Intentional Weight Loss Reduces Cardiovascular Outcomes

Faithful readers will recall previous posts on the results of the SCOUT trial, in which we studied 10,744 overweight or obese subjects (≥55 years) with pre-existing cardiovascular disease and/or type 2 diabetes mellitus, who received the anti-obesity drug sibutramine plus weight management during a 6-week lead-in Period, before randomisation to continue on sibutramine (N=4906) or to receive placebo (N=4898) plus ongoing lifestyle management for another 4-5 years.

In SCOUT, participants randomised to sibutramine had an 11% higher risk of experiencing a non-fatal cardiovascular outcome (non-fatal myocardial infarction, non-fatal stroke, or resuscitated cardiac arrest) compared to the placebo group. This finding, led to the voluntary withdrawal of sibutramine in most countries (including the US and Canada).

However, as discussed before, one of the critical design features of the SCOUT trial, was that participants had to continue on medication irrespective of whether or not they actually lost weight. This is obviously very different from how an anti-obesity drug would be used in clinical practice, where no patient would likely continue taking a drug that was clearly not effective.

Thus, while the original paper, published in the New England Journal of Medicine, presented the intention-to-treat analysis, which simply compared the two treatment arms, irrespective of whether individuals lost weight or not, we have now published an analysis in Obesity, Diabetes, and Metabolism that looks at the cardiovascular outcomes in relationship to the actual weight loss during the 6-week lead-in period and over the first 12 months of the trial.

While average weight loss in the 6-week lead-in period was -2.54 kg, post-randomisation 12-month weight loss was significantly greater in the sibutramine-treated participants (-4.18 kg) compared to placebo (-1.87 kg). There was of course a considerable spread in changes in body weight both during the lead-in period and within each treatment arm post-randomisation with some participants losing little (or even gaining some) weight with others losing considerable weight (well into the 10-15% range).

The analysis clearly shows that the degree of weight loss during both the lead-in Period and through month 12 was associated with a progressive reduction in risk for the total population of experiencing ‘hard’ outcomes like having a stroke, a heart attack, or dying of other causes over the 5-year assessment.

To my knowledge, this is the first demonstration of a reduction in ‘hard’ cardiovascular outcomes with intentional (non-surgical) weight loss (3-10 kg).

Although more events occurred in the randomised sibutramine group, on average, a modest weight loss of approximately 3kg achieved in the Lead-in Period appeared to offset this increased event rate.

Thus, this analysis demonstrates that even moderate weight loss over short-term (6 weeks) and longer-term (6-12 months) periods is associated with reduction in subsequent cardiovascular mortality for the following 4-5 years even in those with pre-existing cardiovascular disease.

There are some limitations in the interpretation of these findings in that they represent a post-hoc analysis and the participants all had at least mild, moderate, or severe cardiovascular disease (EOSS 2-3). Thus, we still do not know whether or not losing weight reduces risk in obese individuals without pre-existing heart disease (EOSS 0-1).

Despite these caveats, this study certainly represents a ‘historical’ milestone in being the first to show that even modest intentional weight loss can reduce cardiovascular outcomes in a high-risk population.

Not a bad way to start off the new year.

AMS
Berlin, Germany

Caterson ID, Finer N, Coutinho W, Van Gaal LF, Maggioni AP, Torp-Pedersen C, Sharma AM, Legler UF, Shepherd GM, Rode RA, Perdok RJ, Renz CL, James WP, & on the behalf of the SCOUT Investigators (2011). Maintained Intentional Weight Loss Reduces Cardiovascular Outcomes: Results from the Sibutramine Cardiovascular Outcomes (SCOUT) Trial. Diabetes, obesity & metabolism PMID: 22192338