Intensive Life Intervention Improves Risks for Type 2 Diabetes Patients

The Look AHEAD trial showed dramatic results for the impact of lifestyle intervention in patients with type 2 diabetes and their risk for cardiovascular disease (CVD). 

A trial was conducted to identify whether intensive lifestyle intervention is associated with differential risk for cardiovascular disease (CVD). In addition, multiple studies investigated whether type 2 diabetes (T2D) can be partitioned into subgroups that differ in clinical profiles and underlying genetic risk.  

Five thousand one hundred forty-five participants with T2D, aged 45-76 years with overweight or obesity, were randomly assigned to 10 years of intensive lifestyle interventions or a control condition of diabetes support and education. Four subgroups were characterized as older age at diabetes onset, severe obesity, poor glucose control, and younger age at diabetes onset. The intensive lifestyle intervention focused on achieving and maintaining weight loss of ≥ 10% through increased physical activity and decreased caloric intake. For the first four years of the trial, the diabetes support education consisted of three group educational sessions each year, then one annual session. In addition, health care providers made medication adjustments; the study staff made any changes to glucose-lowering medications to reduce hypoglycemia risk. 

Individuals were interviewed to collect medical history, education, employment, and other pertinent information. Vitals were taken at baseline and annual clinic visits. The primary endpoint was the first occurrence of a composite cardiovascular outcome, which initially included nonfatal myocardial infarction, death from cardiovascular causes, and nonfatal stroke over a follow-up period of 11.5 years. After two years of follow-up, hospitalization for angina was added to the primary endpoint. Finally, the follow-up was extended for another two years, leading to a maximum of 13.5 years. The secondary endpoint included three outcomes as follows: 

• Death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.  
• Death from any cause, myocardial infarction, stroke, or hospitalization for angina. 
• Death from any cause, myocardial infarction, stroke, hospitalization for angina, coronary artery bypass grafting (CABG), percutaneous coronary intervention, hospitalization for heart failure, carotid endarterectomy, or peripheral vascular. 

K-means clustering was applied to characterize diabetes subgroups. Once the diabetes subgroups’ characterizing was completed, each subset’s randomization allocation, demographic composition, and clinical characteristics were assessed. Finally, Cox proportional hazard regression was used to observe whether the intensive lifestyle interventions were associated with differential risk for the primary and secondary endpoints for the diabetes subgroups. A p-value of < 0.05 was considered evidence to support interaction. 

The four subgroups qualitative hallmarks included 24% for poor glucose control, 42% for older age at diabetes onset, 24% for severe obesity, and 20% for the younger age at diabetes onset. The younger age at onset group was more likely to be women than the older age group. The use of insulin and diabetes medication was highest in the poor glucose control group and lowest for the older age onset subgroup. The most atherosclerotic lipid profile was in the poor glucose control subgroup. 

Eight hundred twenty-one events occurred for the primary cardiovascular outcome. With an unadjusted incidence rate per 1,000 person-years, the highest incidence rate was in the poor glucose control subgroup (23.6), followed by the older onset (18.9), severe obesity (18.2), and lastly, younger-onset (15.7). The interaction term between intervention and diabetes for the second (P = <0.05) and third subgroup (P = 0.04) was a statistically significant p-value except for the first composite secondary outcome (P = 0.11). The effect of intensive lifestyle intervention on each secondary outcome was similar to the primary outcome. The effect of the intensive lifestyle intervention on the individual outcomes of death was assessed. Within the older-onset, severe obesity, and younger-onset subgroups, the incidence for each of the individual outcomes was higher for the diabetes support and education group than in the intensive lifestyle intervention group, except for carotid endarterectomy peripheral vascular disease, which was rare. For the poor glucose-control subgroup in the intensive lifestyle intervention group, the incidence of myocardial infarction, hospitalized angina, stroke, CABG, and carotid endarterectomy was higher than in the diabetes support education group, and the absolute risk difference was greater for hospitalized angina. 

The increased risk of CVD was observed from the intervention in a subgroup of the trial participants with poor glucose control at baseline. The trial results provide support to investigate whether the findings apply to other diabetes complications and assess what interventions would be beneficial.   

Practice Pearls: 

• The outcomes of death were lower in the intensive lifestyle intervention. 
• The intensive lifestyle intervention was ineffective in the poor glucose control groups. 

• The poor glucose control group participants were at an increased risk of CVD. 

Bancks M P et al. Look AHEAD Research Group. Type 2 Diabetes Subgroups, Risk for Complications, and Differential Effects Due to an Intensive Lifestyle Intervention. Diabetes Care 2021 

Brenda Oppong, PharmD Candidate, LECOM School of Pharmacy