DPP

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Knowler WC, et al. "Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin". The New England Journal of Medicine. 2002. 346(6):393-403.
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Clinical Question

In patients at high risk of developing type 2 diabetes, do intensive lifestyle changes or metformin treatment prevent or delay the onset of diabetes?

Bottom Line

In patients at high risk of developing type 2 diabetes, intensive lifestyle changes and metformin treatment both reduced the incidence of diabetes.

Major Points

Adults with prediabetes have a high incidence of developing overt T2DM. In the end of the 20th century, there was little evidence to guide prevention of progression to T2DM among prediabetics. Given the high incidence of obesity and low levels of exercise among prediabetics and diabetics, intensive lifestyle interventions promoting weight loss and exercise might be effective. Also, metformin is an oral diabetes medication associated with weight loss and reduced gluconeogenesis. Whether intensive lifestyle it may prevent progression of prediabetes to T2DM was also unknown.

Published in 2002, the Diabetes Prevention Program (DPP) randomized 3,234 patients at high risk of T2DM (elevated BMI and prediabetes as defined by elevated fasting plasma glucose and elevated plasma glucose 2 hours after an OGTT) to receive standard lifestyle modification and placebo, standard lifestyle modification and metformin, or an intensive lifestyle intervention program. After 2.8 years of mean follow up, the study was closed early for efficacy of the active interventions. Intensive lifestyle intervention and metformin reduced the incidence of T2DM by 58% (95% CI 48-66%) and 31% (95% CI 17-43%) respectively, as compared to placebo. The interventions were generally well-tolerated, except for metformin, which had a higher rate of GI-related symptoms than placebo. This is consistent with the known GI side effect profile of metformin in T2DM.[1]

The DPP study was included in a 2008 meta-analysis of 8 studies (n=5,956 patients) to assess the effects of exercise and diet interventions for preventing T2DM.[2] Exercise and diet interventions reduced the risk of developing diabetes as compared to standard recommendations (RR 0.63, 95% CI 0.49-0.79) and showed favorable effects on weight reduction. Additionally, within-trial cost-effectiveness analysis concluded that the lifestyle and metformin interventions were cost-effective.[3]

The core intervention of the intensive lifestyle arm targeting 150 min/week of moderate-intensity physical activity and 7% target weight loss is now referred to therapeutically as a 'DPP' and is an evidence-based intervention intended for adults with prediabetes. A CDC-approved curriculum of 16 classes is now covered by Medicare, with online and in-person courses available across the country.[4][5]

Guidelines

ADA Standards of Medical Care in Diabetes (2018, adapted)[6]

  • Prediabetics should be referred to a DPP targeting 7% weight loss and 150 min/week of moderate-intensity exercise (grade A)
  • Consider metformin in prediabetics, especially if BMI ≥35 kg/m2, age <60, and if prior GDM in women (grade A)

Design

  • Multicenter, double-blind, parallel-group, randomized, controlled trial
  • N=3,234
    • Placebo (n=1,082)
    • Metformin (n=1,073)
    • Intensive-lifestyle (n=1,079)
  • Setting: 27 centers in the United States
  • Enrollment: 1996-1999
  • Mean follow-up: 2.8 years (stopped early for benefit)
  • Analysis: Intention-to-treat
  • Primary outcome: Diabetes diagnosed according to the 1997 criteria of the American Diabetes Association[7]

Population

Inclusion Criteria

  • Age ≥25 years
  • BMI ≥24.0 kg/m2 (≥22.0 in Asians)
  • Non-diabetic patients at high risk with both of the following:
    • Fasting plasma glucose of 95-125 mg/dL (5.3-6.9 mmol/L)
      • Note, there was no lower limit for American Indians due to their high risk of T2DM
    • 2-hour post OGTT plasma glucose of 140-199 mg/dL (7.8-11.0 mmol/L)

Exclusion Criteria

  • Taking medications known to alter glucose tolerance (eg, thiazide and beta-blockers)
  • Significant illness that would limit life expectancy.

Baseline Characteristics

All patients

  • Demographics: Female sex 68%, age 51 years, white race 55%, black race 20%, hispanic 16%, American Indian 4%, asian 4%
  • BMI: 34 kg/m2, waist circumference 105 cm, waist:hip 0.92
  • Diabetes history: Family history of diabetes 69%, gestational diabetes in women 16%, fasting glucose 106 mg/dL, 2h OGTT 165 mg/dL, A1c 5.9%
  • Physical activity by the Modifiable Activity Questionnaire: 16 MET-hr/week

Interventions

  • Randomization to a group:
    • Intensive lifestyle - Intensive lifestyle modifications targeting 7% weight loss through diet (low calorie, low-fat diet) and exercise (≥150 min/week) delivered through a 16 lesson curriculum, details are published elsewhere[8]
    • Metformin - 850 mg PO BID (uptitrated from daily), with standard lifestyle recommendations
    • Placebo - With standard lifestyle recommendations
    • Note, there was originally a troglitazone arm, which was discontinued given the medication's elevated incidence of liver damage.

