Effect of canagliflozin use on body weight and blood pressure at one-year follow-up: A systematic review and meta-analysis

Abstract

The sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective hypoglycemic agents indicated for the treatment of type 2 diabetes mellitus (T2DM). In addition to glycemic control, there is evidence that SGLT2 inhibitors can reduce body weight and blood pressure (BP) through osmotic diuresis. Most clinical trials on SGLT2 inhibitors have been limited by small sample sizes and have therefore been underpowered to reliably demonstrate these effects. To overcome this, meta-analyses have been conducted to increase the sample size. A recent meta-analysis that included all randomized control trials of SGLT2 inhibitors showed significant reductions in body weight (weighted mean difference (WMD): 1.88 kg (95% confidence interval (CI) 2.11 to 1.66) and systolic and diastolic BP (WMD: 2.46mmHg and 1.46mmHg respectively). However, this study was subject to considerable heterogeneity; possibly due to variation in follow-up time (range 4–104 weeks) and specific agent/drug dosage across included studies. Canagliflozin is one of the most widely prescribed drugs in the SGLT2 inhibitors class, and it is likely to be available as a generic drug soon, which will result in a surge in its distribution. Therefore, we aimed to conduct a focused analysis to study the long-term effects of canagliflozin on body weight and BP. Additionally, we stratified by dosage to reduce heterogeneity. We queried electronic databases (MEDLINE, Scopus and Cochrane CENTRAL) from their inception to July 2017 for published randomized controlled trials of canagliflozin. We used the search string ‘‘canagliflozin OR TA-7284’’. Studies with a follow-up period of at least one year and reporting change in BP or percentage change in body weight were selected. Mean change and standard deviation for each arm were extracted from included trials. The search and data extraction were carried out independently by two reviewers (MSU and TJS). A third reviewer (MSK) was consulted in order to resolve discrepancies. Analysis was conducted on RevMan V.5.3. Trials were pooled using a random effects model and results were presented as WMD with 95% CIs. Subgroup analysis according to dosage (100mg/300mg) was performed. Chi-squared ( ) test was conducted to test for subgroup differences. Heterogeneity was evaluated using Higgins’ I. I< 50% was considered acceptable heterogeneity. The initial search yielded 1904 potential studies. After exclusions, five trials remained for analysis. The detailed literature search is highlighted in the PRISMA Flow Chart (Supplementary Material Figure 1 online). The included trials randomized 13,158 T2DM patients, with 7680 in the canagliflozin arm and 5478 in the control arm. Characteristics of participants from the included studies are shown in Table 1, of which 61% were male with a mean age of 61 years, mean body weight 90.8 kg, and mean systolic BP of 136. Assessment of risk of bias in the included studies is shown in Supplementary Table 1. Our pooled analysis demonstrates that canagliflozin use was associated with significant reduction in body weight when compared with controls (WMD: 3.32% (–4.04, 2.60); p< 0.001; I1⁄4 3%). Significant weight reduction was seen with both 100mg (–3.08% (–5.01, 1.01); p< 0.001; I1⁄4 36%) and 300mg (–3.45% ( 4.64, 2.26); p< 0.001; I1⁄4 0%). However, this effect was not dose dependent (p ( )1⁄4 0.76), and there was no significant change in the risk of volume