August 8, 2014

expert reaction to study looking at type 2 diabetes, metformin and lifespan

Researchers publishing in the journal Diabetes, Obesity and Metabolism investigated lifespan in patients with type 2 diabetes prescribed with metformin with patients prescribed with another common diabetes drug called sulphonylurea.

Prof Kevin McConway, Professor of Applied Statistics, The Open University, said:

“The title of this paper itself is not helpful in that anyone reading it might get the wrong idea – this study cannot actually answer the question it poses (“Can people with type 2 diabetes live longer than those without?”) for reasons discussed below, and it sounds almost as if there are grounds to advise people without diabetes to take metformin. But in fact the study isn’t saying that at all.

“In the press release, Craig Currie says “People lose on average around eight years from their life expectancy after developing diabetes” and goes on to explain why. So if the life expectancy of people with type 2 diabetes is so much shorter, how on earth can they “live longer than people without the disease”, as the title of the release and the paper both say?

“The answer is that the comparison in the paper runs only over the time period when the patients with diabetes were on first-line treatment with metformin, on its own (and there’s a similar comparison involving patients whose first-line treatment is with sulphonylureas). At some point after this first-line treatment starts, many of the patients with diabetes would be switched from metformin alone onto a second-line treatment, and this switch is (or should be) necessary because the diabetes or its effects have got worse. But at that point the comparison in this study simply stops.

“So the quote in the press release about an eight year reduction in life expectancy, in people who develop type 2 diabetes, is talking about the entire rest of a person’s life after the diagnosis, including the time when they might be on a more aggressive second-line treatment. But the comparison in the paper is looking only at the time before the treatment changes. You can’t fit all that into a simple headline, but it is important to note that the story here is not so simple.

“But, if the survival for people with diabetes, taking metformin, is significantly better than the survival for people without diabetes, even just over the limited timespan of this study, might that still not mean that people without diabetes should take metformin in order to live longer than they otherwise would? No, it’s not saying that. The apparent difference might be due to something other than the metformin.

“The researchers did match the controls with patients with diabetes in certain ways, and in their statistical analysis they try to allow statistically for other differences between the people with diabetes and the controls. But the paper itself points out some issues. The researchers could not take into account certain possible confounders (other variables that might affect the comparison) because they did not have data on them for enough of the controls. Even without that important issue, statistical adjustment for confounders is never perfect. The difference in survival between people with diabetes on metformin, and controls without diabetes, was statistically significant but in fact rather small, and probably within the range where it could be explained by residual confounding (that is, the effect of other variables that was not taken into account by the analysis).

“Further, the paper itself also points out that people with diabetes are more likely be monitored for, and receive interventions for, problems with the heart and circulation. This extra intervention and monitoring, and the possibility of residual confounding, between them cast huge doubt on the possibility that the better survival in the patients taking metformin, compared to controls without diabetes, was simply because they were taking metformin.

“Metformin does come out well in comparison to the other diabetes treatment looked at in the study, sulphonylureas, where survival does seem to be clearly worse than it is for control people without diabetes (the paper mentions that metformin is not suitable for some people with diabetes, hence the use of sulphonylureas).  Comparing such patients with people without diabetes does not tell us much about whether it is right to prescribe them sulphonylureas. To investigate that, one would need to compare them with patients taking some other treatment that would also be appropriate for them (and not metformin, which is not appropriate for them), and this study didn’t look at that at all.”

‘Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls’ by C. A. Bannister et al. published in Diabetes, Obesity and Metabolism on Friday 8 August 2014.

Declared interests

None declared