Safety of saxagliptin: events of special interest in 9156 patients with type 2 diabetes mellitus

Hirshberg, Boaz; Parker, Anna; Edelberg, Helen K.; Donovan, Mark; Iqbal, Nayyar

doi:10.1002/dmrr.2502

Cited by 54 publications

(44 citation statements)

References 52 publications

(78 reference statements)

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“…The discrepancy is further supported by the difference between the findings in this trial and the results of a post hoc pooled analysis of 20 phase 2 and 3 trials (n = 9,156) comparing saxagliptin with placebo or active comparator, which found an increased risk for fractures with saxagliptin treatment (HR 1.81 [95% CI 1.04-3.28]) (30). The patient population in the pooled analysis was younger; had a shorter duration of diabetes, better renal function, and less concomitant medication; and was generally healthier compared with the SAVOR TIMI-53 patient population.…”

Section: The Incretin System and Bone Metabolismmentioning

confidence: 61%

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

et al. 2015

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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.

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Section: The Incretin System and Bone Metabolismmentioning

confidence: 61%

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

et al. 2015

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“…Two meta-analyses suggested that the DPP-4 inhibitors are associated with reduced CV risk (23,24). Importantly, however, these data were obtained predominantly from relatively small and/or short-term investigations (18,19,30), systematic reviews (21,28,29), and pooled analyses (20,22,(25)(26)(27)31,32) in by-and-large younger and healthier study participants with very limited, and generally unadjudicated, CV safety information.…”

Section: Discussionmentioning

confidence: 99%

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

Leiter

Teoh²,

Braunwald

et al. 2015

Diabetes Care

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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

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“…Although there is no evident association between the application of saxagliptin and the incidence of gastrointestinal adverse events, infections, hypersensitivity, pancreatitis, skin lesions, lymphopenia, thrombocytopenia, hypoglycaemia, bone fracture, severe cutaneous adverse reactions, opportunistic infection, angioedema, malignancy, and worsening renal function, the patients still need to be cautious to initiate the saxagliptin treatment. 154 For example, hypersensitivity-related urticaria and facial oedema in the 5-study pooled analysis up to week 24 were reported in 1.5%, 1.5%, and 0.4% of patients who received saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, respectively, though none of these events in patients who received saxagliptin required hospitalization or were reported as a life-threatening event. 155,156 Notably, the concern about the possible association between saxagliptin and cardiovascular risk has been raised.…”

Section: Safety Of Saxagliptinmentioning

confidence: 95%

Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

Chen

Zhou

et al. 2015

Clin Exp Pharma Physio

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SUMMARYDipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that improve glycaemic control without causing weight gain or increasing hypoglycaemic risk in patients with type 2 diabetes mellitus (T2DM). The eight available DPP-4 inhibitors, including alogliptin, anagliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin, are small molecules used orally with identical mechanism of action and similar safety profiles in patients with T2DM. DPP-4 inhibitors may be used as monotherapy or in double or triple combination with other oral glucoselowering agents such as metformin, thiazolidinediones, or sulfonylureas. Although DPP-4 inhibitors have the same mode of action, they differ by some important pharmacokinetic and pharmacodynamic properties that may be clinically relevant in some patients. The main differences between the eight gliptins include: potency, target selectivity, oral bioavailability, elimination half-life, binding to plasma proteins, metabolic pathways, formation of active metabolite(s), main excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug-drug interactions. The off-target inhibition of selective DPP-4 inhibitors is responsible for multiorgan toxicities such as immune dysfunction, impaired healing, and skin reactions. As a drug class, the DPP-4 inhibitors have become accepted in clinical practice due to their excellent tolerability profile, with a low risk of hypoglycaemia, a neutral effect on body weight, and once-daily dosing. It is unknown if DPP-4 inhibitors can prevent disease progression. More clinical studies are needed to validate the optimal regimens of DPP-4 inhibitors for the management of T2DM when their potential toxicities are closely monitored.

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Safety of saxagliptin: events of special interest in 9156 patients with type 2 diabetes mellitus

Abstract: Pooled data from 20 studies confirm that saxagliptin has a favourable safety and benefit-risk profile.

Cited by 54 publications

References 52 publications

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

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

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

Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

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