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Sodium-glucose cotransporter 2 inhibitors and fracture risk in patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled trials

ABSTRACT: Background: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fracture compared with those without T2DM. Some oral glucose-lowering agents may increase the incidence of fracture. Whether sodium-glucose co-transporter 2 inhibitors (SGLT2is) are associated with increased risk of fracture remains unclear. Methods: We retrieved articles from PubMed, Embase, Cochrane Library database, and other sources up to 24 October 2019. We included randomized controlled trials (RCTs) that reported fractures and analyzed the fracture incidence of SGLT2i, canagliflozin, dapagliflozin, and empagliflozin. Subgroup analysis was also performed based on baseline characteristics. Results: A total of 78 RCTs with 85,122 patients were included in our analysis. The overall SGLT2i fracture incidence was 2.56% versus 2.77% in the control group [odds ratio (OR), 1.03; 95% confidence interval (CI) (0.95, 1.12); p?=?0.49]. Compared with the control treatment, treatment with canagliflozin led to a higher rate of fractures [OR, 1.17; 95% CI (1.00, 1.37); p?=?0.05], but no significant difference was observed when compared with dapagliflozin [OR, 1.02; 95% CI (0.90, 1.15); p?=?0.79] or empagliflozin [OR, 0.89; 95% CI (0.73, 1.10); p?=?0.30]. Subgroup analysis showed that, in a follow-up of less than 52?weeks, SGLT2i decreased the incidence of fracture by 29% [OR, 0.71; 95% CI (0.55, 0.93); p?=?0.01], but this benefit was lost when the follow-up extended to more than 52?weeks [OR, 1.08; 95% CI (0.98, 1.18); p?=?0.12]. Conclusion: Canagliflozin seems to increase the risk of fracture, while other SGLT2is do not result in a higher incidence of fracture.

SUBMITTER: Lou Y

PROVIDER: S-EPMC7534105 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:Background Recent studies have increasingly shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors may have beneficial cardiovascular and metabolic effects in patients without diabetes mellitus. Hence, we conducted a systematic review and meta-analysis to determine the effect of SGLT2 inhibitors on cardiovascular and metabolic outcomes in patients without diabetes mellitus. Methods and Results Four electronic databases (PubMed, Embase, Cochrane, and SCOPUS) were searched on August 30, 2020 for articles published from January 1, 2000 to August 30, 2020, for studies that examined the effect of SGLT2 inhibitors on cardiovascular and metabolic outcomes in patients without diabetes mellitus. A random-effects pairwise meta-analysis model was used to summarize the studies. A total of 8 randomized-controlled trials were included with a combined cohort of 5233 patients. In patients without diabetes mellitus, those with heart failure treated with SGLT2 inhibitors had a 20% relative risk reduction in cardiovascular deaths and heart failure hospitalizations, compared with those who were not treated (risk ratio, 0.78; P<0.001). We additionally found that treatment with SGLT2 inhibitors improved multiple metabolic indices. Patients on SGLT2 inhibitors had a reduction in body weight of -1.21 kg (P<0.001), body mass index of -0.47 kg/m2 (P<0.001), systolic blood pressure of -1.90 mm Hg (P=0.04), and fasting plasma glucose of -0.38 mmol/L (P=0.05), compared with those without. There were no between-group differences in NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, waist circumference, diastolic blood pressure, glycated hemoglobin, low-density lipoprotein cholesterol levels, and estimated glomerular filtration rates. Across our combined cohort of 5233 patients, hypoglycemia was reported in 22 patients. Conclusions SGLT2 inhibitors improve cardiovascular outcomes in patients without diabetes mellitus with heart failure. In patients without diabetes mellitus, SGLT2 inhibitors showed positive metabolic outcomes in weight and blood pressure control.

Project description:Background and objectivesSodium-glucose cotransporter-2 (SGLT2) inhibitors have been associated with a higher risk of skeletal fractures in some randomized, placebo-controlled trials. Secondary hyperparathyroidism and increased bone turnover (also common in CKD) may contribute to the observed fracture risk. We aimed to determine if SGLT2 inhibitor use associates with a higher risk of fractures compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, which have no known association with fracture risk. We hypothesized that this risk, if present, would be greatest in patients with lower eGFR.Design, setting, participants, & measurementsWe conducted a population-based cohort study in Ontario, Canada between 2015 and 2019 using linked provincial administrative data to compare the incidence of fracture between new users of SGLT2 inhibitors and DPP-4 inhibitors. We used inverse probability of treatment weighting on the basis of propensity scores to balance the two groups of older adults (≥66 years of age) on indicators of baseline health. We compared the 180- and 365-day cumulative incidence rates of fracture between groups. Prespecified subgroup analyses were conducted by eGFR category (≥90, 60 to <90, 45 to <60, and 30 to <45 ml/min per 1.73 m2). Weighted hazard ratios were obtained using Cox proportional hazard regression.ResultsAfter weighting, we identified a total of 38,994 new users of a SGLT2 inhibitor and 37,449 new users of a DPP-4 inhibitor and observed a total of 342 fractures at 180 days and 689 fractures at 365 days. The weighted 180- and 365-day risks of a fragility fracture did not significantly differ between new users of a SGLT2 inhibitor versus a DPP-4 inhibitor: weighted hazard ratio, 0.95 (95% confidence interval, 0.79 to 1.13) and weighted hazard ratio, 0.88 (95% confidence interval, 0.88 to 1.00), respectively. There was no observed interaction between fracture risk and eGFR category (P=0.53).ConclusionsIn this cohort study of older adults, starting a SGLT2 inhibitor versus DPP-4 inhibitor was not associated with a higher risk of skeletal fracture, regardless of eGFR.

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Sodium-glucose cotransporter 2 inhibitors and fracture risk in patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled trials

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