Incidence of Fractures in Patients With Type 2 Diabetes in the SAVOR-TIMI 53 Trial

Abstract

OBJECTIVEPatients with type 2 diabetes have an increased risk of bone fractures, the predisposing factors for which are unknown. Treatment with thiazolidinediones (TZDs) further increases the incidence of osteoporotic fractures. In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes MellitusThrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial, fractures were considered an adverse event of special interest, and information regarding fractures was collected. RESEARCH DESIGN AND METHODSWe compared the incidence of fractures among the 8,280 patients who were assigned to treatment with saxagliptin with that in the 8,212 patients who were assigned to placebo. We further analyzed the participants' baseline characteristics and fracture risk. RESULTSDuring a median follow-up of 2.1 years, 241 patients (2.9%) in the saxagliptin group and 240 (2.9%) in the placebo group experienced a fracture (hazard ratio [HR] 1.00 [95% CI 0.83-1.19]). Event rates for fractures were the same in both treatment arms: 14.7 per 1,000 patient-years in the entire population and 14.0 in the ontreatment population (first event only). Fracture risk was similar in patients treated with saxagliptin or placebo across different subgroups defined by race, cardiovascular risk, and renal function. A multivariable Cox regression analysis showed that risk of fracture was associated with female sex (P < 0.0001), longer diabetes duration (P < 0.0001), older age (P = 0.002), major hypoglycemic events (P = 0.01), noncompliance with study drug (P = 0.01), and treatment with TZDs (P = 0.03). CONCLUSIONSIn a large population of older patients with type 2 diabetes, treatment with saxagliptin was not associated with an increased risk of fractures. The association between longer diabetes duration and increased risk of bone fracture is an intriguing finding.There is a growing body of evidence that type 1 and type 2 diabetes both predispose to bone fractures (1,2). A recent nested cohort study demonstrated a hazard ratio (HR) of 1.66 (95% CI 1.6-1.72) for the risk of fractures requiring surgery in patients with diabetes compared with age-and sex-matched control subjects (3). The same study also demonstrated increased risk for postfracture complications among the population with diabetes, including deep wound infection, septicemia, and mortality.

Dipeptidyl peptidase-4 inhibitors and bone metabolism: is vitamin D the link?

“…The main finding of this study is the existence of an association between DPP4-Is therapy and higher serum 25(OH)D levels in patients with type 2 diabetes, independent of major confounders and likely not related to GLP-1 [4,5,7,8] but not in patients treated with weakly selective DPP4-Is [9][10][11]. This is the first study investigating vitamin D status in the course of DPP4 inhibition, as in patients with type 2 diabetes under DPP4-Is treatment.…”

“…In particular, favorable bone outcomes resulted from treatment with agents highly inhibitory and selective toward DPP4, i.e., sitagliptin [4,5,7,8]; contrariwise, no protective effects were shown in patients treated with weakly selective DPP4-Is, such as saxagliptin [9,10] and vildagliptin [11].…”

Long‐term use of dipeptidyl peptidase‐4 inhibitors and risk of fracture: A retrospective population‐based cohort study

“…After stratification by continuous duration of use we showed no associa- 19,20 Both meta-analyses showed no association between use of DPP-4 inhibitors and risk of fracture. The adverse events fracture data of a large clinical trial (n = 16 492) comparing saxagliptin, a DPP-4 inhibitor, with placebo have been analysed in more depth 21 and showed a relative risk of 1. The present results are also supported by the results of an analysis of the fracture data of a cardiovascular trial comparing sitagliptin, a DPP-4 inhibitor, with placebo in patients with T2DM (N = 14 671), which showed no association with risk of fracture.…”

Diabetes pharmacotherapy and effects on the musculoskeletal system

“…Additionally, saxagliptin (as monotherapy or add‐on therapy), in recent data from pooled analysis of 20 randomized control studies demonstrated a higher incidence of fracture with saxagliptin, a risk which was not, however, reported in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus‐Thrombolysis in Myocardial Infarction trial …”