Assessment of the cardiovascular safety of saxagliptin in patients with type 2 diabetes mellitus: pooled analysis of 20 clinical trials

Iqbal, Nayyar; Parker, Anna; Frederich, Robert; Donovan, Mark; Hirshberg, Boaz

doi:10.1186/1475-2840-13-33

Cited by 57 publications

(50 citation statements)

References 49 publications

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“…26,27 There was no signal of fluid retention, weight gain, or heart failure with saxagliptin in the Phase 2 and Phase 3 development program. 28 Moreover, previous preclinical data and small studies with other incretin-based agents suggested potential improvement of left ventricular function, 26 but these data are inconsistent. Two preliminary reports of other studies in patients with DDP-4 inhibitors produced unanticipated findings that highlight potential mechanisms by which treatment with DPP-4 inhibitors could exacerbate heart failure.…”

Section: Discussionmentioning

confidence: 99%

Heart Failure, Saxagliptin, and Diabetes Mellitus: Observations from the SAVOR-TIMI 53 Randomized Trial

et al. 2014

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iabetes mellitus (DM) adds incremental risk of the development and subsequent exacerbation of heart failure even after adjusting for common risk factors, such as ischemic heart disease and hypertension.1 Although incompletely understood, cardiac metabolic dysregulation of glycolysis and fatty acid oxidation observed in the heart of patients with Background-Diabetes mellitus and heart failure frequently coexist. However, few diabetes mellitus trials have prospectively evaluated and adjudicated heart failure as an end point. Methods and Results-A total of 16 492 patients with type 2 diabetes mellitus and a history of, or at risk of, cardiovascular events were randomized to saxagliptin or placebo (mean follow-up, 2.1 years). The primary end point was the composite of cardiovascular death, myocardial infarction, or ischemic stroke. Hospitalization for heart failure was a predefined component of the secondary end point. Baseline N-terminal pro B-type natriuretic peptide was measured in 12 301 patients. More patients treated with saxagliptin (289, 3.5%) were hospitalized for heart failure compared with placebo (228, 2.8%; hazard ratio, 1.27; 95% confidence intercal, 1.07-1.51; P=0.007). Corresponding rates at 12 months were 1.9% versus 1.3% (hazard ratio, 1.46; 95% confidence interval, 1.15-1.88; P=0.002), with no significant difference thereafter (time-varying interaction, P=0.017). Subjects at greatest risk of hospitalization for heart failure had previous heart failure, an estimated glomerular filtration rate ≤60 mL/min, or elevated baseline levels of N-terminal pro B-type natriuretic peptide. There was no evidence of heterogeneity between N-terminal pro B-type natriuretic peptide and saxagliptin (P for interaction=0.46), although the absolute risk excess for heart failure with saxagliptin was greatest in the highest N-terminal pro B-type natriuretic peptide quartile (2.1%). Even in patients at high risk of hospitalization for heart failure, the risk of the primary and secondary end points were similar between treatment groups. Conclusions-In the context of balanced primary and secondary end points, saxagliptin treatment was associated with an increased risk or hospitalization for heart failure. This increase in risk was highest among patients with elevated levels of natriuretic peptides, previous heart failure, or chronic kidney disease. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01107886.

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Section: Discussionmentioning

confidence: 99%

Heart Failure, Saxagliptin, and Diabetes Mellitus: Observations from the SAVOR-TIMI 53 Randomized Trial

et al. 2014

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“…While long-term studies are ongoing, combined analyses of shorterterm trials can provide some insights on possible CV actions of new treatments. In the case of DPP-4 inhibitors, pooled analyses of CV events in randomized phase II-III studies have been published for all molecules (38)(39)(40)(41)(42); all these analyses yielded risk estimates ,1, although differences from comparator groups were not statistically significant (Table 2). Data from different analyses are not comparable, because the definition of events and the trial entry criteria are heterogeneous.…”

Section: Pooled Analyses and Meta-analyses: Combining CV Outcome Studmentioning

confidence: 99%

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

2016

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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

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“…Nevertheless, it seems relatively clear that young patients without CVD have a very low rate of heart failure, and saxagliptin does not increase the risk in this population. 18 Although there were only 74 total major cardiovascular events in a population of 8903 in this 20-study saxagliptin meta-analysis, the events were not adjudicated. The bulk of the patients in these trials were younger than 65 years of age, had diabetes for o5 years, and had no pre-existing CVD.…”

Section: Discussionmentioning

confidence: 98%

Do Dipeptidyl Peptidase IV (DPP-IV) Inhibitors Cause Heart Failure?

Clifton

2014

Clinical Therapeutics

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Assessment of the cardiovascular safety of saxagliptin in patients with type 2 diabetes mellitus: pooled analysis of 20 clinical trials

Cited by 57 publications

References 49 publications

Heart Failure, Saxagliptin, and Diabetes Mellitus: Observations from the SAVOR-TIMI 53 Randomized Trial

Heart Failure, Saxagliptin, and Diabetes Mellitus: Observations from the SAVOR-TIMI 53 Randomized Trial

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

Do Dipeptidyl Peptidase IV (DPP-IV) Inhibitors Cause Heart Failure?

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