Introduction
Type 2 diabetes mellitus (T2DM) affects approximately 10% of adults in the United States, accounts for $327 billion of annual costs, and is associated with increased risk of cardiovascular disease.¹ Over the past two decades, there has been a shift in complications among patients with T2DM with large declines in hospitalizations for ischemic heart disease but less improvements in heart failure (HF). Despite optimal control of traditional risk factors, including glycemia, blood pressure, low-density lipoprotein cholesterol, albuminuria, and smoking abstinence, patients with T2DM have excess risk of HF.² This residual risk of HF among patients with T2DM suggests that alternative approaches to HF prevention are needed.

Lifestyle Interventions and Risk of Heart Failure – Look AHEAD Trial
Epidemiological studies suggested that higher levels of physical activity, cardiorespiratory fitness, and lower body mass index (BMI) were each associated with lower risk of HF.^3,4 The beneficial associations of these lifestyle interventions have been evaluated for prevention of cardiovascular disease in clinical trials. The Look AHEAD (Action for Health in Diabetes) trial was a landmark, multicenter, randomized clinical trial that examined whether an intensive lifestyle intervention would reduce the risk of cardiovascular disease among 5,145 patients with T2DM and overweight or obesity.⁵ The lifestyle intervention targeted at least 7% weight loss through diet and increased physical activity. Over a median follow-up of 9.6 years, participants in the intensive lifestyle intervention treatment group had greater reductions in body weight and waist circumference and more improvements in cardiorespiratory fitness and glycemic control. However, the intensive lifestyle intervention did not reduce the risk of a composite atherosclerotic cardiovascular disease endpoint, including nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for angina, or death from cardiovascular disease.

The effect of intensive lifestyle interventions on risk of incident HF, particularly risk of HF subtypes including HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), has not been systematically evaluated. This is particularly relevant as prior studies have demonstrated differential associations of physical activity and BMI with risk of HF subtypes such that these lifestyle factors were each consistently associated with risk of HFpEF but not HFrEF.^6-8 Thus, an intensive lifestyle intervention targeting weight loss and greater physical activity may differentially impact downstream risk of HF subtypes, specifically reduce the risk of HFpEF but not HFrEF. This hypothesis was evaluated in an ancillary analysis to the Look AHEAD trial in which incident HF events were further characterized as HFpEF and HFrEF over an extended follow-up period.⁹ During a median follow-up of 12.4 years, there were 257 incident HF events. The incidence of overall HF was similar in the intensive lifestyle intervention and control groups. Moreover, the intensive lifestyle intervention was not associated with lower risk of HFpEF or HFrEF among patients with T2DM and overweight or obesity.

Association of Changes in Fitness, Body Mass Index, and Heart Failure Risk
Potential explanations for the lack of cardiovascular benefits of the intensive lifestyle intervention in the Look AHEAD trial includes lack of sustained and sufficient weight loss and improvements in cardiorespiratory fitness and blood pressure over the study period. As part of the ancillary study of the Look AHEAD trial, the associations of baseline and longitudinal changes in cardiorespiratory fitness and BMI with risk of HF events were examined.⁹ Consistent with prior observations, baseline cardiorespiratory fitness was an independent marker of risk for HF.⁴ Furthermore, among HF subtypes, cardiorespiratory fitness was strongly associated with risk of HFpEF but not HFrEF, after accounting for traditional cardiovascular disease risk factors. Additionally, 4-year improvements in cardiorespiratory fitness and BMI were each associated with lower risk of HF suggesting that both lifestyle factors may be key modifiable targets for prevention.

Targeting Sustained and Large Improvements in Lifestyle Factors
The protective associations were only observed for 4-year, not 1-year, changes in cardiorespiratory fitness and BMI with risk of HF in the Look AHEAD trial, suggesting that durable improvements in lifestyle factors may be necessary for prevention. Thus, interventions that substantially improve fitness and promote weight loss over longer periods of follow-up may be needed to modify the underlying risk of HF among patients with T2DM. For example, a previous study of 2-year exercise training demonstrated improvements in cardiac stiffness, while shorter training periods did not modify this important intermediate cardiac phenotype.^10,11 These differences may also be related to the age of the study populations as older adults may be less likely to respond to exercise training.

