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Long-Term Safety of Dapagliflozin in Older Patients with Type 2 Diabetes Mellitus: A Pooled Analysis of Phase IIb/III Studies.

ABSTRACT: To evaluate the 104-week safety of dapagliflozin in older patients with type 2 diabetes mellitus.Pooled analysis assessing general safety (nine phase III studies ?104 weeks) and cardiovascular safety (21 phase IIb/III studies ?208 weeks) by age (<65; ?65; ?75 years). Patients with type 2 diabetes mellitus (±background glucose-lowering therapy) received: dapagliflozin 10 mg (n = 2026) vs. placebo (n = 1956) (nine-study pool); or dapagliflozin (2.5-50 mg; n = 5936) vs. control (placebo/comparator) (n = 3403) (21-study pool).Adverse events (AEs) and discontinuations owing to AEs were more common in older vs. younger patients, and were more frequent with dapagliflozin than placebo (AEs: <65 years: 73.1 vs. 70.7 %; ?65 years: 77.4 vs. 73.1 %; ?75 years: 80.4 vs. 75.3 %, respectively; discontinuations: <65 years: 5.9 vs. 5.0 %; ?65 years: 14.4 vs. 12.2 %; ?75 years: 26.8 vs. 22.1 %, respectively); serious AE (SAE) frequency was similar (<65 years: 11.0 vs. 11.8 %; ?65 years: 20.0 vs. 20.2 %; ?75 years: 19.6 vs. 18.2 %, respectively). Hypoglycaemia frequency was similar across age groups and was higher with dapagliflozin than placebo (<65 years: 18.0 vs. 13.4 %; ?65 years: 20.2 vs. 17.7 %; ?75 years: 17.5 vs. 16.9 %, respectively); major episodes were rare. Urinary tract infection frequency was similar between treatment groups in older patients, with no increase vs. younger patients (<65 years: 8.8 vs. 5.5 %; ?65 years: 8.1 vs. 7.6 %; ?75 years: 8.2 vs. 9.1 %, respectively); urinary tract infection SAEs were rare. Genital infection AEs were more common with dapagliflozin, with no increase in older patients (<65 years: 8.2 vs. 1.0 %; ?65 years: 6.6 vs. 0.9 %; ?75 years: 7.2 vs. 0.0 %, respectively) and no SAEs. Volume reduction AEs were uncommon, with a higher frequency with dapagliflozin vs. placebo and in patients ?75 years (<65 years: 1.7 vs. 1.2 %; ?65 years: 2.3 vs. 1.7 %; ?75 years: 3.1 vs. 2.6 %, respectively). Dapagliflozin did not increase the risk of fractures (<65 years: 1.1 vs. 1.1 %; ?65 years: 1.1 vs. 2.7 %; ?75 years: 1.0 vs. 2.6 %, respectively) or falls (<65 years: 0.7 vs. 0.7 %; ?65 years: 0.6 vs. 2.1 %; ?75 years: 0.0 vs. 1.3 %, respectively), regardless of age. AEs of renal function were more common with dapagliflozin than placebo and increased with age (<65 years: 3.5 vs. 2.3 %; ?65 years: 14.0 vs. 7.9 %; ?75 years: 29.9 vs. 20.8 %, respectively). Most were non-serious small transient increases in serum creatinine. Dapagliflozin did not increase cardiovascular risk regardless of age [hazard ratio (95 % confidence interval) vs.<65 years: 0.726 (0.473, 1.114); ?65 years: 0.879 (0.565, 1.366); ?75 years: 0.950 (0.345, 2.617), respectively].Dapagliflozin treatment up to 104 weeks was well tolerated in older patients. Older dapagliflozin-treated patients had more renal AEs than placebo-treated patients; the majority of which were non-serious small transient changes in serum creatinine.

SUBMITTER: Fioretto P

PROVIDER: S-EPMC4937081 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Long-Term Safety of Dapagliflozin in Older Patients with Type 2 Diabetes Mellitus: A Pooled Analysis of Phase IIb/III Studies.

Fioretto Paola P Mansfield Traci A TA Ptaszynska Agata A Yavin Yshai Y Johnsson Eva E Parikh Shamik S

Drugs & aging 20160701 7

<h4>Objective</h4>To evaluate the 104-week safety of dapagliflozin in older patients with type 2 diabetes mellitus.<h4>Methods</h4>Pooled analysis assessing general safety (nine phase III studies ≤104 weeks) and cardiovascular safety (21 phase IIb/III studies ≤208 weeks) by age (<65; ≥65; ≥75 years). Patients with type 2 diabetes mellitus (±background glucose-lowering therapy) received: dapagliflozin 10 mg (n = 2026) vs. placebo (n = 1956) (nine-study pool); or dapagliflozin (2.5-50 mg; n = 5936 ...[more]