Outcomes

P-Y is person year."

Primary Outcomes

Incident diabetes
Intensive lifestyle vs. placebo: 4.8 vs. 11.0/100 P-Y (Reduction in incidence 58%; 95% CI 48-66%)
Metformin vs. placebo: 7.8 vs. 11.0/100 P-Y (Reduction in incidence 31%; 95% CI 17-43%)
Intensive lifestyle vs. metformin: 4.8 vs. 7.8/100 P-Y (Reduction in incidence 39%; 95% CI 24-51%)
Estimated cumulative incidence of diabetes at 3 years
Intensive lifestyle: 14.4% (NNT 7)
Metformin: 21.7% (NNT 14)
Placebo: 28.9 %

Secondary Outcomes

Weight loss
Intensive lifestyle vs. placebo: 5.6 vs. 0.1 kg (P<0.001)
Metformin vs. placebo: 2.1 vs. 0.1 kg (P<0.001)
Decrease in daily caloric intake
Intensive lifestyle vs. placebo: 450 vs. 249 kcal (P<0.001)
Metformin vs. placebo: 296 vs. 249 kcal (P<0.001)
Decrease in fat intake
Intensive lifestyle vs. placebo: 6.6% vs. 0.8% (P<0.001)
Metformin vs. placebo: 0.8% vs. 0.8% (P=NS)
Adherence to interventions
Intensive lifestyle adherence
50% achieved the goal of losing ≥7 percent of initial body weight by 2 years
74% met the goal of ≥150 minutes/week of physical activity by 2 years
Medication adherence
Placebo vs. metformin: 77% vs. 72% (P<0.001)

Adverse Events

Gastrointestinal symptoms
Intensive lifestyle vs. placebo: 12.9 vs. 30.7 events/100 P-Y (P<0.01)
Metformin vs. placebo: 77.8 vs. 30.7 events/100 P-Y (P<0.01)
Musculoskeletal symptoms
Intensive lifestyle vs. placebo: 24.1 vs. 21.1 events/100 P-Y (P<0.01)
Metformin vs. placebo: 20.0 vs. 21.1 events/100 P-Y (P=NS)

There were no differences between groups for hospitalizations or deaths.

Criticisms

  • Weight loss secondary to metformin is a possible confounder in the drug's effect of reducing insulin resistance. [9]
  • The intervention may be difficult to implement in daily clinical practice. [10]
  • Other variables such as socioeconomic status should be considered as well. [11]

Funding

  • NIDDK, ORMH, NICHD, NIA, NCRR
  • Indian health service
  • CDC
  • GCRC program
  • ADA
  • Bristol-Myers Squibb
  • Parke-Davis
  • Various other private groups provided support, listed on page 401

Further Reading

  1. Dujic T et al. Association of Organic Cation Transporter 1 With Intolerance to Metformin in Type 2 Diabetes: A GoDARTS Study. Diabetes 2015. 64:1786-93.
  2. Orozco LJ et al. Exercise or exercise and diet for preventing type 2 diabetes mellitus. Cochrane Database Syst Rev 2008. :CD003054.
  3. Diabetes Prevention Program Research Group. Within-trial cost-effectiveness of lifestyle intervention or metformin for the primary prevention of type 2 diabetes. Diabetes Care. 2003 Sep;26(9):2518–23.
  4. CMS.gov MDPP coverage announcement.
  5. CDC.gov DPP website.
  6. American Diabetes Association 5. Prevention or Delay of Type 2 Diabetes: Standards of Medical Care in Diabetes-2018. Diabetes Care 2018. 41:S51-S54.
  7. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997. 20:1183-97.
  8. The Diabetes Prevention Program. Design and methods for a clinical trial in the prevention of type 2 diabetes. Diabetes Care 1999. 22:623-34.
  9. Diabetes Prevention. New England Journal of Medicine. 2002 Jun 6;346(23):1829–30.
  10. Leung M, Kwan D, Evans MF. Lifestyle intervention or treatment with metformin. Which delays onset of type 2 diabetes? Can Fam Physician. 2004 Mar 1;50(3):369–71.
  11. Greene B. A lifestyle intervention or metformin prevented or delayed the onset of type 2 diabetes in people at risk. Evid Based Nurs. 2002 Oct;5(4):109.