metformin in the prevention of onset of type 2 diabetes

Last edited 05/2019 and last reviewed 03/2022

There is evidence that in overweight people with increased fasting and postload plasma glucose concentrations, an intensive lifestyle intervention or treatment with metformin plus standard lifestyle recommendations was more effective than standard lifestyle recommendations alone for preventing or delaying the onset of type 2 diabetes.

This study evidence comes a 'landmark' study the Diabetes Prevention program. This was a randomised, blinded, placebo controlled trial with mean follow up of 2.8 years.

• the study included 3234 participants (mean age 51 years, 68% women) without diabetes who had a body index >= 24 (>= 22 for Asians) and a plasma glucose concentration of 5.3 to 6.9 mmol/l in the fasting state and 7.8 to 11.0 mmol/l two hours after a 75g oral glucose load
  
  
• study participants were allocated to an intensive programme of lifestyle modification (n=1079), standard lifestyle recommendations plus glucose control with metformin (850 mg twice daily), or placebo (n=1082)
  • intensive lifestyle modification
    • intensive lifestyle goals were of at least a 7 percent weight loss and at least 150 minutes of physical activity per week
    • a 16-lesson curriculum covering diet, exercise, and behavior modification was designed to help the participants achieve these goals. The curriculum, taught by case managers on a one-to-one basis during the first 24 weeks after enrollment, was flexible, culturally sensitive, and individualized. Subsequent individual sessions (usually monthly) and group sessions with the case managers were designed to reinforce the behavioral changes
      
      
• at 3 years, the cumulative incidence of diabetes was lower in the intensive lifestyle modification and metformin group than in the placebo group. The incidence rates of diabetes were 4.8, 7.9 and 11.0 patients per 100 person years for the intensive lifestyle intervention, metformin and placebo groups respectively
  
  
• thus, from the study data, the most effective intervention for preventing or delaying the onset of type 2 diabetes is intensive lifestyle modification rather than metformin treatment

A further analysis has been undertaken to determine the prevalence of the metabolic syndrome at baseline in the Diabetes Prevention Program and the effect of intensive lifestyle intervention and metformin therapy on the syndrome's incidence and resolution (2):

• the cumulative incidence of metabolic syndrome was lower in the intensive lifestyle intervention and metformin groups than in the placebo group (38%, 50% and 61% respectively)
• resolution of metabolic syndrome was greater in the intensive lifestyle intervention group than in the placebo group (38% v 18%, p- 0.002), metformin and placebo did not differ for resolution (23% v 18%, p>0.05)
• this study analysis revealed that, in persons with impaired glucose tolerance:
  • treatment with an intensive lifestyle intervention or, metformin plus a standard lifestyle, was more effective than a standard lifestyle alone in order to prevent or delay the onset of metabolic syndrome
  • the incidence of metabolic syndrome was lowest in the intensive lifestyle modification group

Intensive lifestyle interventions can reduce the incidence of type 2 diabetes in people with impaired glucose tolerance, but how long these benefits extend beyond the period of active intervention

• in adults with impaired glucose tolerance, group-based lifestyle interventions delayed or prevented diabetes for up to 14 years after the acute intervention (3)

In conclusion:

Interventions involving physical activity have been shown to reduce the risk of developing Type 2 Diabetes by between 47 and 58% in high-risk groups (1,4,5)

• this reduction in incidence has been shown to persist for 10 years following the initial intervention (6)
• long-term follow-up in one of these studies has demonstrated a significant reduction in both cardiovascular and all-cause mortality at 30 years (7) - i.e. continuing significant legacy effect of the intervention

Notes:

• the DREAM ((Diabetes REduction Assessment with ramipril and rosiglitazone Medication) investigators (8) found that the use of rosiglitazone at 8 mg daily for 3 years substantially reduced incident type 2 diabetes and increases the likelihood of regression to normoglycaemia in adults with impaired fasting glucose or impaired glucose tolerance, or both. However unpublished washout data suggests a similar incidence of type 2 diabetes in rosiglitazone and placebo treated groups after discontinuation of rosiglitazone (9).

Reference:

• 1. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. NEJM 2002; 346:393-403.
• 2. Orchard TJ et al. The effect of metformin and intensive lifestyle on the metabolic syndrome: the Diabetes Prevention Program randomized controlled trial. Ann Intern Med 2005;142:611-9
• 3. Li G et al. The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study. Lancet. 2008 May 24;371(9626):1783-9.
• 4. Pan XR, et al Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997;20:537-44.
• 5 Tuomilehto J et al . Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-50.
• 6. Knowler WC, Fowler SE, Hamman RF et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009;374:1677-86
• 7. Li G et al.Morbidity and mortality after lifestyle intervention for people with impaired glucose tolerance: 30-year results of the Da Qing Diabetes Prevention Outcome Study.Lancet Diabetes Endocrinol. 2019 Apr 26. pii: S2213-8587
• 8. Gerstein HC et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006 Sep 23;368(9541):1096-105
• 9. Evidence Based Medicine 2007; 12(4):108.