PracticeUpdate: Diabetes

EDITOR’S PICKS 15

Canagliflozin and Renal Outcomes in Type 2 Diabetes The Lancet Diabetes & Endocrinology Take-home message • In this exploratory analysis of theCANVAS program, 10,142 participants whowere randomized to receive canagliflozin or placebowere evalu- ated for long-term renal outcomes. Comparedwith the placebo group, patients who received canagliflozin experienced the composite out- come of sustained doubling of serum creatinine, end-stage kidney disease, and death from renal causes significantly less frequently (1.5 vs 2.8 per 1000 patient-years). The mean urinary albumin-to-creati- nine ratio was 18% lower and the annual eGFR decline was slower in patients who received canagliflozin compared with placebo. Serious renal adverse events were similar between the groups. • These results further support a potential renoprotective effect of canagliflozin in people with type 2 diabetes. Abstract BACKGROUND In the Canagliflozin Cardiovascular Assessment Study (CANVAS) Pro- gram, canagliflozin reduced the rates of major adverse cardiovascular events and the results suggested a renal benefit in patients with type 2 diabetes who were at high risk for cardiovascular events, compared with those treated with placebo. Here we report the results of a prespecified exploratory analysis of the long-term effects of canagliflozin on a range of sustained and adjudicated renal outcomes. METHODS The CANVAS Program consists of two double-blind, randomised trials that assessed canagliflozin versus placebo in participants with type 2 diabetes who were at high risk of cardiovascular events, done at 667 centres in 30 coun- tries. People with type 2 diabetes and an HbA1c of 7·0-10·5% (53-91 mmol/mol) who were aged at least 30 years and had a history of symptomatic atheroscle- rotic vascular disease, or who were aged at least 50 years and had at least two cardiovascular risk factors were eligible to participate. Participants in CANVAS were randomly assigned (1:1:1) to receive 300 mg canagliflozin, 100 mg canagli- flozin, or matching placebo once daily. Participants in CANVAS-R were randomly assigned (1:1) to receive canagliflozin or matching placebo, at an initial dose of 100 mg daily, with optional uptitration to 300 mg from week 13 or matching pla- cebo. Participants and all study staff were masked to treatment allocations until study completion. Prespecified outcomes reported here include a composite of sustained and adjudicated doubling in serum creatinine, end-stage kidney dis- ease, or death from renal causes; the individual components of this composite outcome; annual reductions in estimated glomerular filtration rate (eGFR); and changes in urinary albumin-to-creatinine ratio (UACR). FINDINGS Between Nov 17, 2009, and March 7, 2011 (CANVAS), and Jan 17, 2014, and May 29, 2015 (CANVAS-R), 15 494 people were screened, of whom 10 142 partic- ipants (with a baseline mean eGFR 76·5 mL/min per 1·73 m 2 , median UACR 12·3 mg/g, and 80% of whom were receiving renin-angiotensin system blockade) were randomly allocated to receive either canagliflozin or placebo. The composite out- come of sustained doubling of serum creatinine, end-stage kidney disease, and death from renal causes occurred less frequently in the canagliflozin group com- pared with the placebo group (1·5 per 1000 patient-years in the canagliflozin group vs 2·8 per 1000 patient-years in the placebo group; hazard ratio 0·53, 95% CI 0·33- 0·84), with consistent findings across prespecified patient subgroups. Annual eGFR decline was slower (slope difference between groups 1·2 mL/min per 1·73 m 2 per year, 95% CI 1·0-1·4) and mean UACR was 18% lower (95% CI 16-20) in participants treated with canagliflozin than in those treated with placebo. Total serious renal-re- lated adverse events were similar between the canagliflozin and placebo groups (2·5 vs 3·3 per 1000 patient-years; HR 0·76, 95% CI 0·49-1·19). INTERPRETATION In a prespecified exploratory analysis, canagliflozin treatment was associated with a reduced risk of sustained loss of kidney function, attenuated eGFR decline, and a reduction in albuminuria, which supports a possible reno- protective effect of this drug in people with type 2 diabetes. Canagliflozin and Renal Outcomes in Type 2 Diabetes: Results From the CAN- VAS Program Randomised Clinical Trials. Lancet Diabetes Endocrinol 2018 Jun 21;[EPub Ahead of Print], V Perkovic, D Zeeuw, KW Mahaffey, et al. www.practiceupdate.com/c/69910

Hypoglycemia Associated With Risk of Cardiac Arrhythmia in Patients With

Diabetes Mellitus Diabetes, Obesity & Metabolism Take-home message

• This systematic review and meta-analysis included data from 20 studies to examine the association between hypoglycemia and risk of cardiac arrhythmia in patients with type 1 diabetes (T1D) and type 2 diabetes (T2D). Data from 241 patients with T1D and 116 patients with T2D were included. Increase in arrhythmia occurrence and decrease in heart rate variability were both associated with hypoglycemia. The QTc interval was prolonged during hypoglycemia compared with its duration during euglycemia, but this finding was only statistically significant for T1D when analyzed by subgroup (T1D or T2D). This asso- ciation varied by study design and was strongest in experimental studies, possibly due to confounders in observational studies and differing definitions of hypoglycemia. Additionally, the smaller number of studies including patients with T2Dmake it difficult to draw conclusions about QTc interval in this population. • This study shows that hypoglycemia in patients with diabetes increases the risk of arrhythmia. There is a need for more studies to better examine variables that may affect this, especially in patients with T2D. Abstract AIMS Hypoglycaemia is associated with increased cardiovascular risk among individuals with diabetes mellitus. It has been hypothe- sized that hypoglycaemia may trigger autonomic changes leading to increased cardiac arrhythmia risk. We conducted a systematic review and meta-analysis to explore this association. MATERIALS AND METHODS Ovid Medline, Embase, Scopus, Web of Science and Cochrane were searched from inception to October 10, 2017. We included studies of adults with diabetes (Type 1 or Type 2) that compared acute electrocardiogram (ECG) changes during episodes of hypoglycaemia and euglycaemia. RESULTS Our search resulted in 4625 citations, among which 20 studies met the predefined inclusion criteria. Finally, 12 studies were included in the descriptive analysis and 15 in the meta-anal- ysis. Overall hypoglycaemia was associated with a reduction in heart rate variability and an increase in arrhythmia occurrence. QTc interval length was more significantly prolonged during hypogly- caemia compared to euglycaemia (pooled mean difference [95% confidence intervals] [0.64 (0.27-1.01], P=·001). Subgroup analysis based on diabetes type showed that QTc prolongation occurred in individuals with Type 1 and Type 2 diabetes; however, the change between euglycaemia reached statistical significance only among individuals with Type 1 diabetes. CONCLUSION Our findings suggest that hypoglycaemia results in ECG alterations that are associated with increased risk of cardiac arrhythmia, which is associated with increased cardio- vascular events and mortality. More clinical studies are needed to determine the cardiac risks of hypoglycaemia in individuals with diabetes, especially in Type 2 diabetes. Association of Hypoglycaemia and Risk of Cardiac Arrhythmia in Patients With Diabetes Mellitus: A Systematic Review and Meta-Analysis. Diabetes Obes Metab 2018 May 08;[EPub Ahead of Print], C Fitzpatrick, S Chatterjee, S Seidu, et al. www.practiceupdate.com/c/68923

VOL. 2 • NO. 3 • 2018