Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes

Weight loss is perhaps the most effective therapeutic approach for preventing progression of cardiometabolic disease to type 2 diabetes and/or cardiovascular events.

“Thus, weight loss is perhaps the most effective therapeutic approach for preventing the progression of CMD to T2D and/or CVD events.”

In the Look Ahead trial, 6% weight loss over eight years yielded improvements in cardiovascular risk factors, glycemic control, lipids, less medication usage, and reduced hospitalizations and healthcare costs.

“In the Look Ahead trial, 6% weight loss over eight years yielded improvements in a range of cardiovascular risk factors, including glycemic control and lipids, as well as less medication usage, and reduced hospitalizations and healthcare costs87,88.”

The anthropometric component is largely satisfied by BMI, which is used to diagnose individuals as lean (BMI 18.5-24.9 kg/m2), overweight (BMI 25-29.9 kg/m2), or obese (BMI ≥30 kg/m2).

“The anthropometric component is largely satisfied by BMI, which is used to diagnose individuals as lean (BMI 18.5 to 24.9 kg/m2), overweight (BMI 25 to 29.9 kg/m2), or obese (BMI ≥30 kg/m2).”

Available evidence supports weight-loss therapy for glycemic control in type 2 diabetes, prevention of type 2 diabetes in people with prediabetes, blood pressure lowering, and improvements in osteoarthritis, mobility, and physical function.

“because available evidence supports weight-loss therapy in these conditions.”

In people with ABCD and prediabetes and/or metabolic syndrome, weight loss is highly effective for preventing progression to type 2 diabetes.

“In persons with ABCD (both overweight or with obesity) and prediabetes and/or metabolic syndrome, weight loss is a highly effective way to prevent progression to T2D.674”

Weight reduction prevents or treats multiple cardiovascular risk factors and additional complications of ABCD.

“In addition, weight reduction prevents or treats multiple CVD risk factors and additional complications of ABCD.674”

Adding obesity medications to lifestyle interventions produces more weight loss than lifestyle intervention alone and leads to greater reductions in incident type 2 diabetes and improvements in cardiovascular risk factors.

“The addition of obesity medications to lifestyle interventions produces more weight loss than attributable to lifestyle intervention alone and leads to greater reductions in incident T2D and improvements in CVD risk factors.674”

Obesity medications used with lifestyle changes can sustain greater weight loss over time to preserve cardiometabolic benefits.

“Obesity medications used together with lifestyle changes can be used to sustain a greater degree of weight loss over time to preserve CMD benefits.674,759”

Weight loss is effective for preventing and treating type 2 diabetes, hypertension, dyslipidemia, NAFLD/NASH, cardiovascular risk factors, and chronic kidney disease.

“Furthermore, obesity can exacerbate insulin resistance and accelerate progression of CMD toward these end-stage developments, and weight loss is an effective intervention in preventing and treating T2D, as well as hypertension, dyslipidemia, NAFLD/NASH, CVD risk factors, and CKD.674”

Look AHEAD found no significant difference in cardiovascular morbidity and mortality between the intensive lifestyle intervention and diabetes support and education groups after an average follow-up of 9.6 years.

“The trial’s primary outcome was cardiovascular morbidity and mortality, on which no significant differences were observed between participants assigned to ILI or a usual care group (i.e., diabetes support and education [DSE]) after a mean follow-up of 9.6 years.2”

In the Look AHEAD trial, intensive lifestyle intervention did not reduce the risk of heart failure or its subtypes among participants with diabetes.

“There was no reduction in the risk of HF or its subtypes among Look AHEAD participants that underwent the intensive lifestyle intervention.”

Exercise training and lifestyle physical activity interventions have failed to demonstrate a reduction in the risk of heart failure in limited randomized controlled trials.

“However, exercise training and lifestyle PA interventions have failed to demonstrate a reduction in the risk of HF in limited RCTs.”

Lifestyle and pharmacologic interventions for overweight or obesity tested in previous trials have uniformly failed to improve cardiovascular outcomes.

“Semaglutide improved cardiovascular outcomes in this trial, whereas lifestyle and pharmacologic interventions for overweight or obesity tested in previous trials have uniformly failed to do so. 11,14”

The concept of treating obesity to reduce the risk of cardiovascular complications has been hampered by the lack of evidence from trials indicating that lifestyle or pharmacologic interventions for overweight or obesity improve cardiovascular outcomes.

“the concept of treating obesity to reduce the risk of cardiovascular complications has been hampered by the lack of evidence from trials indicating that lifestyle or pharmacologic interventions for overweight or obesity improve cardiovascular outcomes. 11-15”

Progressive metabolic benefits were seen with greater degrees of weight loss from >5% to ≥15%.

