Cardiovascular outcomes of sodium glucose cotransporter‐2 inhibitors in patients with type 2 diabetes

Dawwas, Ghadeer K.; Smith, Steven M.; Park, Haesuk

doi:10.1111/dom.13477

Cited by 62 publications

(68 citation statements)

References 31 publications

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“…Recent ITT analyses conducted in the MarketScan CCAE population by Yuan et al (aHR 0.98, 95% CI 0.68‐1.41) and Ryan et al (aHR 1.01, 95% CI 0.80‐1.28) reported null associations of below‐knee amputation risk among new users of canagliflozin versus new users of all non‐SGLT2 inhibitor GLDs . Using as‐treated analysis, Dawwas et al obtained a similar result versus both DPP‐4 inhibitor (aHR 0.88, 95% CI 0.65‐1.15) and SU users (aHR 0.74, 95% CI 0.57‐0.96), and Ryan et al reported a protective effect of SGLT2 inhibitors versus all non‐SGLT2 inhibitor GLDs (aHR 0.56, 95% CI 0.32‐0.92).…”

Section: Discussionmentioning

confidence: 90%

“…In response, the US Food and Drug Administration issued a bulletin regarding amputation risk in May 2016 and a drug‐labelling change in July 2017 . Recently, several observational studies have sought to corroborate this finding in broader populations, with mixed conclusions …”

Section: Introductionmentioning

confidence: 96%

“…10 Recently, several observational studies have sought to corroborate this finding in broader populations, with mixed conclusions. [11][12][13][14][15][16] To address the variation in observed risk of amputation with SGLT2 inhibitors, we implemented an active comparator new-user (ACNU) study 17 to estimate and compare the risk of LEA between patients initiating SGLT2 inhibitors and patients initiating two secondline GLDs, dipeptidyl peptidase-4 (DPP-4) inhibitors and sulphonylureas (SUs), which are prescribed as alternatives to SGLT2 inhibitors.…”

mentioning

confidence: 99%

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Sodium‐glucose co‐transporter‐2 inhibitor use and risk of lower‐extremity amputation: Evolving questions, evolving answers

Yang

Wang

Pate

et al. 2019

Diabetes Obesity Metabolism

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Aim To examine whether sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors are associated with a higher risk of lower‐extremity amputation than dipeptidyl‐peptidase‐4 (DPP‐4) inhibitors and sulphonylureas. Methods We conducted a retrospective cohort study, using the MarketScan Commercial Claims and Encounters Database (2013‐2015), to compare the incidence of lower‐extremity amputation (LEA) between initiators of SGLT2 inhibitors and initiators of two second‐line drugs, DPP‐4 inhibitors and sulphonylureas (SUs). We estimated crude incidence rates (IRs) and adjusted hazard ratios (aHR), with 95% confidence intervals (CIs), before and after propensity‐score weighting. We additionally conducted sensitivity analyses using a comparator group of all non‐metformin, non‐SGLT2 inhibitor glucose‐lowering drugs, as previous studies used this approach. Results In a cohort of 328 150 individuals aged 18 to 64 years, the IR of LEA ranged from 1.5 to 2.4 per 1000 person‐years. In as‐treated analysis, the estimated hazard of LEA was increased among SGLT2 inhibitor initiators compared to DPP‐4 inhibitor initiators (aHR 1.69, 95% CI 1.20‐2.38), but not compared to SU initiators (aHR 1.02, 95% CI 0.67‐1.55) or non‐metformin, non‐SGLT2 inhibitor initiators (aHR 1.02, 95% CI 0.54‐1.93). Results were consistent in intention‐to‐treat analysis and across a number of sensitivity analyses. Conclusions Among commercially insured patients in the United States, our results suggest that initiation of SGLT2 inhibitors may increase the risk of LEA compared to initiation of DPP‐4 inhibitors. Contrasting results when comparing SGLT2 inhibitor initiators to DPP‐4 inhibitor and SU initiators highlight the importance of choosing appropriate comparator drugs when addressing comparative effectiveness and safety questions that can inform clinical decision‐making.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 96%

mentioning

confidence: 99%

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Sodium‐glucose co‐transporter‐2 inhibitor use and risk of lower‐extremity amputation: Evolving questions, evolving answers

Yang

Wang

Pate

et al. 2019

Diabetes Obesity Metabolism

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“…Third, the use of DPP‐4i increased rapidly. However, despite the promising cardiovascular safety profile of SGLT‐2i, they remain uncommonly used . A similar trend of antidiabetic medication use over time, including TZDs, was observed in the general diabetes population.…”

