Sodium-Glucose Co-Transporter 2 Inhibitors and Fracture Risk.
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ABSTRACT:
SUBMITTER: Erythropoulou-Kaltsidou A
PROVIDER: S-EPMC6965547 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Sodium-Glucose Co-Transporter 2 Inhibitors and Fracture Risk.
Erythropoulou-Kaltsidou Anastasia A Polychronopoulos Georgios G Tziomalos Konstantinos K
Diabetes therapy : research, treatment and education of diabetes and related disorders 20191116 1
Patients with type 2 diabetes mellitus (T2DM) appear to have increased risk for fractures. In this context, the finding that canagliflozin, a sodium-glucose co-transporter-2 (SGLT) inhibitor, increased the risk for fracture compared with placebo in the Canagliflozin Cardiovascular Assessment Study (CANVAS), a large randomized controlled trial (RCT) in patients with established cardiovascular disease or multiple cardiovascular risk factors, created concern. In the present review, we summarize the ...[more]
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Project description:AimTo compare the cardiovascular risks between users and non-users of sodium-glucose co-transporter-2 (SGLT2) inhibitors based on electronic medical record data from a large integrated healthcare system in South Louisiana.Materials and methodsDemographic, anthropometric, laboratory and medication prescription information for patients with type 2 diabetes who were new users of SGLT2 inhibitors, either as initial treatments or as add-on treatments, were obtained from electronic health records. Mediation analysis was performed to evaluate the association of use of SGLT2 inhibitors and changes of metabolic risk factors with the risk of incident ischaemic heart disease.ResultsA total of 5338 new users of SGLT2 inhibitors were matched with 13 821 non-users. During a mean follow-up of 3.26 years, 2302 incident cases of ischaemic heart disease were defined. After adjusting for multiple confounding factors, patients using SGLT2 inhibitors had a lower risk of incident ischaemic heart disease compared to patients not using SGLT2 inhibitors (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.54-0.73). Patients using SGLT2 inhibitors also had a lower risk of incident ischaemic heart disease within 6 months (HR 0.36, 95% CI 0.25-0.44), 12 months (HR 0.40, 95% CI 0.32-0.49), 24 months (HR 0.53, 95% CI 0.43-0.60) and 36 months (HR 0.65, 95% CI 0.54-0.73), respectively. Reductions in systolic blood pressure partly mediated lowering risk of ischaemic heart disease among patients using SGLT2 inhibitors.ConclusionsThe real-world data in the present study show the contribution of SGLT2 inhibitors to reducing risk of ischaemic heart disease, and their benefits beyond glucose-lowering.
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Project description:OBJECTIVE:To assess the association between use of sodium-glucose co-transporter 2 (SGLT2) inhibitors and risk of serious renal events in data from routine clinical practice. DESIGN:Cohort study using an active comparator, new user design and nationwide register data. SETTING:Sweden, Denmark, and Norway, 2013-18. PARTICIPANTS:Cohort of 29?887 new users of SGLT2 inhibitors (follow-up time: dapagliflozin 66.1%; empagliflozin 32.6%; canagliflozin 1.3%) and 29?887 new users of an active comparator, dipeptidyl peptidase-4 inhibitors, matched 1:1 on the basis of a propensity score with 57 variables. Mean follow-up time was 1.7 (SD 1.0) years. EXPOSURES:SGLT2 inhibitors versus dipeptidyl peptidase-4 inhibitors, defined by filled prescriptions and analysed according to intention to treat. MAIN OUTCOME MEASURES:The main outcome was serious renal events, a composite including renal replacement therapy, death from renal causes, and hospital admission for renal events. Secondary outcomes were the individual components of the main outcome. RESULTS:The mean age of the study population was 61.3 (SD 10.5) years; 11?108 (19%) had cardiovascular disease, and 1974 (3%) had chronic kidney disease. Use of SGLT2 inhibitors, compared with dipeptidyl peptidase-4 inhibitors, was associated with a reduced risk of serious renal events (2.6 events per 1000 person years versus 6.2 events per 1000 person years; hazard ratio 0.42 (95% confidence interval 0.34 to 0.53); absolute difference -3.6 (-4.4 to -2.8) events per 1000 person years). In secondary outcome analyses, the hazard ratio for use of SGLT2 inhibitors versus dipeptidyl peptidase-4 inhibitors was 0.32 (0.22 to 0.47) for renal replacement therapy, 0.41 (0.32 to 0.52) for hospital admission for renal events, and 0.77 (0.26 to 2.23) for death from renal causes. In sensitivity analyses in each of the Swedish and Danish parts of the cohort, the model was further adjusted for glycated haemoglobin and estimated glomerular filtration rate (Sweden and Denmark) and for blood pressure, body mass index, and smoking (Sweden only); in these analyses, the hazard ratio moved from 0.41 (0.26 to 0.66) to 0.50 (0.31 to 0.81) in Sweden and from 0.42 (0.32 to 0.56) to 0.55 (0.41 to 0.74) in Denmark. CONCLUSIONS:In this analysis using nationwide data from three countries, use of SGLT2 inhibitors, compared with dipeptidyl peptidase-4 inhibitors, was associated with a significantly reduced risk of serious renal events.
