Interaction Between Non-Insulin Glucose-Lowering Medication and Exercise in Type 2 Diabetes Mellitus - New Findings on SGLT2 Inhibitors.

Abstract

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which block glucose reabsorption in the kidneys, represent a novel class of non-insulin glucose-lowering medication used in the pharmacological therapy of type 2 diabetes mellitus (T2DM). They became available after the introduction of incretin-based therapies with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or dipeptidyl peptidase-4 (DPP4) inhibitors (1). All these newer drugs have multiple effects that go beyond their glucose-lowering effect (2). It has been concluded in a meta-analysis that patients with T2DM who take SGLT2 inhibitors experience fewer major adverse cardiovascular events and show reduced all-cause mortality (3). Another meta-analysis (including data from patients with T2DM, heart failure or chronic kidney disease) demonstrates that SGLT2 inhibitor use can reduce the risk of cardiac arrhythmia (4). Yet another meta-analysis shows that SGLT2 inhibitor use can reduce blood pressure in T2DM patients (5). The beneficial effects of SGLT2 inhibitors on the cardiovascular system do not only depend on the glucose-lowering effect, but are also based on other possible mechanisms, e.g. increased natriuresis and diuresis [for an overview, see (6)]. Although it is generally accepted that regular exercise also has glucose-lowering and beneficial cardiovascular effects, the combination of non-insulin glucose-lowering medication and regular exercise does not necessarily have to have additive effects on glycemic variables and/or cardiovascular health/cardiorespiratory fitness. By contrast, it has been concluded in some studies involving insulin resistant patients who take metformin, which is often recommended as the first-line medication in T2DM, that certain exercise adaptations (improvements in insulin sensitivity, peak oxygen uptake, blood pressure, lipid profile) are not further increased or can even be attenuated through metformin use (7–11). Details on the underlying molecular mechanisms of how metformin and exercise interact and affect exercise training outcomes have yet to be determined. Among others, changes in (exercise-induced) oxidative stress and/or inflammation (with effects on post-exercise cellular signals) or in (exercise-induced) autophagy have been discussed (10, 12). It should be noted, however, that not all studies report similar or blunted adaptations for all outcomes when exercise training is combined with metformin use. In the study of Viskochil et al. (13), for example, metformin and exercise training, but not exercise alone, lowered proinsulin concentrations and increased insulin clearance in adults with prediabetes. But what about the influence of SGLT2 inhibitors on training outcomes?