Section overview: Cardiometabolic risk reduction

Look AHEAD: Study design Look AHEAD is a National Institutes of Health (NIH)-sponsored trial assessing lifestyle modification in overweight and obese individuals with T2DM. A total of 5145 individuals were randomized to a diabetes support and education (DSE) group or to an intensive lifestyle intervention (ILI) group. The DSE group receives usual medical care from their own primary care physician plus 3 group educational sessions yearly for the first 4 years of the trial. One session is devoted to diet and nutrition, another to exercise, and the third to social support. The ILI group receives usual medical care plus an intensive 4-year program designed to increase physical activity and reduce weight by 7% or more. The 3 phases are as follows: Months 1-6: Three group meetings weekly in addition to 1 individual counseling session per month Months 7-12: Biweekly group meetings plus 1 individual counseling session per month Months 13-48: A minimum of 2 contacts per month are targeted. One contact is on-site; the other is conducted off-site by phone, mail, or e-mail Month 49 to trial end: Maintenance phase, with 2 or more on-site contacts yearly A total follow-up of 11.5 years is planned. Anticipated completion is in 2012.

Look AHEAD: Patients meeting risk factor goals at 1 year The average weight loss at 1 year in the ILI group was 8.6% (7.6% in the group on insulin) vs 0.7% in the DSE group (P < 0.001). The need for glucose-lowering medicines decreased by 7.8% in the ILI group but increased by 2.2% in the DSE group (P < 0.001). Despite a reduction in use of glucose-lowering medications, fasting glucose levels and A1C improved significantly in the ILI vs the DSE group (P < 0.001 for both). Antihypertensive medicine use decreased by 0.1% in the ILI group but increased by 2.2% in the DSE group (P = 0.02). Use of lipid-lowering medications increased in both groups, but the increase was significantly less in the ILI vs the DSE group (3.7% vs 9.4%, P < 0.001). Systolic and diastolic BP, TG, HDL-C, and urine albumin-to-creatinine ratio improved significantly more in ILI vs DSE participants (all P = 0.002 or less). Participants in the ILI group who met the ADA goal of <7% A1C increased from 46% to 73%; those who met all 3 ADA goals for A1C, BP, and LDL-C increased from 10.8% to 23.6%.

SCOUT: Study design Sibutramine Cardiovascular Outcomes Trial (SCOUT) is a large, multinational clinical outcomes trial of sibutramine in patients with high-risk adiposity. Eligible subjects entered a 6-week single-blind lead-in period, during which they received sibutramine 10 mg and were instructed in the following lifestyle modifications: Diet: Individualized hypocaloric diet (600 kcal/day deficit) Exercise: 150 minutes per week or more of moderately intense physical activity The lifestyle modification program was translated into the languages of all 16 participating countries, with adaptations to meet local dietary preferences and traditions. Participants were randomized to either placebo or sibutramine 10-15 mg. The first patient was randomized in February 2003. The investigators plan to randomize approximately 9000 patients. Study completion is anticipated in 2008.

SCOUT: Change in cardiometabolic risk factors during lead-in phase The 6-week lead-in period was designed as a safety screen, because of the well-documented increases in BP and pulse rate associated with sibutramine. However, during this period, 4.7% of subjects experienced sustained increases in BP (defined as two consecutive increases of >10 mm Hg) and 3.5% experienced sustained increases in pulse rate of >10 bpm.

SOS: Study design The Swedish Obese Subjects (SOS) study was a prospective, nonrandomized, controlled trial conducted in 4047 obese subjects (BMI at least 34 kg/m[2] for men and at least 38 kg/m[2] for women). The surgery group underwent gastric surgery while the matched control group received usual care (ranging from lifestyle intervention and behavioral modification to no treatment). The primary outcome was all-cause mortality.

SOS: Weight change by treatment over time An increase in weight was observed in all surgical subgroups, although the weight regain leveled off after 8 to 10 years.

Surgical weight loss is associated with remission of diabetes Dixon et al conducted a controlled trial of bariatric surgery in 60 obese patients with recently diagnosed T2DM. The trial was randomized but not blinded. Study subjects were assigned to either a conventional therapy group, in which they received best available medical practice for treatment, education, and follow-up of diabetes, or to a surgery group for placement of a laparoscopic adjustable gastric band. The surgery group achieved a 20% weight loss at 2 years compared with 1.4% in the conventional therapy group (P < 0.001, data not shown). Remission of their diabetes was achieved by 73% and 13% of subjects, respectively. This is the first prospective study to demonstrate diabetes remission with surgical weight loss and it is consistent with previous observational studies.

SOS: Mortality reduction with weight-loss surgery During a mean 10.9-year follow-up, there were 129 deaths (6.3%) in the control group vs 101 deaths (5.0%) in the surgery group. Weight loss from bariatric surgery was associated with a reduction in overall mortality that was further improved after adjustment for major confounders Unadjusted HR 0.76, 95% CI 0.59-0.99, P = 0.04 Adjusted HR 0.71, 95% CI 0.54-0.92, P = 0.01

SOS: Causes of death CV events were the causes of 53 deaths in the control group and 43 in the surgery group, with most due to MI, sudden death, or cerebrovascular events. Non-CV events caused 58 deaths in the surgery group and 76 in the control group, with the majority due to cancer.

Long-term mortality after gastric bypass surgery The same issue of the New England Journal of Medicine that contained the SOS mortality data also published a retrospective study of long-term mortality after gastric bypass surgery. Surgical patients (n = 7925) were matched with 7925 obese controls identified from records of applications for Utah driver’s licenses and state identification (ID) cards. All surgeries were performed by a single Utah surgical practice group between 1984 and 2002. During a mean follow-up of 7.1 years, there were 213 deaths (2.7%) in the surgery group and 321 deaths (4.1%) in the control group. After covariate adjustment, the rate of all-cause death was 40% lower in the surgical group: HR 0.60 (95% CI 0.45-0.67, P < 0.001). As shown on the slide, subjects with BMI <45 kg/m(2) appeared to gain greater benefit from surgery than those with BMI 45 kg/m(2) or greater.

Gastric bypass surgery and matched controls: Causes of death CV causes of death consistently occurred at a lower rate in the surgical group compared with controls. Diabetes-, cancer-, and other disease-related causes of deaths also occurred at a lower rate in the surgical group compared with controls. However, non-disease-related causes of death were more frequent in the surgical group compared with controls. In particular, study results suggest a need for psychological evaluation and, if necessary, psychiatric treatment before surgery.

Effects of weight loss on progression of cardiovascular and metabolic disease: Summary Positive data have been reported on the effects of weight-loss surgery on clinical outcomes. Clinical outcomes trials of other weight-management strategies are in progress, with results of the SCOUT trial of sibutramine expected in 2008.

Cardiometabolic risk reduction: Mechanistic rationale and the burden of proof: Summary Weight loss is an important component of cardiometabolic risk reduction strategies. Importantly, there is evidence that surgical weight loss is associated with reduction in all-cause and CV mortality. Trials of other weight-loss strategies are in progress.