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The role of SGLT-2 inhibitors in diabetes management and cardiovascular disease risk

The role of SGLT-2 inhibitors in diabetes management and cardiovascular disease risk

The haemodynamic effects of empagliflozin are likely responsible for the cardiovascular benefits seen in patients with high cardiovascular disease risk and type 2 diabetes

Although cardiovascular (CV) mortality is the leading cause of death in individuals with type 2 diabetes (T2DM), reduction of plasma glucose concentration has little effect on cardiovascular disease (CVD) risk.1 Thus, novel strategies to reduce CVD risk in patients with T2DM are needed. Results from the empagliflozin cardiovascular outcome event trial in T2DM patients (EMPA-REG OUTCOME) study demonstrated that empagliflozin, added to patients’ standard care, reduced the primary major adverse cardiac event end point (CV death, nonfatal myocardial infarction, nonfatal stroke) by 14% in high CVD risk patients with T2DM compared with placebo. This beneficial effect was driven by a 38% reduction in CV mortality with no significant decrease in the rate of nonfatal myocardial infarction or stroke. Empagliflozin also caused a 35% reduction in the rate of hospitalization for heart failure without affecting the hospitalization rate for unstable angina.2 Although sodium-glucose cotransporter 2 (SGLT-2) inhibitors exert multiple metabolic benefits (decreases in HbA1c, body weight and blood pressure and an increase in high density lipoprotein cholesterol), all of which could reduce CVD risk, it is unlikely that the reduction in CV mortality can be explained by empagliflozin's metabolic effects alone. More likely, haemodynamic effects, specifically reduced blood pressure and decreased extracellular volume, are responsible for the reduction in CV mortality and hospitalizations due to heart failure.

SGLT2 inhibitors cause a shift from glucose to fat oxidation. The end product of fatty acid oxidation is acetyl coenzyme A, which can either enter the tricarboxylic acid cycle or be converted to ketones, the latter being favoured by the SGLT2 inhibitor-induced stimulation of glucagon secretion.3 The rise in plasma ketone concentration is small. Since the amount of oxygen required to generate the same amount of ATP is less with ketones compared with glucose and fatty acid4 the heart avidly extracts and consumes ketone bodies and ketone body oxidation may improve cardiac muscle efficiency.4 Further studies to examine whether the preferential oxidation of ketones by the heart provides an energy benefit to the failing myocardium are required.

A contributing factor to the positive CV outcomes of the EMPA-REG OUTCOME trial could be an increase in oxygen delivered to tissues. SGLT2 inhibitors cause an increase in haematocrit,5 which in the EMPA-REG OUTCOME trial averaged 5% in absolute values and 11% in percentage points. This change likely reflects the haemoconcentration associated with the diuretic effect of this class of drugs. Interestingly, the blood volume contraction was not associated with a significant increase in heart rate, suggesting that cardiac output was maintained at least at pretreatment levels. A higher haematocrit for the same blood flow will deliver more oxygen to tissues. In patients (including patients with diabetes) with decompensated heart failure and renal dysfunction, haemoconcentration induced with very high doses of a loop diuretic has been associated with a substantially improved survival time, despite the deterioration of renal function.6

The EMPA-REG OUTCOME study demonstrates that the addition of empagliflozin to the anti-diabetes treatment regimen in high-risk T2DM patients with established CVD reduces CV mortality by 38%. The dramatic effect on CV mortality justifies inclusion of empagliflozin in the treatment regimen of T2DM patients with similar clinical characteristics to those in the EMPA-REG OUTCOME study, that is, those with established CVD. In T2DM patients who are earlier in the natural history of the disease and do not have well-established CVD, there are no data to support the use of one SGLT2 inhibitor over another.  Currently, there are no data suggesting any SGLT2 inhibitor will have a CV protective effect in a T2DM population without clinically evident CVD. Therefore, the physician should feel comfortable using any of the three SGLT2 inhibitors in patients with diabetes without advanced cardiac disease. All SGLT2 inhibitors on the market similarly reduce HbA1c, blood pressure and body weight and have a good safety profile.

            As the results of the EMPA-REG OUTCOME study suggest that the beneficial effect of empagliflozin in lowering CV mortality in T2DM patients most likely results from its haemodynamic rather than its metabolic effects, it would be intriguing to examine the impact of the drug in subjects with and without diabetes with reduced left ventricular function (e.g., post-myocardial infarction) and in subjects with existing chronic heart failure. The beneficial effect of empagliflozin on CV mortality and chronic heart failure hospitalization rates in these patient populations is likely to be quite robust.  Additional studies to examine this possibility are indicated.


References

1. Sattar N. Revisiting the links between glycaemia, diabetes and cardiovascular disease. Diabetologia 2013;56:686–695.

2. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–2128.

3. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014;124:499–508.

4.  Sato K, Kashiwaya Y, Keon CA, et al. Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J 1995;9:651–658.

5. Mudaliar S, Polidori D, Zambrowicz B, Henry RR. Sodium-glucose cotransporter inhibitors: effects on renal and intestinal glucose transport: from bench to bedside. Diabetes Care 2015;38:2344–2353.

6.  Mentz RJ, O’Connor CM. Pathophysiology and clinical evaluation of acute heart failure. Nat Rev Cardiol 2016;13:28–35.

Chaicharn Deerochanawong

Professor of Medicine
Dept. of Medicine
Diabetes and Endocrinology Unit
Rajavithi Hospital
Bangkok, Thailand
Type 2 diabetes mellitus
cardiovascular disease risk
SGLT-2 Inhibitors
empagliflozin
haemodynamic and metabolic effects