Optimization of Metformin in the GRADE Cohort: Effect on Glycemia and Body Weight

Conclusions

We report the effect of adjusting metformin dosage in 6,823 participants with an initial HbA_1c level of ≥6.8% (51 mmol/mol) over a mean run-in period of 7.9 ± 2.4 weeks. Adjusting dosage to 2,000 mg/day or to a maximally tolerated lower dose was associated with a mean decrease in HbA_1c of 0.52 ± 0.94% (5.7 ± 10.3 mmol/mol). Greater increases in dosing were associated with greater reductions in HbA_1c. However, participants with no change in metformin dosing, and even those with a dose reduction, also exhibited decreases in HbA_1c levels, suggesting that improvement in adherence to the medication and/or lifestyle behavior also contributed.

Several reports have compared the effects of different doses of metformin on HbA_1c levels (5,7,14–19). For total daily doses of 1,000 mg versus 2,000 mg (15,16,19) or 1,500 mg versus 3,000 mg (17), improvements in HbA_1c were in the range of 0.2–0.3% (2.2–3.3 mmol/mol). However, another study (5) reported a difference of ∼0.8% (8.7 mmol/mol) for 1,000 versus 2,000 mg daily after subtracting out the change in HbA_1c in placebo-treated participants. In that study, the placebo group had a 1.2% (13.1 mmol/mol) increase in HbA_1c over 14 weeks, while baseline HbA_1c values for all groups were relatively high at ∼10.0% (86 mmol/mol).

Our current study differs from the above reports in an important way. Those studies compared the effectiveness of metformin in participants not previously taking the drug who were randomly assigned to different doses. In this study, we adjusted metformin dosing in persons already taking the drug, typical of what would be done in clinical practice. In some of the previous studies (14,18), comparative doses of metformin were examined in persons also taking another glucose-lowering drug. We are not aware of other studies that compared the effects of differential adjustments in metformin dosage in participants already taking the drug and not using another glucose-lowering drug.

Three smaller studies compared increments in metformin dosing from 1,000 to 2,000 mg/day to continuation of metformin 1,000 mg/day with additions of sitagliptin (20), vildagliptin (21), or rosiglitazone (22). Respectively, for participants whose metformin dose was increased, these studies showed changes in HbA_1c of −0.80% (−8.7 mmol/mol) from a baseline mean of 8.7% (72 mmol/mol), −0.37% (−4.0 mmol/mol) from a baseline mean of 7.3% (56 mmol/mol), and −0.71% (−7.8 mmol/mol) from a baseline mean of 8.0% (64 mmol/mol). These reports did not examine differential increments in metformin dosing and, importantly, did not provide a control group (metformin unchanged) to estimate the effect of lifestyle and adherence recommendations or of trial entry. Moreover, the relationships of increments in HbA_1c to pretreatment HbA_1c or other factors affecting metformin responsiveness were not assessed, beyond one report showing a greater effect of incrementing metformin in participants whose baseline HbA_1c was >8% (64 mmol/mol) compared with <8% (change of −0.46% or −5.0 mmol/mol vs. −0.31% or −3.4 mmol/mol). Taken together, the data from these studies are roughly in agreement with our findings.

We acknowledge that we adjusted metformin dosing in the context of a clinical trial in which the drug was provided free of cost and with emphasis on medication adherence, diet, and exercise. These factors may in part explain why participants with no change in metformin dose had a decrease in HbA_1c and weight. Moreover, there is evidence that glycemia improves upon entry into a clinical trial per se (23). Despite this, adherence and lifestyle modification alone cannot explain all of the improvement in HbA_1c with optimization of dosage, because HbA_1c fell significantly more in participants whose dose was increased by 1,000 mg/day, when compared with the group for which dose was unchanged (Fig. 1).

We observed that in participants whose metformin dose was reduced, either because they were taking >2,000 mg at the time of initial run-in or because of intolerance, HbA_1c improved less than in participants whose dose was unchanged (Fig. 1). The reduction in metformin dose was from an average of 2,219 to 1,617 mg/day, while the average metformin dose of those who were unchanged was 1,948 mg/day. This differs from an older report in which there was no difference in HbA_1c levels, with 2,500 mg daily compared with 2,000 mg/day (5). However, that study compared different doses in different individuals, whereas we made dose adjustments within the same participants. This discrepancy cannot be attributed to the emphasis on medication adherence and lifestyle change in our study, as that should not have differed among participants.