PMID: 27357173

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Project description:IntroductionIpragliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). The objective of this pooled analysis was to characterise the safety profile of ipragliflozin based on safety data from published randomised controlled trials.MethodsSafety data from 12 randomised, phase II/III/IV placebo-controlled, parallel group, comparative studies of ipragliflozin in patients with T2DM were pooled. Treatment-emergent adverse events (TEAEs) were analysed for patients who had received at least one dose of ipragliflozin 50 mg (n = 1209) or placebo (n = 796) in studies lasting for up to 24 weeks. TEAEs of special interest and serious adverse events (SAEs) were assessed, as well as abnormal laboratory test and vital sign measurements.ResultsThe overall incidences of TEAEs and SAEs between the ipragliflozin and placebo groups were similar, 63.8% vs 59.3% and 2.5% vs 3.3%, respectively. The incidence of TEAEs leading to permanent discontinuation was lower for ipragliflozin (3.6%) than placebo (6.5%). The incidences of TEAEs of special interest including those related to urinary tract infection, cardiovascular events, renal disorder, fracture, malignant tumours and hypoglycaemia were also similar between the groups. Genital infections were more frequent with ipragliflozin (2.4%) than placebo (0.6%), as were pollakiuria/polyuria (6.0% vs 2.0%), volume depletion (4.9% vs 1.8%) and skin/subcutaneous tissue disorders (7.7% vs 4.4%). There were no reported cases of diabetic ketoacidosis, fractures, lower-limb amputation or Fournier's gangrene in ipragliflozin-treated patients across the 12 studies.ConclusionIn randomised, placebo-controlled trials of patients with T2DM, ipragliflozin was well tolerated, with a similar overall incidence of TEAEs to placebo. No new safety signals were observed.Trial registration numbersNCT01071850, NCT00621868, NCT01057628, NCT01117584, NCT01135433, NCT01225081, NCT01242215, NCT02175784, NCT01505426, NCT02452632, NCT02794792, NCT01316094.FundingAstellas Pharma Inc.

Project description:BackgroundLong-term treatment with antipsychotic agents is indicated for patients with schizophrenia, but treatment is associated with adverse events (AEs) that contribute to medication discontinuation and nonadherence. Understanding drug safety profiles is critical to avoid unwanted side effects. Cariprazine is a potent dopamine D3/D2 receptor partial agonist that is approved for the treatment of adults with schizophrenia (EU, US) and acute manic/mixed and depressive episodes associated with bipolar I disorder (US).MethodsPost hoc analyses were conducted to characterize the safety profile of cariprazine within the recommended 1.5-6 mg/d dose range for schizophrenia; data from 8 short- or long-term clinical trials were analyzed.ResultsIn the pooled cariprazine-treated safety population (n=2048), the rate of study completion was 52.8%, with withdrawal of consent, insufficient response, and AEs the most common reasons for premature discontinuation. The most commonly reported AEs (>10%) in the overall cariprazine-treatment group were akathisia (14.6%), insomnia (14.0%), and headache (12.1%); most AEs were considered mild (71.0%) or moderate (26.5%). Most akathisia was mild/moderate (97.5%) and >93% of patients remained on treatment; akathisia events were managed by rescue medications (56.3%) or dose reduction (18.3%). The metabolic profile of cariprazine was neutral in patients with short- and long-term exposure; mean weight gain was 1 kg for overall cariprazine, with an AE of weight increased reported for 5.1%. Other AEs of special interest that occurred at >3% for overall cariprazine were extrapyramidal disorder (7.0%), sedation (3.7%), and somnolence (3.1%); prolactin elevation, cognition impairment, sexual dysfunction, suicidality, and QT prolongation occurred at ≤1%.ConclusionAkathisia, the most common cariprazine-related AE, was mild/moderate and resulted in few study discontinuations; symptoms were well managed and most patients remained on treatment. Results of this analysis indicated that cariprazine in the recommended dose range was safe and generally well tolerated in patients with schizophrenia.Trial registrationStudies registered with ClinicalTrials.gov (NCT00404573, NCT01104779, NCT00694707, NCT01104766, NCT01104792, NCT00839852, and NCT01412060) and EudraCT (2012-005485-36).

Project description:Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). The efficacy and safety of canagliflozin were evaluated in patients with T2DM <65 and ?65 years of age.Pooled data from 4 randomised, placebo-controlled, 26-week, Phase 3 studies (N?=?2,313) evaluating canagliflozin 100 and 300 mg were analysed by age: <65 years (n?=?1,868; mean age, 52.8 years) or ?65 years (n?=?445; mean age, 69.3 years). Efficacy evaluations included change from baseline in glycaemic parameters and systolic blood pressure (BP), and percent change from baseline in body weight. Assessment of safety/tolerability included adverse event (AE) reports, incidence of documented hypoglycaemia, and percent change from baseline in fasting plasma lipids.Canagliflozin 100 and 300 mg reduced HbA1c and fasting plasma glucose relative to placebo in patients <65 and ?65 years of age. Both canagliflozin doses reduced body weight and systolic BP relative to placebo in patients <65 and ?65 years of age. Incidence of overall AEs was similar across all treatment groups in patients <65 and ?65 years of age. Incidences of serious AEs and AE-related discontinuations were similar across all treatment groups in patients <65 years of age and higher with canagliflozin 100 mg than other groups in patients ?65 years of age. As in patients <65 years of age, incidences of genital mycotic infections and osmotic diuresis-related AEs were higher with canagliflozin relative to placebo in those ?65 years of age. Incidences of urinary tract infections (UTIs), renal-related AEs, AEs related to volume depletion, and documented hypoglycaemia episodes were similar across all treatment groups in patients ?65 years of age; no notable trends were observed with canagliflozin 100 and 300 mg relative to placebo in these AEs among patients <65 years of age. Changes in lipid parameters with canagliflozin were similar in both age subsets.Canagliflozin improved glycaemic control, body weight, and systolic BP, and was generally well tolerated in older patients with T2DM.ClinicalTrials.gov, NCT01081834; NCT01106677; NCT01106625; NCT01106690.

Dataset Information

Long-Term Safety of Dapagliflozin in Older Patients with Type 2 Diabetes Mellitus: A Pooled Analysis of Phase IIb/III Studies.

Publications

Long-Term Safety of Dapagliflozin in Older Patients with Type 2 Diabetes Mellitus: A Pooled Analysis of Phase IIb/III Studies.

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