“Progressive metabolic bene fi ts were seen with greater degrees of weight loss from > 5% to $ 15%”

An overall suggestion that ≥10% weight loss may be required to see benefits for CVD events and mortality rate and other complications, such as nonalcoholic steatohepatitis.

“with an overall suggestion that $ 10% weight loss may be required to see benefi ts for CVD events and mortality rate and other complications, such as nonalcoholic steatohepatitis (50,90,92 -95).”

Other studies on the effect of exercise on morbidity and mortality include combined lifestyle interventions and populations with diseases and have fewer monitored and relatively short periods of supervised exercise.

“Other studies on the effect of exercise on morbidity and mortality include combined lifestyle interventions24 and populations with diseases25 26 and have fewer monitored and relatively short periods of supervised exercise.26 27”

Look AHEAD benefits included weight loss, improved physical fitness, increased HDL cholesterol, lowered systolic blood pressure, reduced A1C levels, reduced waist circumference, and reduced need for medications.

“Benefits included weight loss, improved physical fitness, increased HDL cholesterol, lowered systolic blood pressure, reduced A1C levels, reduced waist circumference, and reduced need for medications (80).”

The intensive lifestyle intervention in Look AHEAD had multiple clinical benefits including weight loss, improved physical fitness, increased HDL cholesterol, lowered systolic blood pressure, reduced A1C levels, reduced waist circumference, and reduced need for medications.

“Benefits included weight loss, improved physical fitness, increased HDL cholesterol, lowered systolic blood pressure, reduced A1C levels, reduced waist circumference, and reduced need for medications (87).”

The Look AHEAD intensive lifestyle intervention produced multiple clinical benefits, including weight loss, improved physical fitness, increased HDL cholesterol, lowered systolic blood pressure, reduced A1C levels, reduced waist circumference, and reduced need for medications.

“the intensive lifestyle intervention produced multiple clinical benefits, including weight loss, improved physical fitness, increased HDL cholesterol, lowered systolic blood pressure, reduced A1C levels, reduced waist circumference, and reduced need for medications”

Despite modest weight losses from behavioral interventions, small weight losses can lead to impressive health improvements and risk factor reductions.

“Despite the modest weight losses associated with behavioral interventions, small weight losses can lead to impressive health improvements and risk factor reductions.”

Physical activity is a key part of lifestyle treatment.

“Increased physical activity is an important component of lifestyle therapy.674,727”

The ILI and DSE groups did not differ significantly on baseline characteristics.

“ILI and DSE participants did not differ significantly on baseline characteristics, as reported previously (see Table 1).2,33”

In the Look AHEAD trial, major cardiovascular events were similar in both groups, which may be partially explained by the greater use of cardioprotective medications in the diabetes support and education group.

“However, major CV events were similar in both groups, which may be partially explained by the greater use of cardioprotective medications in the diabetes support and education group [107] .”

Lifestyle interventions that encourage increased physical activity concurrent with calorie restriction have been shown to sustain moderate weight loss.

“Furthermore, lifestyle interventions that encourage increased physical activity concurrent with calorie restriction have been shown to sustain moderate weight loss. 18,19”

The total weight loss of 16% is also more than the 1-year weight loss of 7 to 9% of the initial body weight observed with concurrent intensive diet and physical activity programs.

“It is also more than the 1-year weight loss of 7 to 9% of the initial body weight that has been observed with concurrent intensive diet and physical activity programs. 18,19”

The effects of intensive lifestyle intervention on cardiovascular events appeared to be blunted or even absent in people with type 2 diabetes.

“Notably, the effects of intensive lifestyle intervention on cardiovascular events appeared to be blunted or even absent in people with type 2 diabetes [52,53].”

Intensive lifestyle interventions and total dietary replacement can achieve significant improvements in glycaemic control and sustained weight loss in people with type 2 diabetes.

“However, more recent data from the Look Ahead (Wing 2013) and DiRECT (Lean 2018) studies suggest that significant improvements in glycaemic control, as well as sustained weight loss can be achieved in people with T2D with intensive lifestyle interventions and total dietary replacement.”

While the Look AHEAD trial did not achieve its primary outcome of reducing cardiovascular events, the intensive lifestyle intervention had multiple clinical benefits that are important to the quality of life of older adults.

“While the Look AHEAD trial did not achieve its primary outcome of reducing cardiovascular events, the intensive lifestyle intervention had multiple clinical benefits that are important to the quality of life of older adults.”