Although multiple factors beyond metformin dose change per se were predictive of the effect of metformin on HbA_1c levels, by far the strongest was the HbA_1c level prior to metformin dose adjustment (Table 3 and Supplementary Fig. 2). Baseline HbA_1c levels contributed independently both among participants whose dose was increased by ≥1,000 mg/day and for participants whose dose was not increased or increased by lesser amounts. In multivariate analyses, older age, African American, Native American, or other/multiple race (compared with white), Hispanic ethnicity, and higher creatinine levels were less strongly associated with a decrease in HbA_1c (Table 3), while higher weight and longer diabetes duration were associated with a mild increase. Consistent with our findings, an examination of electronic health records of 19,672 patients showed that African American heritage was associated with a greater reduction in HbA_1c than European American following prescription of metformin (24). However, an association with race/ethnicity was not reported in other studies (25,26).

Adherence to metformin therapy during run-in appeared to be strong in that 71.1% of participants reported no missed pills in the past week, and 27.1% reported missing only 0–20% (Table 1). Further supporting tolerance to metformin, 90.7% of participants were at 2,000 mg/day (Table 1), and the mean dose at final screening was 1,932 mg/day. Importantly, intolerance was expected to be low, because all participants were required to be taking metformin in order to be eligible for screening. This may explain why nonadherence was lower in this study than in other reports (27).

The American College of Physicians (ACP) recently suggested a target HbA_1c value of 8.0% (64 mmol/mol) as appropriate for “most patients with type 2 diabetes” (12). Although many consider this ACP target of 8.0% as too high for many individuals (13), we point out that the curvilinear relationships in Supplementary Fig. 1 show that the impact of metformin dose adjustment was greater for those with an initial HbA_1c level of ≥8.0% (64 mmol/mol). Therefore, increasing metformin may be particularly effective for those with an HbA_1c level above the ACP target.

Our findings have broad clinical implications. Figure 1 shows that there is potential for metformin dose adjustment to improve glycemic control even in individuals with lower HbA_1c values or values already within guidelines (11–13). Moreover, Table 2 shows that participants whose dose was increased by ≥1,000 mg/day entered screening taking a mean of 905 mg metformin daily with a mean HbA_1c of 8.2% (66 mmol/mol). These observations, in common, suggest that there may be benefit from metformin dose adjustment in many patients with type 2 diabetes. In support of this concept, there were no reports of severe hypoglycemia during the GRADE run-in. Moreover, although not specifically tabulated, participant-reported hypoglycemia of any degree was very unusual, as expected based on other reports indicating that metformin causes little hypoglycemia, when used as the sole glucose-lowering drug (28–30). Further, we point out that metformin is often used in the absence of diabetes for prevention of the disease (8) or for therapy of polycystic ovarian disease in persons without diabetes (31).

In contrast, beyond hypoglycemia, there are other well-known adverse effects of metformin (4), and benefit must be considered relative to risk. We found that the fall in HbA_1c was very modest for individuals entering run-in with HbA_1c values in the lower range (Supplementary Fig. 1).

There are some limitations to this study. The run-in period was variable and as low as 4 weeks for participants entering the study already taking 2,000 mg/day, in whom the metformin dose was not changed. Thus, changes in HbA_1c in those with short duration of follow-up may have underestimated the effect that might have been seen if a usual interval HbA_1c had been obtained (i.e., ≥2 months). However, this effect may have been mitigated in that all participants had to be taking metformin for at least 8 weeks at the time of screening. As noted, we adjusted metformin dosing in the context of a clinical trial and, as per study protocol, this was done along with recommendations for medication adherence and changes in behavior, diet, and exercise. The initial HbA_1c values were determined by local laboratories, while the HbA_1c values at final run-in were all determined by our study core laboratory. However, the methodology for HbA_1c is now well standardized in relation to average glycemia and would not be expected to differ by baseline HbA_1c or metformin dose (32,33). Adherence to therapy was based on participant self-report rather than pill counts. Moreover, adherence to therapy should not have been affected by affordability, because metformin was provided free of cost to all participants.

In conclusion, adjusting metformin dosing to 2,000 mg/day or to a maximally tolerated lower dose combined with promoting lifestyle changes and medication adherence improved glycemic control by an average of 0.52% (5.7 mmol/mol) in patients who had an average HbA_1c of ≥6.8% (51 mmol/mol) and reported taking an average of 1,543 mg/day at baseline. The improvement was greater in those with a higher initial HbA_1c. These findings serve as a guide that could help to improve management in persons on submaximal metformin therapy.