Dataset Information

Association of Sodium-Glucose Cotransporter-2 Inhibitors With Fracture Risk in Older Adults With Type 2 Diabetes.

ABSTRACT:

Importance

Whether sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are associated with an increased risk of fractures in older adults with type 2 diabetes (T2D) outside of clinical trials remains unknown.

Objective

To examine the association of incident fracture among older adults with T2D with initiating an SGLT-2i compared with initiating a dipeptidyl peptidase 4 inhibitor (DPP-4i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA).

Design, setting, and participants

This is a population-based, new-user cohort study including older adults (aged ≥65 years) with T2D enrolled in Medicare fee-for-service from April 2013 to December 2017. Data analysis was performed from October 2020 to April 2021.

Exposures

New users of an SGLT-2i, DPP-4i, or GLP-1RA without a previous fracture were matched in a 1:1:1 ratio using 3-way propensity score matching.

Main outcomes and measures

The primary outcome was a composite end point of nontraumatic pelvic fracture, hip fracture requiring surgery, or humerus, radius, or ulna fracture requiring intervention within 30 days. After 3-way 1:1:1 propensity score matching, multivariable Cox proportional hazards regression models were used to generate hazard ratios (HRs) for SGLT-2i compared with DPP-4i and GLP-1RA and Kaplan-Meier curves to visualize fracture risk over time across groups.

Results

Of 466 933 new initiators of study drugs, 62 454 patients were new SGLT-2i users. After 3-way matching, 45 889 (73%) new SGLT-2i users were matched to new users of DPP-4i and GLP-1RA, yielding a cohort of 137 667 patients (mean [SD] age, 72 [5] years; 64 126 men [47%]) matched 1:1:1 for analyses. There was no difference in the risk of fracture in SGLT-2i users compared with DPP-4i users (HR, 0.90; 95% CI, 0.73-1.11) or GLP-1RA users (HR, 1.00; 95% CI, 0.80-1.25). Results were consistent across categories of sex, frailty (nonfrail, prefrail, and frail), age (<75 and ≥75 years), and insulin use (baseline users and nonusers).

Conclusions and relevance

In this nationwide Medicare cohort, initiating an SGLT-2i was not associated with an increased risk of fracture in older adults with T2D compared with initiating a DPP-4i or GLP-1RA, with consistent results across categories of frailty, age, and insulin use. These findings add to the evidence base evaluating the potential risks associated with SGLT-2i use for older adults outside of randomized clinical trials.

SUBMITTER: Zhuo M

PROVIDER: S-EPMC8552056 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Association of Sodium-Glucose Cotransporter-2 Inhibitors With Fracture Risk in Older Adults With Type 2 Diabetes.

Zhuo Min M Hawley Chelsea E CE Paik Julie M JM Bessette Lily G LG Wexler Deborah J DJ Kim Dae H DH Tong Angela Y AY Kim Seoyoung C SC Patorno Elisabetta E

JAMA network open 20211001 10

<h4>Importance</h4>Whether sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are associated with an increased risk of fractures in older adults with type 2 diabetes (T2D) outside of clinical trials remains unknown.<h4>Objective</h4>To examine the association of incident fracture among older adults with T2D with initiating an SGLT-2i compared with initiating a dipeptidyl peptidase 4 inhibitor (DPP-4i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA).<h4>Design, setting, and participants< ...[more]

