Understanding the Benefit of Combining GLP-1 Agonists With Exercise: Time Will Tell

glycemic control, pancreatic function, insulin sensitivity, type 2 diabetes, physical activity, weight loss

Exercise improves blood glucose control among people with type 2 diabetes (T2D), and can lead to reduced need for glucose medications (1, 2). Although the optimal exercise “dose” (eg, intensity, modality, time of day, and/or duration) remains to be determined, it is appropriate to recognize that the improvements seen across people vary—with some experiencing little benefit to even slight rises (2). Subsequently, pharmacological agents are likely needed for some people to manage blood glucose to prevent/attenuate macrovascular and microvascular complications associated with the disease. Much attention over the past decade has focused on understanding how metformin, the first-line agent for treatment of hyperglycemia, interacts with exercise (3). In recent years, interest in other glucose medications in combination with exercise have been investigated.

Glucagon-like peptide-1 (GLP-1) agonists are both effective glycemic agents and potent weight loss therapy aids. In fact, there has been much excitement for GLP-1 agonists, namely semaglutide relative to others (eg, liraglutide), regarding weight loss (4). Novel work (5) presented in the Journal of Clinical Endocrinology & Metabolism demonstrates that the combination of semaglutide plus aerobic training improved beta-cell insulin secretion function more than training alone as evaluated by a 2-stepped hyperglycemic (20 and 20 mM) clamp in people with T2D. Interestingly, these findings were supported by use of an oral glucose tolerance test, whereby beta-cell glucose sensitivity was improved independent of circulating GLP-1 or total glucose-dependent insulinotropic polypeptide (GIP). Of note, patients were allocated to semaglutide for 20 weeks prior to training and then evaluated before and after aerobic training. Aerobic exercise consisted of cycling 3 days/week at 75% of maximum heart rate reserve for 45 minutes/session for 12 weeks. Semaglutide was administered once weekly by subcutaneous injection and ramped up over 8 weeks until 0.5 mg or 1.0 mg was achieved by week 9 and ensued for the remainder of the study. Treatment with semaglutide significantly reduced HbA1c and fasting glucose as well as visceral fat and total body fat before training commenced. However, after commencement of exercise, training with or without semaglutide improved glycemic control and body composition comparably.

The main findings of the work (5) were semaglutide plus exercise positively impacted beta-cell function, suggesting cotherapy is beneficial. This seems to be reasonable given people with T2D have lost upwards of ∼80% of their beta-cell function. However, the idea of improving beta-cell function would be ideally linked to greater glycemic control. This did not occur. So, it seems fair to ask if there was no added glycemic benefit during the time of exercise training, what does a rise in insulin secretion capacity mean for people? A consideration is individuals in this study with diabetes had sustained insulin secretion capacity (5). This raises thoughts on the patient population studied. For instance, diabetes duration reflects exposure time to disease severity and may influence responses to treatment. As diabetes duration increases (eg, >7 years), the propensity toward favorable lifestyle therapy responses are attenuated (6). Patients in this study with semaglutide and training (5) had a diabetes duration of 5.2 years on average with HbA1c of 8.1% compared with training only, which had a duration of 4.2 years and HbA1c of 7.4%. People on insulin treatment were excluded as well. Whether these subtle differences in diabetes duration/glycemia influenced treatment responses, and/or if GLP-1 agonists plus exercise would have similar effects in a patient population of longer duration and/or on insulin treatment is unclear. Nevertheless, another interesting observation is how semaglutide may have enhanced pancreatic function during exercise training. Exercise alone is thought to reduce insulin secretion during activity through, in part, the rise in catecholamine release that over time lowers daily insulin secretion needs. Herein (5) it was observed that insulin levels were reduced in both treatment groups during submaximal exercise prior to training. However, after treatment, aerobic training had increased the noradrenaline (norepinephrine) response to submaximal exercise while the combined treatment group did not. This is interesting because training was performed at similar intensities and there was no difference in maximal aerobic fitness. The findings point toward a need to understand beta-cell function adaptations with the cotherapy.

Perhaps an important take away from the study too is that timing of drug use with exercise could matter. “Prehabilitation” with semaglutide favored reductions in hyperglycemia (5), such that it may have lowered inflammation and/or oxidative stress and enabled greater response to exercise. This was not a focus of the current paper (5), but some evidence for drug–lifestyle timing comes from work whereby individuals with obesity were provided an 8-week low-calorie diet (800 kcal/day) and lost nearly 12% body weight (7). People were then randomized to placebo, exercise (150 minutes/week of moderate intensity and/or 75 minutes/week of vigorous activity), liraglutide (3.0 mg/day; another GLP-1 agonist) or the combination. Interestingly, in people who lost weight on average, only liraglutide and the combination further reduced metabolic syndrome severity (ie, z-score), while all 3 treatments lowered android body fat compared with placebo and the combination treatment decreased high-sensitivity C-reactive protein (inflammatory marker) (7). These findings are in line with the current work (5) because they suggest the combination of GLP-1 agonist plus exercise may be more beneficial for overall health vs. either treatment alone.

There has been much excitement recently for using semaglutide as a weight loss drug. However, this study among others raises the idea that timing may matter. Other reports indicate when GLP-1 agonists are withdrawn, people regain weight (4). If so, what does this mean long-term for people trying to be healthy with or without exercise? One aspect is that withdrawal of either drug or exercise shows that obesity/diabetes is a chronic condition that requires consistent attention. When considering the literature, identifying strategies that foster the adoption of healthy lifestyle behaviors early in the diagnosis of T2D is more important than ever since there is no quick, sustainable fix. Thus, examining drug to exercise timing could provide health care professionals better guidance on how to prescribe medications with exercise for long-term patient well-being.

Funding

S.K.M. is supported by National Institutes of Health RO1-HL130296.

Disclosures

None to report.

Abbreviations

 
• GLP-1

  glucagon-like peptide-1

 
• T2D

  type 2 diabetes