In South Asian, East Asian, and Southeast Asian populations, health is adversely affected at lower BMI levels, and alternate criteria have been advocated: BMI 18.5-22.9 kg/m2 for normal weight, 23-24.9 kg/m2 for overweight, and ≥25 kg/m2 for obesity.

“In South Asian, East Asian, and Southeast Asian populations, health is adversely affected at lower levels of BMI, and alternate criteria have been advocated, with BMI 18.5 to 22.9 kg/m2 indicative of normal weight, 23 to 24.9 kg/m2 overweight, and ≥25 kg/m2 obese.674”

Physical activity and aerobic exercise guidelines are similar in people with type 2 diabetes independent of lean versus overweight or obese BMI.

“Physical activity and aerobic exercise guidelines are similar in persons with T2D independent of lean vs overweight/obese BMI.431,674,727,728”

The comprehensive diagnosis of ABCD requires both anthropometric and clinical components.

“The comprehensive diagnosis of ABCD requires both anthropometric and clinical components674,675”

Weight loss, whether from lifestyle therapy, obesity medications, or bariatric surgery, enhances insulin sensitivity.

“Whether due to lifestyle therapy, obesity medications, or bariatric surgery, weight loss has been shown to (1) enhance insulin sensitivity;”

Obesity can worsen insulin resistance and speed progression of cardiometabolic disease toward end-stage developments.

“Furthermore, obesity can exacerbate insulin resistance and accelerate progression of CMD toward these end-stage developments, and weight loss is an effective intervention in preventing and treating T2D, as well as hypertension, dyslipidemia, NAFLD/NASH, CVD risk factors, and CKD.674”

Prospective studies that evaluated the effect of nonsurgical weight loss interventions on cardiovascular event reduction have been disappointing.

“Prospective studies that evaluated the effect of nonsurgical weight loss interventions on CV event reduction have been disappointing [4, 5, 6, 7, 8].”

Effects on weight and risk-factor control diminished after 5 years in those with low adherence to the lifestyle programme.

“Effects on weight and risk-factor control diminished after 5 years in those with low adherence to the lifestyle programme.56”

In the Look AHEAD trial, lifestyle intervention by nutritional counselling, meal replacement, and exercise induced an average of 8.6% weight loss, which was associated with a significant reduction in HbA1c and blood pressure.

“In T2DM, as investigated in the Action for Health in Diabetes trial (Look AHEAD; 5145 T2DM patients, 59% female, mean age 58 years, mean body mass index [BMI] 36 kg/m 2 ), lifestyle intervention by nutritional counselling, meal replacement, and exercise induced an average of 8.6% weight loss, which was associated with a significant reduction in HbA1c and BP.56”

The Look AHEAD trial did not demonstrate a reduction in the composite CV outcome with lifestyle intervention in patients with obesity and T2DM with 10 years' follow-up.

“In addition, the Look AHEAD trial, introducing lifestyle intervention in patients with obesity and T2DM with 10 years' follow-up, did not demonstrate a reduction in the composite CV outcome.56”

Adherence to lifestyle intervention fades over time, with continuously increasing body weight after 1 year.

“Furthermore, adherence to lifestyle intervention fades over time, with continuously increasing body weight after 1 year.56”

Sucrose is an important dietary source of fructose.

“Sucrose, a disaccharide containing glucose and fructose, represents an important source of fructose in the diet [159,173,174].”

The effect of fructose on plasma triglycerides is dose-dependent; at habitual intake of 15-20% of total energy, plasma triglycerides increase by as much as 30-40%.

“These effects are dose-dependent; with a habitual fructose consumption between 15 and 20% of total energy intake, plasma TG increases by as much as 30-40%.”

Prolonged follow up showed that interventions can reduce development of severe retinopathy.

“and can reduce development of severe retinopathy156.”

Weight losses of 5% or more of initial weight ameliorate obesity complications, with larger losses producing greater health benefits.

“Weight losses of 5% or more of initial weight help to ameliorate these complications, with larger losses producing greater health benefits.(3)”

Greater weight loss reliably produces greater improvements in cardiometabolic risk factors and quality of life, as observed in the STEP trials.

“Greater weight loss reliably produces greater improvements in several cardiometabolic risk factors,(3) as well as quality of life,(41) as was observed in the STEP trials.”

The lack of MACE reduction in Look AHEAD may be due to insufficient weight loss.

“The previously discussed Look AHEAD study did not reduce MACE in patients with type 2 diabetes and overweight/obesity, potentially because of insufficient weight loss [61].”

The Look AHEAD study did not reduce MACE in patients with type 2 diabetes and overweight/obesity.

“The previously discussed Look AHEAD study did not reduce MACE in patients with type 2 diabetes and overweight/obesity, potentially because of insufficient weight loss [61].”

