Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study(2)

The Diabetes Prevention Program Research Group.
Diabetes Care. 2012;35:731-737. 

This overview was created by KnowledgePoint360 Group, LLC, and was not associated with funding via an educational grant or a promotional/commercial interest. 

Results from the Diabetes Prevention Program (DPP) study (a randomized, double-blind trial of metformin or placebo) and its long-term follow-up, the DPP Outcomes Study (DPPOS; an open-label extension of metformin and analysis of adverse events, tolerability, and effects of adherence on weight change and waist circumference) demonstrated a reduction in the development of diabetes among subjects treated with metformin. Weight loss was also maintained in the metformin group during the combined DPP and DPPOS periods.  

The current study provides an update on the DPP and DPPOS results and describes the long-term safety and tolerability profile of metformin. In a post-hoc analysis, the study also examines whether greater adherence to metformin confers greater weight loss and reduction in waist circumference among those randomized to metformin vs those receiving placebo.  

Findings:
Long-Term Use of Metformin in DPPOS: Results from the DPP Double-Blind Phase
 

Medication adherence  

  • The proportion of participants taking ≥80% of the prescribed study doses over time was lower in the metformin group (71%) vs the placebo group (77%; P<0.001).  
  • Variations were seen between race and ethnic groups, with African-Americans demonstrating the lowest levels of adherence during both DPP (metformin + placebo) and follow-up (metformin only).  
  • During DPP, men were more adherent to metformin therapy; this difference was not seen during the follow-up period.  
  • No differences in adherence were observed among those receiving placebo.  

Weight loss  

  • Percent weight loss at the end of Years 1 and 2 were as follows (mean ± standard deviation):
    • End Year 1: 2.7 ± 4.7% in the metformin group vs 0.43 ± 4.7% in the placebo group (P<0.001)  
    • End Year 2: 2.1 ± 5.7% in the metformin group vs 0.02 ± 5.5% in the placebo group (P<0.001)  
     

Waist circumference  

  • Reductions in waist circumference at the end of Years 1 and 2 were as follows (mean ± standard deviation):
    • End Year 1: 2.2 ± 6.2 cm in the metformin group vs 0.71 ± 5.6 cm in the placebo group (P<0.001)  
    • End Year 2: 2.1 ± 7.1 cm in the metformin group vs 0.79 ± 6.5 cm in the placebo group (P<0.001)  
     

Achievement ≥5% loss of body weight  

  • Achievement of weight loss ≥5% of initial body weight at the end of Years 1 and 2 was as follows:
    • End Year 1: 29% of the metformin group vs 13% of the placebo group (P<0.001)  
    • End Year 2: 26% of the metformin group vs 14% of the placebo group (P<0.001)  
     

Achievement ≥10% loss of body weight  

  • Achievement of weight loss ≥10% of initial body weight at the end of Years 1 and 2 was as follows:
    • End Year 1: 8% of the metformin group vs 4% of the placebo group (P<0.001)  
    • End Year 2: 10% of the metformin group vs 5% of the placebo group (P<0.001)  
     

Effect of adherence on body weight, waist circumference  

  • Similar percentages of participants in the metformin and placebo groups were ≥50% adherent or highly adherent to study treatment (72% vs 74%, respectively), although fewer participants in the placebo group were highly adherent.  
  • A strong association was seen between weight loss and adherence among metformin-treated patients; durability of weight loss was also influenced by adherence.  
  • Among highly adherent participants, average weight was 3.5 ± 0.35% below baseline at 2 years, a rate which was similar to 1-year weight loss observed in this group. Participants with low adherence showed a return to their baseline weight by Year 2.  

Long-Term Use of Metformin in DPPOS: Results Including DPPOS Open-Label Treatment  

  • Over the total follow-up period, 62% of metformin participants were ≥50% or highly adherent to study treatment vs 72% of participants in the 2-year double-blind phase.  
  • Average metformin group weight loss was 2.0% (1.9 kg), independent of adherence, during the total follow-up period.  
  • Participants who were highly adherent to metformin showed a 3.5% (3.1 kg) weight loss from baseline.  

Long-Term Use of Metformin in DPPOS: Results During DPP  

  • Through Year 4 of the DPP, a randomized, double-blind trial of metformin or placebo, reports of gastrointestinal symptoms were more common among those in the metformin group vs those in the placebo group (average 28% vs 16%, respectively; P=0.01).  
  • Participants receiving metformin self-reported “study medication-related” gastrointestinal symptoms more frequently than those receiving placebo (9.5% vs 1.1%, respectively; P<0.001).  
  • Average levels of hemoglobin and hematocrit were the same at baseline. Over time, these levels were slightly lower among those receiving metformin vs those receiving placebo (P<0.001 for both comparisons):
    • Hemoglobin: 13.6 mg/dL vs 13.8 mg/dL, respectively  
    • Hematocrit: 40.6% vs 41.1%, respectively  
     
  • No significant between-group difference in percent of participants with low hemoglobin was observed (metformin, 11.2% vs placebo, 7.6%; P=0.17).  
  • The percentage of participants with low hematocrit was higher in the metformin group compared with the placebo group (metformin, 12.6% vs placebo, 8.4%; P=0.035).   

 This overview was created by KnowledgePoint360 Group, LLC, and was not associated with funding via an educational grant or a promotional/commercial interest. 

 

Last Modified: 2/5/2013