The "dose" of physical activity and weight loss may also be an important determinant of the cardioprotective benefits of lifestyle interventions. Prior analyses have demonstrated a dose-response relationship between physical activity and risk of HF that is more consistent for HFpEF versus HFrEF.^3,8 Physical activity levels beyond current guideline recommendations may be necessary to lower HF risk. Similarly, large reductions in weight may be necessary to reduce the risk of HF. Trials examining modest weight loss interventions, such as lorcaserin, had no effect on HF risk.¹² In contrast, bariatric surgery, which leads to marked and persistent weight loss, is associated with substantially lower risk of cardiovascular disease events, especially HF.^13,14

Conclusions
High fitness was significantly associated with lower risk of HF, particularly HFpEF, in patients with T2DM. The intensive lifestyle intervention in the Look AHEAD trial did not significantly lower the risk of HF among patients with T2DM. However, sustained improvements in cardiorespiratory fitness and weight loss were each significantly associated with lower risk of HF. Future studies are needed to evaluate whether lifestyle interventions targeting greater improvements in cardiorespiratory fitness and reductions in weight can reduce the risk of HF among patients with T2DM and overweight or obesity.

References

1. Virani SS, Alonso A, Benjamin EJ, et al. Heart Disease and Stroke Statistics-2020 Update: a report from the American Heart Association. Circulation 2020;141:e139-e596.
2. Rawshani A, Rawshani A, Franzen S, et al. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2018;379:633-44.
3. Pandey A, Garg S, Khunger M, et al. Dose-response relationship between physical activity and risk of heart failure: a meta-analysis. Circulation 2015;132:1786-94.
4. Pandey A, Cornwell WK III, Willis B, et al. Body mass index and cardiorespiratory fitness in mid-life and risk of heart failure hospitalization in older age: findings from the Cooper Center Longitudinal Study. JACC Heart Fail 2017;5:367-74.
5. Wing RR, Bolin P, Brancati FL, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013;369:145-54.
6. Ho JE, Lyass A, Lee DS, et al. Predictors of new-onset heart failure: differences in preserved versus reduced ejection fraction. Circ Heart Fail 2013;6:279-86.
7. Kraigher-Krainer E, Lyass A, Massaro JM, et al. Association of physical activity and heart failure with preserved vs. reduced ejection fraction in the elderly: the Framingham Heart Study. Eur J Heart Fail 2013;15:742-6.
8. Pandey A, LaMonte M, Klein L, et al. Relationship between physical activity, body mass index, and risk of heart failure. J Am Coll Cardiol 2017;69:1129-42.
9. Pandey A, Patel KV, Bahnson JL, et al. Association of intensive lifestyle intervention, fitness, and body mass index with risk of heart failure in overweight or obese adults with type 2 diabetes mellitus: an analysis from the Look AHEAD Trial. Circulation 2020;141:1295-1306.
10. Howden EJ, Sarma S, Lawley JS, et al. Reversing the cardiac effects of sedentary aging in middle age - a randomized controlled trial: implications for heart failure prevention. Circulation 2018;137:1549-60.
11. Fujimoto N, Prasad A, Hastings JL, et al. Cardiovascular effects of 1 year of progressive and vigorous exercise training in previously sedentary individuals older than 65 years of age. Circulation 2010;122:1797-805.
12. Bohula EA, Wiviott SD, McGuire DK, et al. Cardiovascular safety of lorcaserin in overweight or obese patients. N Engl J Med 2018;379:1107-17.
13. Sundstrom J, Bruze G, Ottosson J, Marcus C, Naslund I, Neovius M. Weight loss and heart failure: a nationwide study of gastric bypass surgery versus intensive lifestyle treatment. Circulation 2017;135:1577-85.
14. Aminian A, Zajichek A, Arterburn DE, et al. Association of metabolic surgery with major adverse cardiovascular outcomes in patients with type 2 diabetes and obesity. JAMA 2019;322:1271-82.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Lipid Metabolism, Nonstatins, Acute Heart Failure

Keywords: Diabetes Mellitus, Type 2, Diabetes Mellitus, Metabolic Syndrome, Primary Prevention, Secondary Prevention, Heart Failure, Body Mass Index, Weight Loss, Waist Circumference, Cholesterol, LDL, Risk Factors, Blood Pressure, Albuminuria, Cardiovascular Diseases, Control Groups, Follow-Up Studies

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