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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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Project description:Although several treatment options are available to reduce hyperglycemia, only about half of individuals with diagnosed diabetes mellitus (DM) achieve recommended glycemic targets. New agents that reduce blood glucose concentrations by novel mechanisms and have acceptable safety profiles are needed to improve glycemic control and reduce the complications associated with type 2 diabetes mellitus (T2DM). The renal sodium-glucose co-transporter 2 (SGLT2) is responsible for reabsorption of most of the glucose filtered by the kidney. Inhibitors of SGLT2 lower blood glucose independent of the secretion and action of insulin by inhibiting renal reabsorption of glucose, thereby promoting the increased urinary excretion of excess glucose. Canagliflozin, dapagliflozin, and empagliflozin are SGLT2 inhibitors approved as treatments for T2DM in the United States, Europe, and other countries. Canagliflozin, dapagliflozin, and empagliflozin increase renal excretion of glucose and improve glycemic parameters in patients with T2DM when used as monotherapy or in combination with other antihyperglycemic agents. Treatment with SGLT2 inhibitors is associated with weight reduction, lowered blood pressure, and a low intrinsic propensity to cause hypoglycemia. Overall, canagliflozin, dapagliflozin, and empagliflozin are well tolerated. Cases of genital infections and, in some studies, urinary tract infections have been more frequent in canagliflozin-, dapagliflozin-, and empagliflozin-treated patients compared with those receiving placebo. Evidence from clinical trials suggests that SGLT2 inhibitors are a promising new treatment option for T2DM.
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Project description:Results from cardiovascular outcome trials (CVOT) with 5 different sodium-glucose co-transporter 2 inhibitors (SGLT2i; empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, sotagliflozin), initially developed for their glucose-lowering effect by blocking tubular glucose reabsorption in kidney, have been shown to decrease the risk of heart failure hospitalization (HFH) across a range of patients with and without atherosclerotic cardiovascular disease in patients with type 2 diabetes mellitus (T2DM). Following these CVOT results, SGLT2i (dapagliflozin, empagliflozin, sotagliflozin) also were reported to reduce HFH and cardiovascular death in patients with heart failure with reduced ejection fraction (HFrEF), regardless of existence or absence of T2DM. Ongoing studies have been conducted to evaluate the clinical benefit of SGLT2i (empagliflozin, dapagliflozin) in patients with heart failure with preserved ejection fraction (HFpEF). Although SGLT2i brought us to the entrance of a new era for prevention of HF incidence and worsening of HF, the search for pivotal mechanism of SGLT2i to improve our pharmacological armamentarium should continue in order to protect every HF patient from fatal progression of HF disease. In this review, we summarized the updated clinical evidences on SGLT2i (rather than basic and translational evidence) for reduction of HF risk in T2DM patients and favorable clinical outcomes in both HFrEF and HFpEF patients.
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Project description:AimsTo compare the influence of sodium-glucose co-transporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP-4i) on the risk of lower extremity amputations in patients with type 2 diabetes in Slovenia.MethodsThis retrospective cohort study included patients aged 40 years or more who were administered a newly introduced SGLT2i or DPP-4i between June 2014 and June 2018. Patients treated with insulin at baseline and patients with a history of amputation were excluded. Patients were matched in a 1:1 ratio using propensity score matching. Survival analysis was performed; hazard ratio (HR) and ratios of cumulative hazards at 1, 2, 3, and 4 years were estimated. On-treatment and intention-to-treat approaches were used.ResultsThe study cohort (mean age: 64 years) consisted of 2,939 new users of SGLT2i (empagliflozin, 59%; dapagliflozin, 41%) matched to 2,939 new users of DPP-4i. In the on-treatment analysis (median follow-up of 2 years), the incidence of amputations was higher in SGLT2i than in DPP-4i users (4.2 vs. 2.7 per 1,000 patient years), resulting in a HR of 1.58 (95% CI 0.85-2.92; p = 0.145). An intention-to-treat analysis yielded to similar HR of 1.86 (95% CI: 1.10-3.14; p = 0.020). There was no difference in amputation rates in the first two years, but SGLT2i users had a 2.81-fold higher (95% CI: 1.63-4.84; p = 0.007) cumulative hazard of amputation at 4 years than did DPP-4i users.ConclusionsCompared with DPP-4i use, SGLT2i use did not result in a statistically significant higher overall risk of lower extremity amputations. However, the results suggest that SGLT2i may increase the risk of amputation with long-term use.
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