NC: Diabetes Management (2007)

Citation:

Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. The New England Journal of Medicine 2002;346(6):393-403.

PubMed ID: 11832527
 
Study Design:
Randomized Controlled Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
To determine if a lifestyle intervention or treatment with metformin, a biguanide antihyperglycemic agent, prevents the delay or onset of diabetes. Also, to see if the effectiveness differs between a lifestyle intervention or treatment with metformin and if these two interventions effectiveness differs according to age, sex, or race.
Inclusion Criteria:
  • Nondiabetic persons with elevated fasting and post-load plasma glucose concentrations
  • Age of at least 25 years
  • BMI of 24 or higher
  • Plasma glucose concentration of 95 - 125 mg/dl in fasting state and 140 - 199 mg/dl 2 hours after a 75-g oral glucose load
Exclusion Criteria:
  • Taking medications known to alter glucose metabolism
  • Had illnesses that could seriously reduce life expectancy or their ability to participate in the trial
Description of Study Protocol:

Recruitment

Recruitment was designed to enroll approximately half the participants from racial or ethnic minority groups.  A 4-step screening and recruitment process was developed to identify eligible participants.

Design:  Randomized Controlled Trial

Blinding used (if applicable):  not possible; assignment to metformin and placebo were double-blinded.

Intervention (if applicable)

  • Randomly assigned to placebo, metformin (850 mg twice daily) or lifestyle modification program (16 lesson curriculum covering diet, exercise and behavior modification) with goals of at least 7% weight loss and at least 150 minutes of physical activity per week

Statistical Analysis

  • Study design and treatment followed intention-to-treat principle. 
  • Study design provided 90% power to detect a 33% reduction from an incidence of 6.5 cases of diabetes per 100 person years, with a 10% rate of loss to follow-up per year. 
  • The time to the outcome was assessed using life-table methods.  Modified product-limit curves for the cumulative incidence of diabetes were compared with the use of the log-rank test. 
  • The estimated cumulative incidence at 3 years and the Greenwood estimate of the standard error were used to calculate the number of persons who would need to be treated in order to prevent 1 case of confirmed diabetes during a period of 3 years and the associated 95% confidence interval
  • Risk reduction, heterogeneity among strata, and interactions between treatment assignments and covariates were assessed by proportional hazards regression
  • Fixed-effects models with the assumption of normally distributed errors were used to assess differences over time in body weight and plasma glucose and glycosylated hemoglobin values among the 3 groups 
Data Collection Summary:

Timing of Measurements

Measurements made annually over mean follow-up of 2.8 years.

Dependent Variables

  • Diagnosis of diabetes based on annual oral glucose tolerance test or semiannual fasting plasma glucose test
  • Measurements of glucose and HbA1c were performed centrally 

Independent Variables

  • Randomly assigned to placebo, metformin (850 mg twice daily) or lifestyle modification program with goals of at least 7% weight loss and at least 150 minutes of physical activity per week
  • Adherence to treatment was assessed quarterly using pill counts and structured interviews
  • Self-reported levels of leisure activity were assessed annually with the Modifiable Activity Questionnaire
  • Usual daily caloric intake during the previous year asessed at baseline and at 1 year with modified version of Block FFQ

Control Variables

 

Description of Actual Data Sample:

Initial N: 3234 participants, 68% women.  1082 assigned to placebo, 1073 to metformin, and 1079 to intensive lifestyle modification.

Attrition (final N):  99.6% were still alive

Age:  mean age 51 years

Ethnicity:  45% members of minority groups

Other relevant demographics: mean BMI 34.0

Anthropometrics:  Baseline characteristics including all measured risk factors for diabetes were similar among the 3 study groups.

Location:  27 centers in the United States

 

Summary of Results:

Other Findings

Average follow-up was 2.8 years.

50% of the participants in the lifestyle intervention group had achieved the goal of 7% weight loss or more by the end of the 24-week curriculum.  74% had met the goal of at least 150 minutes of physical activity per week.

Incidence of diabetes was 11.0 cases per 100 person-years in the placebo group, 7.8 cases per 100-person years in the metformin group, and 4.8 cases per 100 person years in the lifestyle intervention group.

The lifestyle intervention reduced the incidence by 58% (95% confidence interval:  48 - 66%) and metformin by 31% (95% confidence interval:  17 - 43%) as compared with placebo.

The estimated cumulative incidence of diabetes at 3 years was 28.9% in the placebo group, 21.7% in the metformin group, and 14.4% in the lifestyle intervention group.

The lifestyle intervention was significantly more effective than metformin.

To prevent 1 case of diabetes during a period of 3 years, 6.9 persons would have to participate in the lifestyle intervention program, and 13.9 would have to receive metformin. 

Author Conclusion:

Our study showed that treatment with metformin and modification of lifestyle were two highly effective means of delaying or preventing type 2 diabetes. The lifestyle intervention was particularly effective, with one case of diabetes prevented per seven persons treated for three years. Thus, it should also be possible to delay or prevent the development of complications, substantially reducing the individual and public health burden of diabetes.

Funding Source:
Reviewer Comments:
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? ???
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes