Variable effect of exercise training programme on cardiovascular outcomes in high-genetic-risk individuals with diabetes Free

This editorial refers to ‘Interaction between type 2 diabetes polygenic risk and physical activity on cardiovascular outcomes’, by C.-L. Lee et al., https://doi.org/10.1093/eurjpc/zwae075.

Type 2 diabetes mellitus (T2DM) had potential detrimental effect on mortality and morbidity including all-cause and cardiovascular (CV) death, major cardiovascular events, renal outcomes, and hospitalization rate.¹ Numerous programmes of lifestyle interventions demonstrated sufficient variability of their effect on CV outcomes among patients with established T2DM.^2,3 On the one hand, intense physical activity and cardiorespiratory fitness in connection with lifestyle modification is associated with decreased new incidence of CV disease, coronary heart disease, obesity, hypertension, heart failure, and all-cause mortality mainly through improving insulin resistance, glucose control, decreasing adiposity, stimulating skeletal muscle/adipose tissue interaction, and anti-inflammatory effect.^4,5 Meta-analysis of eight clinical studies of variable physical training programmes in T2DM individuals by Nery showed that resistance exercise seemed to be more effective than aerobic exercise in promoting an increase in maximal oxygen consumption, whereas there were no difference in the levels of glycated haemoglobin, body mass index, and lipid profile.⁶ Finally, these findings may mean that neither resistance exercise nor aerobic exercise without intensified anti-diabetic therapy may not improve metabolic and clinical outcomes in patients with T2DM.⁷ On the other hand, intensive lifestyle interventions including physical exercise had no superiority to usual care in reducing CV or all-cause mortality when compared with subjects with pre-diabetes and T2DM.⁸

The innate underlying molecular mechanisms, which contribute to the lack of beneficial impact of physical exercise on T2DM-related risk, need to be thoroughly investigated. Perhaps genetic risk of T2DM that might affect metabolic memory, endogenous reparative system, presentation of co-existing CV risk factors and diseases is considered sufficient player in exercise-mediated outcomes among these individuals.⁹ However, the plausible effects of T2DM genetic risk on CV disease and the potential interaction between genetic risk components and lifestyle factors are not understood.

The study by Lee et al.¹⁰ which has been published in this issue of the European Journal of Preventive Cardiology, had first investigated the interaction effect between polygenic risk for type 2 diabetes mellitus (PRS_T2D) and physical activity on CV outcomes in subjects with diabetes (n = 25 701), using the UK Biobank cohort. The main benefit of the results received in the study for readers is undoubtedly strong evidence of the fact that the highest distribution of the PRS_T2D was associated with the prevalence and incidence of diabetes. Yet, the authors found that the effect of genetic risk for T2DM on CV outcomes was markedly influenced by glycaemic control. In this connection, the only intense physical exercise (>80 METs hours per week) in patients with high genetic risk for diabetes mellitus increased the risk of MACE, whereas less intensity of the training was not associated with harmful impact on MACE. In subgroup analysis, Lee et al.¹⁰ reported that the physical activity reduced MACE stronger in insulin users and each 10 metabolic equivalents (METs) hours per week of physical activity remained nominally protective even among participants with PRS_T2D in the fourth quartile (Q4). Aline with it, negative impact of intense physical activity among participants with PRS_T2D Q4 was observed in non-insulin users, but not in insulin users.

However, there are several methodological issues and limitations, which require thoroughly elucidation. First, the authors did not additionally perform subgroup analysis separately looking at anti-diabetic drugs other than insulin, such as sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 agonists, while they separately evaluated previous history of CV event among non-insulin users and insulin users with PRS_T2D–physical activity interaction analysis. The authors correctly noticed that interaction effect seemed to be weaker in insulin users. However, the interrelationship between anti-diabetic drug-induced metabolic control and adaptive exercise training programme on CV outcomes among high genetic risk for T2DM are under scientific question. Second, the authors found that intense physical activity might result in negative impact on MACE due to sympathetic over-activity through increase glycaemic variability, while the risk of complications in diabetic population seems to be independent of mean blood glucose control. Other underlying mechanisms and other factors contributed to negative impact of intense physical activity on MACE only among those with high genetic risk for T2DM remain elusive and require further investigations. Third, the findings seem not to be contradicated the fact that current guideline recommends exercise activity equal 7.5 METs hoursper week of exercise, which corresponds to regular moderte-to-intensity 150 min training per week for the prevention of CV disease.¹¹

Admittedly, findings received by Lee et al.¹⁰ open promising perspectives to effectively stratify the patients at the genetic risk and screen them into high-risk group, in which avoidance of vigorous exercise is likely to be a better strategy for personalized therapy of T2DM. Moreover, the study is the first investigation with the aim of elucidating the dose-dependent effect of physical activity in interaction with genetic risk for T2DM on CV outcomes, which creates a background for scientific discussion around lifestyle modification such as personified exercise programme. Large clinical trial requires clearly elucidating this approach in the future.

Author contribution

A.E.B. being a sole author of the manuscript and is responsible for the conception, design, data interpretation, and final approval of the paper.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References

Author notes