Findings from STORM were published in 2000 amongst widespread optimism that the number of effective weight-loss agents would be doubled, orlistat being the only competitor at the time. An odd study, STORM started all participants on the active drug sibutramine, and only those who lost adequate weight were randomised to continue sibutramine or change to placebo, giving, therefore, an indication of successful weight maintenance on medication. Successfully launched and popular, sibutramine induced significant weight loss and was beneficial in lowering HbA1c. However, there was a licensing obligation with sibutramine to perform a cardiovascular outcomes study, because of an observed increase in blood pressure and pulse.
The SCOUT trial recruited those individuals naturally contraindicated to the drug – elderly high-risk participants, mostly with diabetes and cardiovascular disease (CVD) – and continued administering the drug for five times longer than the clinical licence allowed, even if no weight loss was observed. A possible 16% increase in non-fatal cardiovascular events was observed, and sibutramine was withdrawn on the grounds that any obese person could have latent CVD, a decision that displays astounding lack of scientific nous and common sense by the licensing authorities.
Not to lie down, a sub-analysis (Caterson et al, 2012) proved that, had the licence been followed, even in these high-risk individuals, those who lost weight and stayed on the drug would have benefitted from reduced mortality with an added legacy effect similar to UKPDS.
In this latest episode of the soap, another strange paper has been published, by Ali Ghotbi et al (summarised alongside): the team seem to be trying to suggest that the glucose-lowering (“antiglycaemic”) agents used by people with diabetes in the study may have impacted on the adverse outcomes in the first publication. Even though the end result answers few questions conclusively, SCOUT is now listed among studies, such as VADT, ADVANCE, ACCORD, etc., that recruited a large number of people with diabetes, did something to them and reported results.
In the paper by Ali Ghotbi et al, the use of insulin monotherapy was considered, slightly disturbingly (in view of ACCORD), neutral in terms of CVD risk, sulphonylureas conferred an increased risk, and metformin a decreased risk. The consistent message is that diet alone or regimens including metformin induced significant reduction in CV events. Unfortunately, hypoglycaemia was not recorded, and an obvious assumption is that diabetes was less “severe” or of shorter duration in those for whom diet alone or metformin sufficed. However, an interesting finding is that CVD risk is lower with triple therapy of metformin, insulin and sulphonylureas than dual therapy with insulin and sulphonylureas, despite the fact that a person on triple therapy would be expected to be further along the disease pathway than someone on dual therapy. Another black eye for sulphonylureas; a feather in the cap for metformin. Sadly, sibutramine remains withdrawn.
To view the summaries of each paper, please download the PDF of this article.