Sodium-glucose cotransporter-2 inhibitors in type 2 diabetes
SGLT2 inhibition and heart failure: Current concepts
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are cardioprotective in patients with type 2 diabetes. This review discusses their use as a potential treatment for heart failure.
| Summary points |
- Increased renal glucose excretion caused by SGLT2 blockade is associated with chronic weight loss, reduced blood volume and a diuretic-like reduction in blood pressure.
- In the key EMPA-REG OUTCOME trial, compared with placebo empagliflozin reduced the risk of cardiovascular death by 38% and heart failure hospitalization by 35% in patients with type 2 diabetes mellitus.
- These results were supported by real-world data from the international CVD-Real Study, and by the CANVAS PROGRAM, indicating a class cardiovascular protective effect for SGLT2 inhibitors in T2DM.
- These cardiovascular effects occur early, possibly due to hemodynamic activity.
- Other putative actions include (1) increased ketone production and metabolism, which may have anti-arrhythmogenic effects, (2) interaction with the cardiac cell Na+/H+ exchanger, reducing cytoplasmic sodium and increasing mitochondrial calcium, ultimately mitigating systolic dysfunction, (3) reduced visceral adiposity, (4) improved lipid profile, and (5) decreased uric acid levels.
- Clinical data also support reduced progression of renal disease in type 2 diabetes, and delayed rises in cardiovascular risk biomarkers.
- The most common adverse event has been polyuria.
- Regulatory agencies have issued warnings for increased risks of unexplained leg/foot amputations and ketoacidosis for SGLT2 inhibitors.
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Custodio JS et al. Heart Fail Rev 2018; 23: 409–418. doi: 10.1007/s10741-018-9703-2
SGLT2 inhibitors: Hypotheses on the mechanism of cardiovascular protection
Sodium-glucose cotransporter-2 (SGLT2) inhibitors may have direct, cardioprotective effects, independent of SGLT2 expression, countering the toxic effects of raised glucose levels in stressed cells.
| Summary points |
- Effect 1: Inhibition of the cardiac cell Na+/H+ exchanger. The subsequent decrease in cytosolic calcium and increase in mitochondrial calcium prevents heart failure and is cardioprotective in the context of ischaemia-reperfusion injury.
- Effect 2: Suppression of gp91phox NADPH oxidase activity, a cause of myocardial injury, via inhibition of SGLT1/sodium-myoinositol co-transporter-1. SGLT2 inhibitors may block SGLT1 directly through mixed SGLT2 and SGLT1 inhibition or indirectly via improved glycemic control and a consequent reduction in SGLT1 activation following ischemia.
- Effect 3: Inhibition of SGLT-induced intracellular sodium and calcium accumulation secondary to raised extracellular glucose levels. Improved glucose control with mixed SGLT1/SGLT2 inhibitors may limit SGLT1-mediated glucotoxicity in acutely injured cells.
- Effect 4: Increasing the availability of ketones for metabolism. SGLT2 inhibitors lead to mild ketogenesis, thereby providing challenged organs with an advantageous energy substrate.
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Bell RM, Yellon DM. Lancet Diabetes Endocrinol 2018; 6: 435–437. doi: 10.1016/S2213-8587(17)30314-5
Direct cardiovascular impact of SGLT2 inhibitors: Mechanisms and effects
Sodium-glucose cotransporter-2 (SGLT2) inhibitors have beneficial effects in type 2 diabetes. This review explores mechanisms by which they may directly influence the cardiovascular system.
| Summary points |
- Decreasing Na+/H+ exchanger activity decreases intracellular sodium levels, subsequently causing decreased cytosolic calcium levels in a cardioprotective manner.
- Protective metabolic effects may include direct reductions of plasma glucose levels, lowering myocardial fatty acid storage, and shifting myocardial metabolism to fatty acids and ketones.
- Reduction in plasma glucose concentrations, improvements in cardiac insulin sensitivity and glucose usage, plus lowering triglyceride accumulation in cardiac tissue may facilitate the cardioprotective actions of ketones at the same time as limiting the toxic effects of glucose and lipids.
- SGLT2 inhibition may also reduce oxidative stress and inflammation in the myocardium and vasculature.
- Reductions in body weight, blood pressure, arterial stiffness and vascular resistance may improve cardiac output in patients with type 2 diabetes.
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Kaplan A et al. Heart Fail Rev 2018; 23: 419–437. doi: 10.1007/s10741-017-9665-9
Sodium-glucose cotransporter-2 inhibition for the reduction of cardiovascular events in high-risk patients with diabetes mellitus
This review summarizes known and postulated effects of sodium-glucose cotransporter-2 (SGLT2) inhibition on the cardiovascular system and discusses the role of SGLT2 inhibition for the treatment of high-risk patients with type 2 diabetes and cardiovascular disease.
| Summary points |
- Patients with type 2 diabetes exhibit an increased risk for cardiovascular cardiovascular events.
- Glucose-lowering strategies studied to date have had little to no impact on reducing cardiovascular risk, especially in patients with a long duration of type 2 diabetes and prevalent cardiovascular disease.
- SGLT2 inhibitors increase urinary glucose excretion, thus improving glycemic control independent of insulin.
- The cardiovascular outcome trial, EMPA-REG OUTCOME, demonstrated that the SGLT2 inhibitor empagliflozin significantly reduced the combined cardiovascular endpoint of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke vs placebo in a population of patients with type 2 diabetes and prevalent atherosclerotic cardiovascular disease.
- Empagliflozin also significantly and robustly reduced the individual endpoints of cardiovascular death, overall mortality, and hospitalization for heart failure in this high-risk population.
- Various factors beyond glucose control such as weight loss, blood pressure lowering and sodium depletion, among others may contribute to these beneficial effects of SGLT2 inhibition.
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Marx N, McGuire DK. Eur Heart J 2016; 37: 3192–3200. doi: 10.1093/eurheartj/ehw110
Are SGLT2 inhibitors reasonable antihypertensive drugs and renoprotective?
This review article discusses the potential of the sodium-glucose cotransporter-2 (SGLT2) inhibitor drug class to reduce blood pressure and protect from diabetic nephropathy.
| Summary points |
- Sodium-glucose cotransporter-2 (SGLT2) inhibitors act as osmotic diuretics to lower blood pressure in addition to reducing plasma glucose and assisting with weight loss.
- Although not approved as antihypertensive agents, the ability of this new class of antihyperglycemic agents to lower blood pressure may well assist diabetic patients in reaching recommended blood pressure targets.
- However, given the frequent lack of a nocturnal blood pressure dip among diabetic subjects, the association of nocturnal hypertension with cardiovascular events and emerging evidence regarding the benefits of specifically targeting night time blood pressure, it would seem premature to use SGLT2 inhibitors as primarily antihypertensive agents.
- Results from dedicated cardiovascular and renal outcome studies reports are anticipated shortly to further understanding in this area.
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Lovshin JA, Gilbert RE. Curr Hypertens Rep 2015; 17: 40. doi: 10.1007/s11906-015-0551-3