There is large heterogeneity in response to intensive lifestyle interventions.

“On the other hand, intensive lifestyle interventions could be implemented easier and result in up to 10% mean WL; however, there is large heterogeneity in response and long-term weight maintenance is challenging due to compensatory increases in appetite and reduction in energy expenditure during the WL state [14–16].”

Intensive lifestyle interventions could be implemented easier and result in up to 10% mean WL.

“On the other hand, intensive lifestyle interventions could be implemented easier and result in up to 10% mean WL; however, there is large heterogeneity in response and long-term weight maintenance is challenging due to compensatory increases in appetite and reduction in energy expenditure during the WL state [14–16].”

Long-term weight maintenance after intensive lifestyle interventions is challenging due to compensatory increases in appetite and reduction in energy expenditure during the WL state.

“On the other hand, intensive lifestyle interventions could be implemented easier and result in up to 10% mean WL; however, there is large heterogeneity in response and long-term weight maintenance is challenging due to compensatory increases in appetite and reduction in energy expenditure during the WL state [14–16].”

There is no evidence to demonstrate that an increased protein intake is associated with an increased risk of diabetic nephropathy.

“There is no evidence to demonstrate that an increased protein intake is associated with an increased risk of diabetic nephropathy 17 .”

Long-term exercise is shown to reduce risk factors for cardiovascular disease and improve quality of life (QOL) in patients with type 1 diabetes.

“Despite lack of consensus on its role in improving glycemic control in patients with type 1 diabetes, long‐term exercise is shown to reduce risk factors for cardiovascular disease and improve quality of life (QOL) 15 , 16 , 17 , 18 (grade B: 100% agreement).”

Intermittently viewed CGM (i-CGM) may be more effective than SMBG in shortening hypoglycemic durations in patients with type 1 and type 2 diabetes.

“There are some reports in the literature suggesting that intermittently viewed CGM (i‐CGM) may be more effective than SMBG in shortening the hypoglycemic durations in patients with type 1 and type 2 diabetes 16 , 17 .”

Diabetic retinopathy is a risk factor for diabetic nephropathy and macroangiopathy.

“Diabetic retinopathy is a risk factor for diabetic nephropathy and macroangiopathy 15 , 16 , 17 , 18 , 19 , 20 .”

Patients with diabetic foot are significantly associated with high all-cause mortality, high incidence of cardiovascular/cerebrovascular diseases, depression, and cognitive impairment.

“Patients with diabetic foot are significantly associated with high all‐cause mortality 16 , as well as a high incidence of cardiovascular/cerebrovascular diseases, depression 17 , and cognitive impairment 18 , suggesting that diabetic foot lesions likely represent a risk factor for mortality and these diseases.”

Longer time spent watching television or working in a sitting position is associated with an increased risk of type 2 diabetes.

“Longer time spent in watching television or working in a sitting position is associated with an increased risk of type 2 diabetes 16 , 17 .”

One large-scale, randomised, controlled trial in people overweight or obese people with T2DM did not show a substantial effect on mortality and cardiovascular outcomes with intensive diet plus physical activity compared with control after 9.6 years.

“However, one large-scale, randomised, controlled trial in people overweight or obese people with T2DM did not show a substantial effect on mortality and cardiovascular outcomes with intensive diet plus physical activity compared with control after 9.6 years (Look AHEAD 2013).”

The only long-term RCT assessing the effects of diet plus physical activity in people with T2DM was stopped early due to futility after a median follow-up of 9.6 years.

“However, the only long-term RCT assessing the effects of diet plus physical activity in people with T2DM was stopped early due to futility after a median follow-up of 9.6 years (Look AHEAD 2013).”

In the Look AHEAD trial, the intensive lifestyle intervention clearly improved cardio-metabolic risk factors, but there was no difference in rates of cardiovascular events between groups after a median follow-up of 9.6 years, when the trial was stopped for futility.

“In recently published results, the intensive intervention clearly improved cardio-metabolic risk factors; however, there was no difference in rates of cardiovascular events between groups after a median follow-up of 9.6 years, when the trial was stopped for futility.”

Low-fat diets have not been particularly effective for long-term CVD risk reduction, partly due to difficulty sustaining such a diet long-term.

“It bears mention that low-fat diets have not been particularly effective for long-term CVD risk reduction, partly due to the difficulty sustaining such a diet long-term (284,285).”

Phospholipase A2 (PLA2) is a family of enzymes that hydrolyse fatty acid from membrane phospholipids.

“Phospholipase A2 (PLA 2 ) is a family of enzymes that hydrolyse fatty acid from membrane phospholipids 125 .”