Clinicians find their actions to be under the auspices of politicians or authorising bodies. Naturally, as they don’t see patients, politicians and authorising bodies can sometimes be wrong, which I argue was the case with the withdrawal of sibutramine, a drug used successfully for a decade to reduce weight and improve global risk factors in obese and overweight individuals.
The Sibutramine Cardiovascular Outcomes Trial (SCOUT; James et al 2010) was a post-licensing obligation regarding cardiovascular safety. The study included high-risk patients – elderly, with cardiovascular disease and diabetes who were contraindicated from taking the drug in normal clinical practice – who stayed on the medication for up to five times longer than the licence would have permitted, regardless of whether they responded. In this case, the harm done was minor: a possible 16% increase in non-fatal cardiovascular events. The two papers discussed here (summarised following this commentary) examine data from SCOUT, and Caterson et al (2012) in particular demonstrate a remarkable conclusion.
Andersson et al (2012) address raised HbA1c as a risk marker, and risk factor, advising that the “relationship between HbA1c levels and outcomes may be more complex than previously recognised.” This analysis found “a beneficial effect associated with decreasing HbA1c levels on the all-cause mortality endpoint among those experiencing weight loss, but no effect associated with lowered HbA1c levels among those not experiencing weight loss,” subtley adding to our understanding of the complexities of BMI and HbA1c.
Caterson et al (2012) provide further post hoc analysis of SCOUT, looking at what outcomes would have been, had sibutramine been used in high-risk patients, but as per the guidelines as they existed for the general population. The study concluded that the outcome would have been a reduction in mortality: “Modest weight loss over the short-term (6 weeks) and longer-term (6 to 12 months) is associated with reduction in subsequent cardiovascular mortality for the following 4 to 5 years, even in those with pre-existing cardiovascular disease.”
This outcome has now become apparent long after the withdrawal of this agent. The paper compares the importance of the result with that of the UK Prospective Diabetes Study “legacy” effect: “Even the modest degree of weight loss achieved during the first 6 weeks of the SCOUT trial was associated with benefit irrespective of further drug therapy or weight change. This early weight loss of just over 2 kg reduced the incidence of cardiovascular events and mortality over the subsequent 5 years. A similar ‘memory’ effect has been shown in diabetes treatment and prevention trials. This provides strong confirmatory evidence that interventional weight loss has long term benefit.”
To view the summaries of each paper, please download the PDF.
