Sodium-glucose co-transporter 2 (SGLT2) receptors are primarily located in the proximal
convoluted tubule of the nephron. These receptors are responsible for almost 90% to
95% of tubular reabsorption of the glucose in the nephron. In patients with diabetes
mellitus, due to upregulation of SGLT2 receptors, glucose reabsorption is further
increased. The Food and Drug Administration approved SGLT2 inhibitors, such as canagliflozin,
empagliflozin, dapagliflozin, and ertugliflozin, for the treatment of type 2 diabetes.
In addition to their positive effect on blood glucose, additional cardioprotective
and renoprotective functions have been demonstrated in major trials such as EMPA-REG
OUTCOME, CANVAS, DECLARE-TIMI-58, and CREDENCE. Unlike other antihyperglycemic drugs,
reduction in hospitalization for heart failure (HF) was also seen as a class effect
with this group, mechanisms of which are probably multifactorial. Subgroup analysis
from these major trials indicated a reduction in progression of nephropathy and HF
readmission with SGLT2 inhibitors. Although this unique property of canagliflozin
was further analyzed in the CREDENCE trial, similar trials for empagliflozin (EMPERIAL-Reduced
and EMPERIAL-Preserved) and dapagliflozin (DAPA-HF) are currently underway. Recently
released phase III results from DAPA-HF trial indicate that dapagliflozin shows significant
reduction in death due to cardiovascular causes and hospitalization in HF compared
with the placebo, in both diabetics and nondiabetics. In this review article, the
authors attempt to explore the possible underlying molecular mechanisms and data from
existing trials pertaining to the HF related outcomes associated with SGLT2 inhibitors.
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References
- Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association.Circulation. 1999; 100: 1134-1146
- Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants.Lancet. 2016; 387: 1513-1530
- Diabetes medications and heart failure.Circulation. 2014; 130: 1565-1567
- Sulfonylureas and the risks of cardiovascular events and death: a methodological meta-regression analysis of the observational studies.Diabetes Care. 2017; 40: 706-714
- Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone.JAMA. 2010; 304: 411-418
- Effects of once-weekly exenatide on clinical outcomes in patients with preexisting cardiovascular disease.Circulation. 2018; 138: 2576-2578
- Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial.Circulation. 2014; 130: 1579-1588
- EMPA-REG OUTCOME: the endocrinologist's point of view.Am J Med. 2017; 130: 51-56
- SGLT2 inhibitors: a novel choice for the combination therapy in diabetic kidney disease.Cardiovasc Diabetol. 2017; 16: 65
- An update on SGLT2 inhibitors for the treatment of diabetes mellitus.Curr Opin Endocrinol Diabetes Obes. 2017; 24: 73-79
- Renal hemodynamic effect of Sodium–glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus.Circulation. 2014; 129: 587-597
- Effects of SGLT2 inhibition in human kidney proximal tubular cells–renoprotection in diabetic nephropathy?.PLoS ONE. 2013; 8: e54442
- SGLT2 inhibitors and mechanisms of hypertension.Curr Cardiol Rep. 2018; 20: 1
- Glomerular hyperfiltration and the salt paradox in early [corrected] type 1 diabetes mellitus: a tubulo-centric view.J Am Soc Nephrol. 2003; 14: 530-537
- Canagliflozin reduces epicardial fat in patients with type 2 diabetes mellitus.Diabetol Metab Syndr. 2017; 9: 78
- Sodium-dependent glucose transporters (SGLT) in human ischemic heart: a new potential pharmacological target.Int J Cardiol. 2017; 243: 86-90
- Impact of aging on substrate metabolism by the human heart.J Am Coll Cardiol. 2003; 41: 293-299
- Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes.Cardiovasc Diabetol. 2017; 16: 9
- Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis.Diabetes Obesity Metab. 2018; 20: 479-487
- The sodium-glucose co-transporter 2 inhibitor, empagliflozin, protects against diabetic cardiomyopathy by inhibition of the endoplasmic reticulum stress pathway.Cell Physiol Biochem. 2017; 41: 2503-2512
- Empagliflozin improves left ventricular diastolic dysfunction in a genetic model of type 2 diabetes.Cardiovasc Drugs Ther. 2017; 31: 233-246
- The sodium-glucose cotransporter 2 inhibitor dapagliflozin prevents cardiomyopathy in a diabetic lipodystrophic mouse model.Diabetes. 2017; 66: 1030-1040
- SGLT-2 inhibition with dapagliflozin reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic cardiomyopathy in mice with type 2 diabetes. Further augmentation of the effects with Saxagliptin, a DPP4 inhibitor.Cardiovasc Drugs Ther. 2017; 31: 119-132
- Amelioration of hyperglycemia with a sodium-glucose cotransporter 2 inhibitor prevents macrophage-driven atherosclerosis through macrophage foam cell formation suppression in type 1 and type 2 diabetic mice.PLoS One. 2015; 10e0143396
- The SGLT-2 inhibitor dapagliflozin has a therapeutic effect on atherosclerosis in diabetic ApoE(−/−) mice.Mediators Inflamm. 2016; 2016e6305735
- Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128
- Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial.Eur Heart J. 2016; 37: 1526-1534
- Empagliflozin reduced mortality and hospitalization for heart failure across the spectrum of cardiovascular risk in the EMPA-REG OUTCOME Trial.Circulation. 2019; 139: 1384-1395
- Empagliflozin improves kidney outcomes in patients with or without heart failure.Circ Heart Fail. 2019; 12e005875
- Rationale and design of the EMPERIAL-Preserved and EMPERIAL-Reduced trials of empagliflozin in patients with chronic heart failure.Eur J Heart Fail. 2019; 21: 932-942
- Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657
- Canagliflozin and heart failure in type 2 diabetes mellitus.Circulation. 2018; 138: 458-468
- Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306
- Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306
- Dapagliflozin and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2019; 380: 347-357
- Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus.Circulation. 2019; 139: 2528-2536
- Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial.Lancet Diabetes Endocrinol. 2019; 7: 606-617
- A trial to evaluate the effect of the sodium-glucose co-transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA-HF).Eur J Heart Fail. 2019; 21: 665-675
- SGLT-2 inhibitors and the risk of infections: a systematic review and meta-analysis of randomized controlled trials.Acta Diabetol. 2018; 55: 503-514
- Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program.Diabetes Care. 2015; 38: 1680-1686
Article info
Publication history
Published online: September 09, 2019
Received in revised form:
August 25,
2019
Received:
May 30,
2019
Identification
Copyright
© 2019 Elsevier Inc. All rights reserved.