PMID: 34705014

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Project description:ImportanceSodium-glucose cotransporter-2 inhibitors (SGLT-2is) have demonstrated many cardiovascular and kidney function benefits for patients with type 2 diabetes (T2D). However, the results of SGLT-2i use in primary prevention of atrial fibrillation (AF) were inconsistent in clinical trials, and incident AF was not a prespecified end point.ObjectiveTo examine incident AF with initiation of an SGLT-2i compared with initiation of a dipeptidyl peptidase-4 inhibitor (DPP-4i) or a glucagonlike peptide-1 receptor agonist (GLP-1RA) among older adults (aged ≥66 years) with T2D in routine clinical practice.Design, setting, and participantsA population-based new-user cohort study included older adults with T2D who had no history of AF and were enrolled in Medicare fee-for-service from April 1, 2013, to December 31, 2018. Data analysis was performed from June 28 to December 1, 2021.ExposuresTo control for potential confounding, new users of SGLT-2i were 1:1 propensity score (PS)-matched to new users of DPP-4is or GLP-1RAs in 2 pairwise comparisons based on 138 baseline covariates.Main outcomes and measuresThe primary outcome was incident AF, defined as an inpatient diagnosis code for AF. Hazard ratios (HRs) and rate differences (RDs) per 1000 person-years, with their 95% CIs, were estimated in the PS-matched groups.ResultsNew users of SGLT-2is were 1:1 PS-matched to new users of a DPP-4i (n = 74 868) or GLP-1RA (n = 80 475). Overall, the mean (SD) age of study participants was 72 (5) years, and 165 984 were women (53.4%). The risk of incident AF was lower in the SGLT-2i group than the matched DPP-4i group (HR, 0.82; 95% CI, 0.76 to 0.89; RD, -3.7; 95% CI, -5.2 to -2.2 per 1000 person-years) or the matched GLP-1RA group (HR, 0.90; 95% CI, 0.83 to 0.98; RD, -1.8; 95% CI, -3.2 to -0.3 per 1000 person-years). Results were consistent across several sensitivity and subgroup analyses.Conclusions and relevanceThe findings of this study suggest that the initiation of an SGLT-2i was associated with a reduced risk of incident AF compared with a DPP-4i or GLP-1RA. The results may be helpful when weighing the potential risks and benefits of various glucose level-lowering agents in older adults with T2D.

Project description:ImportanceResults of clinical trials suggest that canagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor for treating type 2 diabetes, may be associated with lower extremity amputation.ObjectiveTo quantify the association between the use of oral medication for type 2 diabetes and 5 outcomes (lower extremity amputation, peripheral arterial disease, critical limb ischemia, osteomyelitis, and ulcer).Design, setting, and participantsA retrospective cohort study was conducted using Truven Health MarketScan Commercial Claims and Encounters data on new users between September 1, 2012, and September 30, 2015. The study focused on 2.0 million commercially insured individuals and used propensity score weighting to balance baseline differences among groups. Sensitivity analyses varied statistical models, assessed the effect of combining dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists as a single referent group, adjusted for baseline use of older oral agents, and included people with baseline amputation.ExposuresNew use of SGLT-2 inhibitors alone, DPP-4 inhibitors alone, GLP-1 agonists alone, or other antidiabetic agents (sulfonylurea, metformin hydrochloride, or thiazolidinediones).Main outcomes and measuresFoot and leg amputation, defined by validated International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes.ResultsAmong 2.0 million potentially eligible individuals, a total of 953 906 (516 046 women and 437 860 men; mean [SD] age, 51.8 [10.9] years) were included in the final analyses, including 39 869 new users of SGLT-2 inhibitors (4.2%), 105 023 new users of DPP-4 inhibitors (11.0%), and 39 120 new users of GLP-1 agonists (4.1%). The median observation time ranged from 99 days for new users of GLP-1 agonists to 127 days for those using metformin, sulfonylureas, and thiazolidinediones, while the crude incident rates ranged from 4.90 per 10 000 person-years for those using metformin, sulfonylureas, and thiazolidinediones to 10.53 per 10 000 person-years for new users of SGLT-2 inhibitors. After propensity score weighting and adjustment for demographics, severity of diabetes, comorbidities, and medications, there was a nonstatistically significant increased risk of amputation associated with new use of SGLT-2 inhibitors compared with DPP-4 inhibitors (adjusted hazard ratio, 1.50; 95% CI, 0.85-2.67) and GLP-1 agonists (adjusted hazard ratio, 1.47; 95% CI, 0.64-3.36). New use of SGLT-2 inhibitors was statistically significantly associated with amputation compared with sulfonylureas, metformin, or thiazolidinediones (adjusted hazard ratio, 2.12; 95% CI, 1.19-3.77). These results persisted in sensitivity analyses.Conclusions and relevanceUse of SGLT-2 inhibitors may be associated with increased risk of amputation compared with some oral treatments for type 2 diabetes. Further observational studies are needed with extended follow-up and larger sample sizes.

