Abstract
Aims
To assess the association between the use of sodium-glucose cotransporter-2 (SGLT2i)
and cardiovascular outcomes and death as a function of obesity among patients with
type 2 diabetes.
Methods
This new-user, active-comparator cohort study used U.K.’s Clinical Practice Research
Datalink linked to Hospital Episodes Statistics repository and Office for National
Statistics. The cohort included 34,128 new-users of SGLT2i matched 1:1 to 34,128 new-users
of dipeptidyl peptidase-4 inhibitors (DPP-4i) on body mass index and propensity score.
Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95%
confidence intervals (CIs) of major adverse cardiovascular events (MACE), overall
and in body mass index (BMI) categories (≤24.9 kg/m2, 25.0–29.9 kg/m2, 30.0–39.9 kg/m2, ≥40 kg/m2). Secondary outcomes included all-cause mortality and hospitalization for heart failure.
Results
SGLT2i were associated with a decreased risk of MACE (HR: 0.78, 95 %CI: 0.69–0.88)
compared to DPP-4i. This decreased risk was most pronounced among obese and severely
obese patients (HR: 0.77, 95 %CI: 0.66–0.91; HR: 0.67, 95% CI: 0.49–0.91, respectively)
but not among overweight patients (HR: 0.94, 95 %CI: 0.73–1.22). Similar patterns
were observed for cardiovascular mortality, all-cause mortality, and heart failure.
Conclusion
Compared with DPP-4i, the cardioprotective effect associated with SGLT2i is stronger
among patients with higher BMI.
Keywords
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References
- Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128https://doi.org/10.1056/NEJMoa1504720
- Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657https://doi.org/10.1056/NEJMoa1611925
- Dapagliflozin and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2019; 380: 347-357https://doi.org/10.1056/NEJMoa1812389
- Effects of obesity on pharmacokinetics implications for drug therapy.Clin Pharmacokinet. 2000; 39: 215-231https://doi.org/10.2165/00003088-200039030-00004
- Effect of obesity on the pharmacokinetics of drugs in humans.Clin Pharmacokinet. 2010; 49: 71-87https://doi.org/10.2165/11318100-000000000-00000
Liebig S, Martin HJ, Mark M, E; M. Comparison in tissue distribution and selectivity among the 3 sodium-glucose co-transporter inhibitors empagliflozin, dapagliflozin and canagliflozin. In. European Association for the Study of Diabetes: Virtual Meeting. Munich, Germany; 2016.
- Validation and validity of diagnoses in the general practice research database: a systematic review.Br J Clin Pharmacol. 2010; 69: 4-14https://doi.org/10.1111/j.1365-2125.2009.03537.x
- Cardiovascular benefits and safety of non-insulin medications used in the treatment of type 2 diabetes mellitus.Postgrad Med. 2017; 129: 811-821https://doi.org/10.1080/00325481.2017.1358064
- Efficacy and cardiovascular safety of insulins.Curr Drug Saf. 2021; 16: 217-232https://doi.org/10.2174/1574886315999201105153458
WHO. Obesity: Preventing and managing the global epidemic. Geneva, Switzerland; WHO; 2000.
Inzucchi SE, Wanner C, Hehnke U, et al. Retinopathy Outcomes With Empagliflozin Versus Placebo in the EMPA-REG OUTCOME Trial. Diabetes Care 2019;42:e53-e55. doi: 10.2337/dc18-1355.
- Dipeptidyl peptidase-4 inhibitor use and risk of diabetic retinopathy: a population-based study.Diabetes Metab. 2018; 44: 361-367https://doi.org/10.1016/j.diabet.2018.03.004
- SGLT2 inhibitors: a focus on cardiac benefits and potential mechanisms.Heart Fail Rev. 2022; 27: 935-949https://doi.org/10.1007/s10741-021-10079-9
- Clinical outcomes with canagliflozin according to baseline body mass index: results from post hoc analyses of the CANVAS Program.Diabetes Obes Metab. 2020; 22: 530-539https://doi.org/10.1111/dom.13920
- Clinical pharmacokinetics of drugs in obesity.An update Clin Pharmacokinet. 1993; 25: 103-114https://doi.org/10.2165/00003088-199325020-00003
- Effect of lipophilicity on drug distribution and elimination: Influence of obesity.Br J Clin Pharmacol. 2021; 87: 3197-3205https://doi.org/10.1111/bcp.14735
- Adipose dipeptidyl peptidase-4 and obesity: correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro.Diabetes Care. 2013; 36: 4083-4090https://doi.org/10.2337/dc13-0496
- Serum level of soluble CD26/dipeptidyl peptidase-4 (DPP-4) predicts the response to sitagliptin, a DPP-4 inhibitor, in patients with type 2 diabetes controlled inadequately by metformin and/or sulfonylurea.Transl Res. 2012; 159: 25-31https://doi.org/10.1016/j.trsl.2011.09.005
- Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients.Diabetes. 2008; 57: 1340-1348https://doi.org/10.2337/db07-1315
- Body mass index history and risk of type 2 diabetes: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-potsdam study.Am J Clin Nutr. 2006; 84: 427-433https://doi.org/10.1093/ajcn/84.1.427
- Body mass index and lifetime healthcare utilization.BMC Health Serv Res. 2019; 19: 696https://doi.org/10.1186/s12913-019-4577-0
- Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis.Diabetes Obes Metab. 2016; 18: 783-794https://doi.org/10.1111/dom.12670
- Emerging role of sglt-2 inhibitors for the treatment of obesity.Drugs. 2019; 79: 219-230https://doi.org/10.1007/s40265-019-1057-0
- Effect of SGLT2 inhibitors on body composition, fluid status and renin-angiotensin-aldosterone system in type 2 diabetes: a prospective study using bioimpedance spectroscopy.Cardiovasc Diabetol. 2019; 18https://doi.org/10.1186/s12933-019-0852-y
- Weight loss associated with sodium-glucose cotransporter-2 inhibition: a review of evidence and underlying mechanisms.Obes Rev. 2018; 19: 1630-1641https://doi.org/10.1111/obr.12755
- The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis.BMC Public Health. 2009; 9https://doi.org/10.1186/1471-2458-9-88
- Body weight considerations in the management of type 2 diabetes.Adv Ther. 2019; 36: 44-58https://doi.org/10.1007/s12325-018-0824-8
- Validation of cardiovascular outcomes and risk factors in the Clinical Practice Research Datalink in the United Kingdom.Pharmacoepidemiol Drug Saf. 2021; 30: 237-247https://doi.org/10.1002/pds.5150
- Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2015; 373: 232-242https://doi.org/10.1056/NEJMoa1501352
- Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial.JAMA. 2019; 321: 69https://doi.org/10.1001/jama.2018.18269
- Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.N Engl J Med. 2013; 369: 1317-1326https://doi.org/10.1056/NEJMoa1307684
- Alogliptin after acute coronary syndrome in patients with type 2 diabetes.N Engl J Med. 2013; 369: 1327-1335https://doi.org/10.1056/NEJMoa1305889
Article Info
Publication History
Published online: September 24, 2022
Accepted:
September 20,
2022
Received in revised form:
September 9,
2022
Received:
August 5,
2022
Identification
Copyright
© 2022 Elsevier B.V. All rights reserved.
