Increased grip strength with sodium–glucose cotransporter 2

In the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME) study, empagliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, significantly reduced the risk of cardiovascular death and hospitalization for heart failure among patients with type 2 diabetes (T2D) and established cardiovascular disease.1 Possible mechanisms for these benefits include decreased blood pressure, visceral fat reduction, weight loss, and volume reduction due to a mild diuretic effect. Sarcopenia is a loss of muscle mass, resulting in reduced strength and functional decline, and in association with diabetes is a major public health concern because it leads to frailty and mortality. Subjects with diabetes exhibit a progressive decline in muscle mass and quality, caused by reduced insulin sensitivity, hormone imbalance, decreased mitochondrial function, and reduced muscle regenerative capacity. In turn, reduced physical activity further worsens sarcopenia. There remains a lack of consensus as to how to screen for sarcopenia. A recent large longitudinal study revealed that hand grip strength was inversely associated with all-cause mortality, cardiovascular mortality, and myocardial infarction in the general population.2 Measurement of maximal hand grip strength could be a simple and inexpensive method for cardiovascular risk stratification among subjects with T2D. We examined the change in maximal hand grip strength before and after SGLT2 inhibitor treatment. The study was performed on 112 Japanese subjects with T2D (92 men, 20 women). In men, mean (± SD) age, baseline body mass index (BMI), and HbA1c was 62.8 ± 10.2 years, 25.6 ± 4.5 kg/m2, and 7.0 ± 1.3 %, respectively. In women, mean (± SD) age, baseline BMI, and HbA1c was 65.2 ± 9.0 years, 24.5 ± 4.3 kg/m2, and 7.3 ± 1.5 %, respectively. Subjects were treated with ipragliflozin 50 mg, luseogliflozin 2.5 mg, or dapagliflozin 5 or 10 mg daily for at least 4 weeks. The mean (± SD) observation period was 10.3 ± 2.9 weeks after SGLT2 inhibitor treatment. In both men and women, grip strength increased in both hands after SGLT2 inhibitor treatment (P < 0.01, paired t-test; Fig. 1). These findings were in contrast with our concern of metabolic side effects in relation to sarcopenia, because SGLT2 inhibitor treatment reduces lean tissue mass as well as fat mass.3 The putative mechanisms responsible for the beneficial effects of SGLT2 inhibition on maximal hand grip strength include reduced chronic inflammation and improved adipokine balance due to reduced visceral adipose tissue mass; improved mitochondrial function; decreased protein turnover due to attenuation of protein oxidative damage and ubiquitination4; reduced interstitial edema; improved microcirculation; and improved peripheral nerve function. Subjects were well-educated about appropriate exercise, thus increased spontaneous physical activity after SGLT2 inhibitor treatment may also improve muscle strength. In addition, subjects compensated for the negative energy balance caused by SGLT2 inhibition by increasing their carbohydrate intake, leading to anabolism,5 which may change the catabolic–anabolic balance set point in muscle. The heart and vasculature may benefit from similar effects of SGLT2 inhibition, thereby reversing heart dysfunction associated with diabetes. Thus, the observations reported herein provide new insight into the EMPA-REG OUTCOME study results.1 However, more detailed studies are needed to elucidate the mechanism underlying the beneficial salutary effect of SGLT2 inhibitor treatment on grip strength demonstrated in the present study. The authors declare no conflicts of interest, including special financial interest or relationship.