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.

Project description:ImportanceDiabetic nephropathy and diabetic retinopathy share many similarities in pathophysiological processes. Preclinical studies have shown that sodium-glucose cotransporter 2 inhibitors (SGLT2is) have a protective role in the risk of diabetic retinopathy.ObjectiveTo compare the risk of sight-threatening retinopathy associated with SGLT2is and other second-line glucose-lowering medications (including pioglitazone, sulfonylureas, and dipeptidyl peptidase-4 inhibitors [DPP-4is]) in patients with type 2 diabetes (T2D).Design, setting, and participantsThis cohort study in Taiwan applied a new-user and active-comparator design. Patient demographic and clinical data were obtained from the National Health Insurance Research Database. Adult patients with newly diagnosed T2D from January 1, 2009, to December 31, 2019, were recruited and followed up until December 31, 2020. Propensity score matching was used to identify pairs of patients treated with SGLT2i vs DPP-4i, SGLT2i vs pioglitazone, and SGLT2i vs sulfonylurea from January 1, 2016, to December 31, 2019. Data were analyzed between August 18, 2022, and May 5, 2023.ExposuresTreatment with SGLT2i, DPP-4i, pioglitazone, and sulfonylureas starting on January 1, 2016.Main outcomes and measuresThe main outcome was sight-threatening retinopathy in participants. Cox proportional hazards regression models were used to assess relative hazards of sight-threatening retinopathy between the matched case and control groups.ResultsA total of 3 544 383 patients with newly diagnosed T2D were identified. After 1:1 propensity score matching, 65 930 pairs of patients treated with SGLT2i vs DPP-4i, 93 760 pairs treated with SGLT2i vs pioglitazone, and 42 121 pairs treated with SGLT2i vs sulfonylurea were identified. These matched patients included 236 574 males (58.6%), with a mean (SD) age of 56.9 (11.8) years. In the matched cohorts, SGLT2i had a significantly lower risk of sight-threatening retinopathy than DPP-4i (adjusted hazard ratio [AHR], 0.57; 95% CI, 0.51-0.63), pioglitazone (AHR, 0.75; 95% CI, 0.69-0.81), and sulfonylureas (AHR, 0.62; 95% CI, 0.53-0.71). The Kaplan-Meier curves showed that SGLT2i was associated with a significantly lower cumulative incidence of sight-threatening retinopathy than DPP-4i (3.52 vs 6.13; P < .001), pioglitazone (4.32 vs 5.76; P < .001), and sulfonylureas (2.94 vs 4.67; P < .001).Conclusions and relevanceThis cohort study found that SGLT2i was associated with a lower risk of sight-threatening retinopathy compared with DPP-4i, pioglitazone, and sulfonylureas. This finding suggests that SGLT2i may play a role not only in reduced risk of diabetic nephropathy but also in the slow progression of diabetic retinopathy in patients with T2D.

Dataset Information

Association of Sodium-Glucose Cotransporter-2 Inhibitors With Fracture Risk in Older Adults With Type 2 Diabetes.

Importance

Objective

Design, setting, and participants

Exposures

Main outcomes and measures

Results

Conclusions and relevance

Publications

Association of Sodium-Glucose Cotransporter-2 Inhibitors With Fracture Risk in Older Adults With Type 2 Diabetes.

Similar Datasets

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