Efficacy and Safety of Saxagliptin in Older Participants in the SAVOR-TIMI 53 Trial

Abstract

OBJECTIVETo examine the safety and cardiovascular (CV) effects of saxagliptin in the predefined elderly ( ‡65 years) and very elderly ( ‡75 years) subpopulations of the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial. RESEARCH DESIGN AND METHODSIndividuals ‡40 years (n = 16,492; elderly, n = 8,561; very elderly, n = 2,330) with HbA 1c ‡6.5% (47.5 mmol/mol) and £12.0% (107.7 mmol/mol) were randomized (1:1) to saxagliptin (5 or 2.5 mg daily) or placebo in a double-blind trial for a median follow-up of 2.1 years. RESULTSThe hazard ratio (HR) for the comparison of saxagliptin versus placebo for the primary end point (composite of CV mortality, myocardial infarction, or ischemic stroke) was 0.92 for elderly patients vs. 1.15 for patients <65 years (P = 0.06) and 0.95 for very elderly patients. The HRs for the secondary composite end points in the entire cohort, elderly cohort, and very elderly cohort were similar. Although saxagliptin increased the risk of hospitalization for heart failure in the overall saxagliptin population, there was no age-based treatment interaction (P = 0.76 for elderly patients vs. those <65 years; P = 0.34 for very elderly patients vs. those <75 years). Among saxagliptin-treated individuals with baseline HbA 1c ‡7.6% (59.6 mmol/mol), the mean change from baseline HbA 1c at 2 years was 20.69%, 20.64%, 20.66%, and 20.66% for those ‡65, <65, ‡75, and <75 years old, respectively. The incidence of overall adverse events (AEs) and serious AEs was similar between saxagliptin and placebo in all cohorts; however, hypoglycemic events were higher for saxagliptin versus placebo regardless of age. CONCLUSIONSThe SAVOR-TIMI 53 trial supports the overall CV safety of saxagliptin in a robust number of elderly and very elderly participants, although the risk of heart failure hospitalization was increased irrespective of age category. AEs and serious AEs as well as glycemic efficacy of saxagliptin in elderly patients are similar to those found in younger patients.Estimates place the global prevalence of diabetes in individuals between 60 and 79 years old at ;19%, with the number of these individuals projected to almost double by 2035 (1). Despite ongoing emphasis on the importance of practicing evidencebased medicine (2), older patients have been underrepresented in type 2 diabetes

Cardiovascular Safety of Incretin-Based Therapies in Type 2 Diabetes: Systematic Review of Integrated Analyses and Randomized Controlled Trials

“…We identified one primary article and one secondary article for the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial [28, 45], one primary article and two secondary articles for the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)–Thrombolysis in Myocardial Infarction (TIMI) 53 (SAVOR-TIMI 53) trial [43, 46, 47], and one primary article for the Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin (TECOS) [44]. Overall, EXAMINE, SAVOR-TIMI 53, and TECOS found no evidence that DPP-4 inhibitor therapy alters MACE risk relative to placebo [28, 43, 44, 48].…”

“…Multivariable analyses revealed that subjects at greatest risk of hospitalization for HF had previous HF (adjusted HR 4.18; 95% CI 3.48–5.02), an eGFR ≤60 mL/min (adjusted HR 2.00; 95% CI 1.65–2.42), or elevated baseline levels (quartile 4) of N-terminal pro B-type natriuretic peptide (adjusted HR 5.51; 95% CI 4.24–7.16) [46]. Risk of MACE in SAVOR-TIMI 53 was similar among elderly (≥65 years, HR 0.92; 95% CI 0.79–1.06; <65 years, HR 1.15; 95% CI 0.96–1.37; interaction P value 0.06) and very elderly (≥75 years, HR 0.95; 95% CI 0.75–1.22; <75 years, HR 1.01; 95% CI 0.89–1.15; interaction P value 0.67) patients who received saxagliptin and placebo [47]. The increased risk of HF-associated hospitalization with saxagliptin relative to placebo was similar regardless of age group [47].…”

“…Risk of MACE in SAVOR-TIMI 53 was similar among elderly (≥65 years, HR 0.92; 95% CI 0.79–1.06; <65 years, HR 1.15; 95% CI 0.96–1.37; interaction P value 0.06) and very elderly (≥75 years, HR 0.95; 95% CI 0.75–1.22; <75 years, HR 1.01; 95% CI 0.89–1.15; interaction P value 0.67) patients who received saxagliptin and placebo [47]. The increased risk of HF-associated hospitalization with saxagliptin relative to placebo was similar regardless of age group [47]. …”

Review of Hypoglycemia in the Older Adult: Clinical Implications and Management

“…A recent retrospective subgroup analysis (279 patients, 65 years of age and older) evaluating saxagliptin 5 mg daily vs. placebo demonstrated the clinically relevant and significant efficacy of saxagliptin in reducing A1C levels in older patients (37). The recently published Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOUR-TIMI) trial also supports the use of DDP-4 inhibitors in the elderly because they are simple, once-daily agents that incur no risk for hypoglycemia (38). However, their use is limited in most countries due to high cost.…”

Lixisenatide Therapy in Older Patients With Type 2 Diabetes Inadequately Controlled on Their Current Antidiabetic Treatment: The GetGoal-O Randomized Trial

“…Few studies specifically in older adults with type 2 diabetes exist, limiting the applicability of the evidence to older, complex patients (11)(12)(13)(14)(15)(16). In recognition of the particular pathophysiologic features of older patients with diabetes, the International Diabetes Federation (IDF) and the American Diabetes Association (ADA) developed guidelines specifically for the older population.…”