Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs

Kosiborod, Mikhail; Cavender, Matthew A.; Fu, Alex Z.; Wilding, John; Khunti, Kamlesh; Holl, Reinhard W.; Norhammar, Anna; Birkeland, Kåre I.; Jørgensen, Marit Eika; Thuresson, Marcus; Arya, Niki; Bodegård, Johan; Hammar, Niklas; Fenici, Peter

doi:10.1161/circulationaha.117.029190

Cited by 712 publications

(365 citation statements)

References 37 publications

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“…11, 12, 22, 23, 24, 25, 26, 27, 28, 29, 30 For cardiovascular outcomes analysis, 3 RCTs11, 12, 22 and 2 observational studies23, 24 were included with 351 476 patients and median follow‐up of 3.1 years. Nine RCTs contributed to the analysis of long‐term noncardiovascular safety and efficacy of SGLT2 inhibitors, with a medium follow‐up of 2 years 11, 12, 22, 25, 26, 27, 28, 29, 30.…”

Section: Resultsmentioning

confidence: 99%

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Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

Zhang

Zhu

Chen

et al. 2018

JAHA

108

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BackgroundThe cardiovascular and long‐term noncardiovascular safety and efficacy of SGLT2 (sodium–glucose cotransporter 2) inhibitors have not been well documented.Methods and ResultsFor cardiovascular outcomes, we performed a meta‐analysis with trial sequential analysis of randomized controlled trials and adjusted observational studies, each with a minimum of 26 weeks and 2000 patient‐years of follow‐up. For long‐term noncardiovascular safety and efficacy outcome analyses, we included only randomized controlled trials with at least 2 years and 1000 patient‐years of follow‐up. Five studies with 351 476 patients were included in cardiovascular outcomes analysis. Meta‐analyses showed that SGLT2 inhibitors significantly reduced the risks of major adverse cardiac events (hazard ratio [HR]: 0.80; 95% confidence interval [CI], 0.69–0.92; P=0.002), all‐cause mortality (HR: 0.67; 95% CI, 0.54–0.84; P<0.001), cardiovascular mortality (HR: 0.77; 95% CI, 0.60–0.98; P=0.03), nonfatal myocardial infarction (HR: 0.86; 95% CI, 0.76–0.98; P=0.02), hospitalization for heart failure (HR: 0.62; 95% CI, 0.55–0.69; P<0.001), and progression of albuminuria (HR: 0.68; 95% CI, 0.58–0.81; P<0.001). No significant difference in nonfatal stroke was found. Analyses limited to randomized controlled trials showed similar findings. Trial sequential analysis provided firm evidence of a 20% reduction in major adverse cardiac events, all‐cause mortality, and hospitalization for heart failure with SGLT2 inhibitors, but evidence remains inconclusive for cardiovascular mortality. Nine randomized controlled trials contributed to long‐term noncardiovascular and efficacy analyses. SGLT2 inhibitors reduced incidence of hypoglycemia and acute kidney injury but increased the risks of urinary tract and genital infections.Conclusions SGLT2 inhibitors showed remarkable cardiovascular‐ and renal‐protective effects and good long‐term noncardiovascular safety with sustained efficacy.

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Section: Resultsmentioning

confidence: 99%

“…All trials were carried out with patients who had type 2 DM. Empagliflozin was used in 2 trials,11, 29 canagliflozin was used in 4 trials,12, 26, 27 and dapagliflozin was used in 3 trials25, 28, 30; the 2 observational studies involved various SGLT2 inhibitors 23, 24. All studies were multicenter, performed across multiple countries.…”

Section: Resultsmentioning

confidence: 99%

Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

Zhang

Zhu

Chen

et al. 2018

JAHA

108

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show abstract

“…Notably, these patients were not at increased CV risk (only 13% had established CV disease). In this propensity‐matched PER using data from medical claims, primary care/hospital records, and national registries in six countries (the United States, Germany, Sweden, Norway, Denmark and the UK), the authors assessed the risks of hospitalization for heart failure (HHF), death, and the combined endpoint of heart failure hospitalization or death, which were all lower in patients receiving an SGLT2‐I, without significant heterogeneity across countries and with consistent results among multiple sensitivity analyses 10. In particular, the pooled analysis of all‐cause death using patient data from five of the countries (this information was not available for the German registry) showed a 51% reduction favouring patients with SGLT2‐Is (0.49; 0.41–0.57; without significant heterogeneity among SGLT2‐Is).…”

Section: Overview Of Resultsmentioning

confidence: 99%

Observational research on sodium glucose co‐transporter‐2 inhibitors: A real breakthrough?

Raschi

Poluzzi

Fadini

et al. 2018

Diabetes Obesity Metabolism

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Sodium glucose co‐transporter‐2 inhibitors have attracted the interest of the scientific community following the results from dedicated cardiovascular outcome trials, which demonstrated remarkable reduction in all‐cause mortality and other cardiovascular (CV) endpoints with empagliflozin and canagliflozin. These impressive results raised further expectations on real world data from large observational cohort studies. They were designed to address the possible existence of a class effect, and the uncertainty on whether this benefit can be extended from secondary to primary CV prevention of patients with type 2 diabetes. In this review, we collated data from existing observational studies (including the celebrated CVD‐REAL cohorts) and critically appraised results and methodological issues with the aim of providing clinical insight, including unsettled aspects, and proposing a research agenda for future investigations.

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“…When a sufficient overlap between patient groups exists,8 PSM can generate quasi‐experimental comparisons that make retrospective studies closer to RCTs. For instance, 2 RCTs indicate that SGLT2 inhibitors improve cardiovascular outcomes in patients with T2D and high risk for or established cardiovascular disease9, 10 and 2 retrospective studies on administrative databases have confirmed these findings in broader T2D patient populations 11, 12…”

Section: Introductionmentioning

confidence: 99%

Use and effectiveness of dapagliflozin in routine clinical practice: An Italian multicentre retrospective study

Fadini

Zatti

Baldi

et al. 2018

Diabetes Obesity Metabolism

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In randomized controlled trials (RCTs), sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors have been shown to confer glycaemic and extra‐glycaemic benefits. The DARWIN‐T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes) study was a multicentre retrospective study designed to evaluate the baseline characteristics of patients receiving dapagliflozin vs those receiving selected comparators (dipeptidyl peptidase‐4 inhibitors, gliclazide, or glucagon‐like peptide‐1 receptor agonists), and drug effectiveness in routine clinical practice. From a population of 281 217, the analysis included 17 285 patients initiating dapagliflozin or comparator glucose‐lowering medications (GLMs), 6751 of whom had a follow‐up examination. At baseline, participants starting dapagliflozin were younger, had a longer disease duration, higher glycated haemoglobin (HbA1c) concentration, and a more complex history of previous GLM use, but the clinical profile of patients receiving dapagliflozin changed during the study period. Dapagliflozin reduced HbA1c by 0.7%, body weight by 2.7 kg, and systolic blood pressure by 3.0 mm Hg. Effects of comparator GLMs were also within the expected range, based on RCTs. This real‐world study shows an initial channelling of dapagliflozin to difficult‐to‐treat patients. Nonetheless, dapagliflozin provided significant benefits with regard to glucose control, body weight and blood pressure that were in line with findings from RCTs.

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Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs

Abstract: Supplemental Digital Content is available in the text.

Cited by 712 publications

References 37 publications

Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

Observational research on sodium glucose co‐transporter‐2 inhibitors: A real breakthrough?

Use and effectiveness of dapagliflozin in routine clinical practice: An Italian multicentre retrospective study

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