Section: Discussionmentioning

confidence: 99%

Twelve‐year trends in pharmacologic treatment of type 2 diabetes among patients with heart failure in the United States

Dawwas

Leonard

Garg

et al. 2020

Diabetes Obesity Metabolism

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We conducted a cross‐sectional analysis using a database from commercial health plans in the United States to describe trends in the use of antidiabetic medications among patients with type 2 diabetes and heart failure (HF) from 2006 through 2017. We used loop diuretic dose as a surrogate for HF severity (mild HF 0‐40 mg/day, moderate‐severe HF >40 mg/day). We assessed antidiabetic medication dispensing in the 90 days following HF diagnosis. Over the 12‐year period, we identified an increase in the use of metformin (39.2% vs. 62.6%), dipeptidyl peptidase‐4 inhibitors (DPP‐4i) (0.5% vs. 17.1%) and sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2i) (0.0% vs. 9.0%), but a decrease in the use of sulphonylureas (47.8% vs. 27.8%) and thiazolidinediones (TZDs) (31.7% vs. 5.3%). In 2017, patients with moderate‐severe HF more commonly used insulin (43.1%); a majority of mild HF patients used metformin (62.8%). A proportion of patients with moderate‐severe HF used TZDs (4.4%). Among patients with diabetes and HF, the use of metformin and DPP‐4i rapidly increased, but a proportion of patients with moderate‐severe HF continued to use TZDs. Despite their promising cardiovascular safety profile, SGLT‐2i use remains limited.

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“…However, whether this risk of amputation occurs singly with canagliflozin or is a class effect remains controversial. Recent observational studies and meta-analyses have reported conflicting results [19][20][21][22][23][24][25][26][27]. An increased risk of LLA was not observed in participants using empagliflozin in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial; however, LLAs were identified manually in a post hoc analysis [28].…”

Section: Discussionmentioning

confidence: 99%

Lower limb events in individuals with type 2 diabetes: evidence for an increased risk associated with diuretic use

et al. 2019

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Aims/hypothesis Recently, safety data signalled an increased risk of amputations in people taking canagliflozin, a sodium −glucose cotransporter 2 (SGLT2) inhibitor. If this side effect is due to drug-induced hypovolaemia, diuretics should also increase that risk. The aim of this study was to analyse the association between diuretic use and the risk of lower limb events (LLEs) in people with type 2 diabetes. Methods SURDIAGENE (SUivi Rénal, DIAbète de type 2 et GENEtique) is a prospective observational cohort that includes people with type 2 diabetes enrolled from 2002 to 2012 and followed-up until onset of LLE, death or 31 December 2015, whichever came first. Primary outcome was the first occurrence of LLE, a composite of lower limb amputation (LLA) and lower limb revascularisation (LLR). The rates of primary outcome were compared between participants taking and not taking diuretics at baseline in a Cox-adjusted model. Results At baseline, of the 1459 participants included, 670 were taking diuretics. In participants with and without diuretics, the mean ages were 67.1 and 62.9 years and 55.8% and 59.8% were men, respectively. During a median follow-up of 7.1 years, the incidence of LLE was 1.80 per 100 patient-years in diuretic users vs 1.00 in non-users (p < 0.001). The HR for LLE in users vs non-users was 2.08 (95% CI 1.49, 2.93), p < 0.001. This association remained significant in a multivariable-adjusted model (1.49 [1.01, 2.19]; p = 0.04) and similar after considering death as a competing risk (subhazard ratio 1. 89 [1.35, 2.64]; p < 0.001). When separated, LLA but not LLR, was associated with the use of diuretics: 2.01 (1.14, 3.54), p = 0.02 and 1.05 (0.67, 1.64), p = 0.84, respectively, in the multivariable-adjusted model. Conclusions/interpretation Among people with type 2 diabetes treated with diuretics, there was a significant increase in the risk of LLE, predominantly in the risk of LLA.

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Cardiovascular outcomes of sodium glucose cotransporter‐2 inhibitors in patients with type 2 diabetes

Cited by 62 publications

References 31 publications

Sodium‐glucose co‐transporter‐2 inhibitor use and risk of lower‐extremity amputation: Evolving questions, evolving answers

Sodium‐glucose co‐transporter‐2 inhibitor use and risk of lower‐extremity amputation: Evolving questions, evolving answers

Twelve‐year trends in pharmacologic treatment of type 2 diabetes among patients with heart failure in the United States

Lower limb events in individuals with type 2 diabetes: evidence for an increased risk associated with diuretic use

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