No abstract

Janssen Research & Development.

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OBJECTIVE -We explored whether cardiovascular disease (CVD) risk and the effects of fenofibrate differed in subjects with and without metabolic syndrome and according to various features of metabolic syndrome defined by the Adult Treatment Panel III (ATP III) in subjects with type 2 diabetes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.RESEARCH DESIGN AND METHODS -The prevalence of metabolic syndrome and its features was calculated. Cox proportional models adjusted for age, sex, CVD status, and baseline A1C levels were used to determine the independent contributions of metabolic syndrome features to total CVD event rates and the effects of fenofibrate.RESULTS -More than 80% of FIELD participants met the ATP III criteria for metabolic syndrome. Each ATP III feature of metabolic syndrome, apart from increased waist circumference, increased the absolute risk of CVD events over 5 years by at least 3%. Those with marked dyslipidemia (elevated triglycerides Ն2.3 mmol/l and low HDL cholesterol) were at the highest risk of CVD (17.8% over 5 years). Fenofibrate significantly reduced CVD events in those with low HDL cholesterol or hypertension. The largest effect of fenofibrate to reduce CVD risk was observed in subjects with marked dyslipidemia in whom a 27% relative risk reduction (95% CI 9 -42, P ϭ 0.005; number needed to treat ϭ 23) was observed. Subjects with no prior CVD had greater risk reductions than the entire group.CONCLUSIONS -Metabolic syndrome components identify higher CVD risk in individuals with type 2 diabetes, so the absolute benefits of fenofibrate are likely to be greater when metabolic syndrome features are present. The highest risk and greatest benefits of fenofibrate are seen among those with marked hypertriglyceridemia. Diabetes Care 32:493-498, 2009

OBJECTIVEThere are limited data about the effects of sodium-glucose cotransporter 2 inhibitors when used with insulin. We report the efficacy and safety of canagliflozin in patients with type 2 diabetes using insulin. RESEARCH DESIGN AND METHODSThe CANagliflozin CardioVascular Assessment Study is a double-blind, placebocontrolled study that randomized participants to placebo, canagliflozin 100 mg, or canagliflozin 300 mg once daily, added to a range of therapies. The primary end point of this substudy was the change in HbA 1c from baseline at 18 weeks among patients using insulin; 52-week effects were also examined. RESULTSIndividuals receiving insulin at baseline were randomized to receive placebo (n 5 690), canagliflozin 100 mg (n 5 692), or canagliflozin 300 mg (n 5 690). These individuals were 66% male and had a median age of 63 years, mean HbA 1c of 8.3% (67 mmol/mol), BMI of 33.1 kg/m 2 , estimated glomerular filtration rate of 75 mL/min/1.73 m 2 , fasting plasma glucose of 9.2 mmol/L, and a median daily insulin dose of 60 IU. Most individuals were using basal/bolus insulin. Reductions in HbA 1c with canagliflozin 100 and 300 mg versus placebo were 20. 62% (95% CI 20.69, 20.54; 26.8 mmol/mol [95% CI 27.5,25.9]; P < 0.001) and 20. 73% (95% CI 20.81, 20.65; 28.0 mmol/mol [95% CI 28.9,27.1]; P < 0.001) at 18 weeks and 20. 58% (95% CI 20.68, 20.48; 26.3 mmol/mol [95% CI 27.4, 25.2]) and 20.73% (95% CI 20. 83, 20.63; 28.0 mmol/mol [95% CI 29.1,26.9]) at 52 weeks. There were significant falls in fasting plasma glucose, body weight, and blood pressure at both time points and there was a greater incidence of hypoglycemia, genital mycotic infections, and hypovolemia with both canagliflozin doses. CONCLUSIONSCanagliflozin added to insulin therapy improved glycemic control and decreased body weight. There was a greater frequency of several anticipated side effects, although few led to discontinuation of treatment.

Sodium glucose co-transporter 2 inhibition is a novel mode of treatment for type 2 diabetes mellitus (T2DM). The sodium glucose co-transporter 2 inhibitor canagliflozin lowered blood glucose, blood pressure, and body weight, with increased risk of urogenital infections in Phase 2 studies. Effects on macrovascular complications of diabetes remain to be determined. CANVAS is a double-blind, placebo-controlled trial designed to evaluate the effects of canagliflozin on the risk of cardiovascular disease and to assess safety and tolerability in patients with inadequately controlled T2DM and increased cardiovascular risk. The first of 2 planned phases randomized 4,330 individuals to placebo, canagliflozin 100 or 300 mg (1:1:1) with planned follow-up of about 2 years to substantiate potential cardiovascular protection by assessing key biomarkers and to achieve initial safety objectives. By the end of mid-September 2012, a total of 7174 patient-years of follow-up were accrued. Mean baseline age was 62 years, duration of diabetes 13 years; hemoglobin A1c 8.2%, fasting plasma glucose 9.3 mmol/L, and body mass index 32 kg/m(2). Of the participants, 34% are female and 57% had a history of atherosclerotic vascular disease. Participants will be followed up to achieve primary safety and tolerability objectives and to investigate secondary outcomes. The planned second phase will not be undertaken. CANVAS will define the effects of canagliflozin on biomarkers and provide data on cardiovascular safety against established regulatory parameters.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.