Diabetes affects about 4% of the world population and is associated with important costs, both in financial and human terms.
The high prevalence, increasing incidence, and associated costs makes
preventing diabetes a public health priority. The diabetes reduction
assessment with ramipril and rosiglitazone medication (DREAM) trial
recently showed that rosiglitazone reduced the risk of diabetes in
people at risk.
The results have prompted aggressive marketing of rosiglitazone as a
preventive therapy; some clinicians are already responding to this
initiative. We argue that the strategy will bring harms and additional
costs while the benefits for patients remain questionable.
Preventing diabetes
Several randomised trials have shown that modest weight loss and physical activity can greatly reduce the risk of diabetes.
The Diabetes Prevention Program documented a 58% relative risk
reduction (confidence interval 48% to 66%) in high risk individuals; other trials have shown similar results.
Nevertheless,
the possibility of preventing diabetes with drugs has caught the
imagination of the drug industry. The medicalisation of pre-disease
states and risk factors has become increasingly common, including
targets of precursors of hypertension, osteopenia, and obesity. The
prospect of marketing existing drugs to otherwise healthy people greatly
expands the market for these drugs while increasing costs for society,
increasing use of health care, and potentially reducing quality of life
by converting healthy people into patients.
Effectiveness of drugs
Several trials have assessed the ability of drugs to prevent diabetes (box).
Overall, except for metformin, the evidence is inconsistent and comes
from trials of limited methodological quality. Two trials included drug
discontinuation phases to determine if the drugs had changed the natural
course of diabetes or was merely treating diabetes.
Both discontinuation studies found that the proportion of diabetes
diagnoses remained lower in the intervention arm; a third to half of the
patients, however, were lost to follow-up and did not provide
discontinuation data. Furthermore, the follow-up period after treatment
was much shorter than the treatment time. None of the trials showed a
reduction in the risk of diabetes complications.
Evidence for drug prevention of diabetes
Metformin
- Consistent evidence from 3 randomised trials
- The Diabetes Prevention Program (DPP) found metformin reduced the 3 year risk of diabetes (relative risk 0.69, 95% confidence interval 0.57 to 0.83), but lifestyle change was more effective
Troglitazone (no longer available)
Two trials found troglitazone was effective in preventing diabetes:
- Study in women with a history of gestational diabetes had large loss to follow-up11
- The DPP discontinued the trial arm because of fear of liver toxicity. Relative risk of diabetes diagnosis after 1 year of troglitazone was 0.25 (P<0.001), but the effect disappeared in the year after drug discontinuation12
Angiotensin converting enzyme inhibitors, angiotensin receptor blockers
- Systematic reviews of trials in hypertension, heart failure, and coronary disease that assessed diabetes as a secondary or post hoc outcome found large preventive effects13
- DREAM trial failed to confirm the effect
DREAM
is a large randomised controlled trial that enrolled patients with
impaired fasting glucose concentrations or impaired glucose tolerance
and assigned them to high dose rosiglitazone or placebo.The trial effectively concealed allocation, adhered to the intention to
treat principle, and achieved negligible loss to follow-up after a
median follow-up of three years.
The trial's primary
outcome was a composite end point of death and the diagnosis of
diabetes. It was stopped early after almost 1000 primary end points had
accumulated because of benefit in the treatment arm (table 1).
The authors noted that for every 1000 people treated with rosiglitazone
8 mg/day for three years, about 144 people who would otherwise cross
the glucose threshold we call diabetes will not do so; four to five
patients without congestive heart failure will develop the condition.
