Cardiovascular Events Associated With SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs

Self Cite

Aims Enrollment criteria vary substantially among cardiovascular outcome trials (CVOTs) of sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2is), which impacts the relationship between a trial population and the general type 2 diabetes (T2D) population. The aim of this study was to evaluate the representativeness of four SGLT‐2i CVOTs of a general T2D population. Methods T2D patients from Germany, The Netherlands, Norway and Sweden were included in the study. Given the available data per country, key inclusion and exclusion criteria were defined by diagnoses, procedures and drug treatments to facilitate comparability among countries. Representativeness was determined by dividing the number of patients fulfilling the key enrolment criteria of each CVOT (CANVAS, DECLARE‐TIMI 58, EMPA‐REG OUTCOME, VERTIS‐CV) by the total T2D population. Results In 2015, a total T2D population of 803 836 patients was identified in Germany (n = 239 485), in The Netherlands (n = 36 213), in Norway (n = 149 782) and in Sweden (n = 378 356). These populations showed a 25% to 44% cardiovascular (CV) disease baseline prevalence and high CV‐preventive drug use (>80%). The general T2D population had less prevalent CV disease and patients were slightly older than those included in the CVOTs. The DECLARE‐TIMI 58 trial had the highest representativeness, 59% compared to the general T2D population, and this representativeness was almost 2‐, 3‐ and 4‐fold higher compared to the CANVAS (34%), EMPA‐REG OUTCOME (21%) and VERTIS‐CV (17%) trials, respectively. Conclusions In large T2D populations within Europe, consistent patterns of representativeness of CVOTs were found when applying the main enrolment criteria. The DECLARE‐TMI 58 trial had the highest representativeness, indicating that it included and examined patients who are most representative of the general T2D patients in the studied countries.

Section: Discussionmentioning

confidence: 75%

How representative of a general type 2 diabetes population are patients included in cardiovascular outcome trials with SGLT2 inhibitors? A large European observational study

Birkeland

Bodegård

Norhammar

et al. 2019

Self Cite

“…Unlike the EMPA‐REG OUTCOME trial and the CANVAS study, which compared SGLT2 inhibitors to placebo, the current study used active comparators which is more relevant to guidance concerning prescribing decisions in routine clinical practice . Observational studies, such as the CVD‐REAL study, have compared SGLT2 inhibitors to other glucose‐lowering agents, with conflicting findings . In the first follow‐up analysis of the CVD‐REAL study, the authors did not find a significant difference between use of dapagliflozin and use of DPP‐4 inhibitors in risk of MI and stroke, but subsequent analyses reported a reduction in risk .…”

Section: Discussionmentioning

confidence: 92%

“…Several observational studies have recently evaluated the cardiovascular safety of SGLT2 inhibitors among patients with type 2 diabetes . One population‐based study, which used data from the Health Improvement Network database, found that, compared to use of other glucose‐lowering agents, the use of empagliflozin was associated with lower risk of all‐cause mortality, irrespective of baseline CVD .…”

Section: Introductionmentioning

confidence: 99%

“…In the first analysis of the CVD‐REAL study, which included data from the United States and Europe, the reduction in risk of heart failure and death was reported across countries, regardless of variability in the use of SGLT‐2 inhibitors, with canagliflozin dominating the United States and dapagliflozin dominating Europe, suggesting a class effect . Similarly, the results of the CVD‐REAL 2 study, which included Asian and Middle Eastern populations, suggested that reduction in cardiovascular outcomes (eg, MI, stroke) with the use of SGLT2 inhibitors was a class effect . Although prior studies have suggested a class effect, none have explicitly evaluated the within‐class effect of SGLT2 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Dawwas

Smith

Park

2018

Using population-based data, incident use of SGLT-2 inhibitors was associated with a decreased incidence of CVD compared to use of sulfonylureas and DPP-4 inhibitors. These findings were consistent between dapagliflozin and canagliflozin, suggesting that CVD reduction is a class effect for SGLT2 inhibitors. In addition, SGLT2 inhibitors portended lower risk of hospitalization because of heart failure (vs sulfonylureas and DPP-4 inhibitors) and lower risk of lower extremity amputation (vs sulfonylureas).

“…[14][15][16][17] Dapagliflozin, approved for treatment of T2DM, may also be effective in patients with T1DM. [14][15][16][17] Dapagliflozin, approved for treatment of T2DM, may also be effective in patients with T1DM.…”

Section: Introductionmentioning

confidence: 99%

Model‐based characterization of the relationship between dapagliflozin systemic exposure and HbA1c response in patients with type 1 diabetes mellitus

Parkinson

Tang

Åstrand

et al. 2019

Aims To quantitatively describe the relationship between dapagliflozin systemic exposure and HbA1c response among patients with type 1 diabetes mellitus (T1DM) and assess the potential impact of covariate effects. Materials and Methods Individual longitudinal HbA1c data from two phase 3 studies in patients with T1DM (24‐week treatment with once‐daily dapagliflozin 5 or 10 mg or placebo, with adjustable insulin) were analyzed using a non‐linear mixed effect modeling approach. Area under the concentration curve was used to measure dapagliflozin systemic exposure. Baseline HbA1c, estimated glomerular filtration rate, reduction in total insulin dose, baseline glucose concentrations, age, sex, race (Asian vs. non‐Asian), and insulin administration method (multiple daily injections vs. insulin pump) were assessed as covariates. Results A maximum effect (Emax) model identified a positive exposure–response relationship. Model‐predicted placebo‐corrected HbA1c reductions after 24 weeks for dapagliflozin 5‐ and 10‐mg doses were − 0.42% [95% confidence interval (CI) −0.47 to −0.36) and − 0.45% (95% CI −0.50 to −0.40), respectively; baseline HbA1c was ~8.4%. This was in good agreement with actual observations from both studies. Baseline HbA1c was a significant covariate: patients with higher baseline HbA1c were predicted to have greater HbA1c reductions. Conclusions The relationship between dapagliflozin systemic exposure and HbA1c response was successfully described in patients with T1DM. None of the tested covariates affected the efficacy of dapagliflozin to a clinically relevant extent. Therefore, no dose adjustment of dapagliflozin is required in patients with T1DM based on the tested covariates. http://ClinicalTrials.gov, NCT02268214; NCT02460978.