HR 0.99 [95% CI 0.65, 1.49]), emphasising (as has been shown with rosiglitazone and DPP4 inhibitors) how phase 2/3 studies with low numbers can give misleading findings for CV outcomes [6,38].…”

Influence of nutritional intervention on children with type 1 diabetes mellitus and DPP-4 in serum

“…The physiological function of GLP-1 is complicated. It is thought to reduce blood glucose by stimulating insulin, controlling glucagon, inhibiting gastric emptying and promoting islet cell regeneration (12–14). GLP-1 can also secrete glucagon and the decomposition of hepatic glycogen by reducing pancreas cell function to promote blood glucose into liver and skeletal muscle, thereby compounding glycogen that is reserved for blood glucose regulation (15,16).…”