Management of hypertension, type 2 diabetes, and cardiovascular disease in low-and middle-income countries: synthesizing evidence on adding exercise to usual care

Background: Globally, hypertension, type 2 diabetes (T2D), or cardiovascular disease (CVD) are among the leading causes of death, and the burden is disproportionately high in low-and middleincome countries (LMICs). Regular exercise is the most recommended lifestyle intervention for people with hypertension, T2D, and/or CVD. Evidence on the beneficial effect of exercise on reducing cardiometabolic risk factors and clinical outcomes exists, but it is still inconsistent and inconclusive. Moreover, previous reviews are often limited to aerobic and resistance exercise, and assessment of other forms of exercise and evidence from LMICs are often unexplored or overlooked.

Aims: The overall aim of this PhD project is to assess the beneficial and harmful effects of adding exercise to usual care in people with hypertension, T2D, and/or CVD. We also further aim to investigate if there is a difference in evidence for trials/participants originating from LMICs compared to trials/participants from high-income countries (HICs).

Method: This PhD project is based on a comprehensive systematic review with meta-analyses and trial sequential analysis. It is developed based on pre-published (Paper I) and preregistered protocols (PROSPERO: CRD42019142313). We searched the CENTRAL, MEDLINE, EMBASE, Science Citation Index Expanded on Web of Science, and BIOSIS databases from inception to July 2020. We also manually searched references from previously published reviews. We included all randomized clinical trials (RCTs), adding any form of trialist-defined exercise to usual care versus usual care in people with hypertension, T2D, and/or CVD, irrespective of setting, publication status, year, and language. Five independent reviewers extracted data and assessed the risk of bias in pairs. Our methodology was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), Grading of Recommendations Assessment, Development and Evaluation (GRADE), and Cochrane Risk of Bias-version 1 (RoB 1). We conducted a trial sequential analysis to control for type I and type II errors.

Results: Paper II: A short duration of any type of exercise seemed to reduce the risk of all-cause mortality by 18% (Risk Ratio (RR): 0.82; 95% CI 0.73 to 0.93; I2=0%, moderate certainty of evidence) and serious adverse events by 21% (RR 0.79; 95% CI 0.71 to 0.88; I2 =0%, moderate certainty of evidence) in people with hypertension, T2D, and/or cardiovascular disease. Exercise seemed to have statistically significant beneficial effects on quality of life, but the effect sizes seemed minimal. Exercise also reduced the risk of cardiovascular mortality by 25% (RR:0.75; 95% CI 0.64 to 0.89; p
Paper III: Any type of exercise intervention significantly reduced both systolic blood pressure (SBP) (Mean Difference (MD) -4.1 mmHg; 95%CI -4.99 to -3.14, p < 0.01; I2= 95.3%; very low certainty of evidence) and diastolic blood pressure (DBP) (MD -2.6 mmHg 95%CI -3.22 to -2.07, p
Paper IV: Exercise when added to the usual care, improved functional capacity as measured by maximal oxygen uptake (VO2max) (MD: 2.72 ml/kg/min; 95%CI 2.38 to 3.06; p < 0.01; I2 = 96.5%; very low certainty of evidence), 6-meter walk test (6MWT) (MD: 43.14 m; 95%CI 35.56 to 50.71; p< 0.01; I2 = 96%; very low certainty of evidence), or 10-meter walk test (10MWT) (MD: 0.06 m/s; 95%CI 0.03 to 0.10; p muscle training for 6MWT. Exercise also reduced body weight (MD: -1.42kg; 95%CI -1.91 to -0.92;p < 0.01; I2 = 86.5; very low certainty of evidence). The reduction was modest and significant in people with hypertension and/or T2D but not in people with CVD and the highest reduction was reported for combined exercise.

Conclusion and implications: Overall, our results highlighted that adding any type of exercise to usual care worked favorably and reduced the risk of all-cause mortality, severe adverse events, and cardiovascular mortality for people with hypertension, T2D, and/or CVD. The underlying mechanism for this significant risk reduction following a relatively short duration of exercise needs further investigation. Exercise also seemed to improve quality of life slightly. Exercise was found to reduce known modifiable cardiovascular risk factors such as SBP and DBP. The blood pressure reducing effect was found to be more pronounced in people with hypertension or T2D compared to CVD, and especially for LMICs where resources to manage, treat, and control blood pressure is suboptimal. Likewise, exercise also improved functional capacity and may be a viable approach for reducing body weight for people with hypertension and T2D but not for people with CVD. The improvement in functional capacity and body weight reduction differed with different exercise types; hence, a more patient-tailored approach in prescribing exercise may be necessary.

Overall, we found a gap in evidence on non-traditional forms of exercise like body-mind therapies and in evidence emerging from LMICs. This underscores the importance of further research in this area to understand better the effect of adding exercise to usual care. The potential of exercise as nonpharmacological therapy crucially relies on whether exercise is safe, prolongs life, enhances functional capacity, and improves quality of life. Thus, this thesis supports the notion that adding exercise to usual care, i.e., integration of exercise as part of health care delivery, could be a complementary strategy for the management of hypertension, T2D, and/or CVD, especially in LMICs.