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      Comparative effectiveness of canagliflozin, SGLT2 inhibitors and non‐SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: A real‐world meta‐analysis of 4 observational databases (OBSERVE‐4D)

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          Sodium glucose co‐transporter 2 inhibitors (SGLT2i) are indicated for treatment of type 2 diabetes mellitus (T2DM); some SGLT2i have reported cardiovascular benefit, and some have reported risk of below‐knee lower extremity (BKLE) amputation. This study examined the real‐world comparative effectiveness within the SGLT2i class and compared with non‐SGLT2i antihyperglycaemic agents.

          Materials and methods

          Data from 4 large US administrative claims databases were used to characterize risk and provide population‐level estimates of canagliflozin's effects on hospitalization for heart failure (HHF) and BKLE amputation vs other SGLT2i and non‐SGLT2i in T2DM patients. Comparative analyses using a propensity score–adjusted new‐user cohort design examined relative hazards of outcomes across all new users and a subpopulation with established cardiovascular disease.


          Across the 4 databases (142 800 new users of canagliflozin, 110 897 new users of other SGLT2i, 460 885 new users of non‐SGLT2i), the meta‐analytic hazard ratio estimate for HHF with canagliflozin vs non‐SGLT2i was 0.39 (95% CI, 0.26‐0.60) in the on‐treatment analysis. The estimate for BKLE amputation with canagliflozin vs non‐SGLT2i was 0.75 (95% CI, 0.40‐1.41) in the on‐treatment analysis and 1.01 (95% CI, 0.93‐1.10) in the intent‐to‐treat analysis. Effects in the subpopulation with established cardiovascular disease were similar for both outcomes. No consistent differences were observed between canagliflozin and other SGLT2i.


          In this large comprehensive analysis, canagliflozin and other SGLT2i demonstrated HHF benefits consistent with clinical trial data, but showed no increased risk of BKLE amputation vs non‐SGLT2i. HHF and BKLE amputation results were similar in the subpopulation with established cardiovascular disease. This study helps further characterize the potential benefits and harms of SGLT2i in routine clinical practice to complement evidence from clinical trials and prior observational studies.

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          Most cited references 15

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          Measuring inconsistency in meta-analyses.

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            Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.

            The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known.
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              Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

              Background Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal. Conclusions In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal. (Funded by Janssen Research and Development; CANVAS and CANVAS-R numbers, NCT01032629 and NCT01989754 , respectively.).

                Author and article information

                Diabetes Obes Metab
                Diabetes Obes Metab
                Diabetes, Obesity & Metabolism
                Blackwell Publishing Ltd (Oxford, UK )
                25 June 2018
                November 2018
                : 20
                : 11 ( doiID: 10.1111/dom.2018.20.issue-11 )
                : 2585-2597
                [ 1 ] Janssen Research & Development, LLC Titusville New Jersey
                [ 2 ] University of North Carolina School of Medicine, Department of Medicine Chapel Hill North Carolina
                [ 3 ] Janssen Research & Development, LLC Raritan New Jersey
                [ 4 ] Johnson & Johnson Titusville New Jersey
                Author notes
                [* ] Correspondence

                Patrick B. Ryan, PhD, Janssen Research & Development, LLC, 1125 Trenton Harbourton Road, Titusville, NJ 08560.

                Email: pryan4@

                © 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                Page count
                Figures: 2, Tables: 4, Pages: 13, Words: 8134
                Funded by: Janssen Research & Development, LLC.
                Original Article
                Original Articles
                Custom metadata
                November 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.1 mode:remove_FC converted:07.11.2018

                Endocrinology & Diabetes

                type 2 diabetes, sglt2 inhibitor


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