Metformin protects over 15 years
Metformin continues to protect high-risk individuals from developing type 2 diabetes (T2D) over 15 years, especially among those with higher glycaemic status at baseline and women reporting a history of gestational diabetes mellitus (GDM), according to long-term results from DPP/DPPOS*.
The role of pharmacologic therapies such as metformin in diabetes prevention has been a topic of constant debate. “Whether metformin should be used for diabetes prevention requires a careful balance of benefits and risks,” the researchers pointed out.
“These results should help to prioritize those groups at high risk of developing diabetes who will benefit most from being treated with metformin,” they added.
During 15 years of follow-up after randomization, incidence of diabetes development was significantly lower among participants who received metformin compared with the placebo group, regardless of whether diabetes was diagnosed based on glucose testing (hazard ratio [HR], 0.83, 95 percent confidence interval [CI], 0.73–0.93) or HbA1c (HR, 0.64, 95 percent CI, 0.55–0.75). [Diabetes Care 2019;42:601-608]
In particular, the protective effect of metformin vs placebo was greater among parous women with a history of GDM than those without, in terms of relative risk reduction (HR, 0.59 vs 0.94; p=0.02) as well as absolute risk reduction (rate difference [RD], -4.57 vs -0.39; p=0.01) when diabetes was diagnosed based on glucose testing.
Also, participants with a higher baseline fasting glucose levels (≥110 mg/dL) derived a greater benefit from metformin than those with baseline fasting glucose levels of 95–109 mg/dL (HR, 0.75 vs 0.83; p=0.0004 and RD, -3.53 vs -0.86; p=0.02).
Similar results were seen when diabetes development was defined by HbA1c, with metformin having a greater benefit at higher baseline glycaemic status. Metformin reduced the absolute risk of developing diabetes to a greater extent among participants with a higher baseline HbA1c (6.0–6.4 percent) than those with baseline HbA1c <6.0 percent (rate difference [RD], -3.88 vs -1.03; p=0.001).
Long-term benefit regardless of testing method
“Whether the glucose-based results or HbA1c-based results should be given greater credence is complicated,” the researchers stated.
The current analysis used both glucose and HbA1c testing to define progression to diabetes because HbA1c was not widely accepted for diabetes diagnosis when DPP started, whereby glucose-based criteria were used for selection of prediabetes participants.
While HbA1c indicates overall mean glycaemia, the fasting glucose level measures hepatic glucose output, according to the researchers.
“Regardless of the means by which diabetes is diagnosed, the long-term effects of metformin on diabetes development in DPP/DPPOS suggest that metformin remains effective in this cohort,” they added.
“In Singapore, HbA1c appropriately measured can be used to screen for diabetes. For HbA1c … between 6.1–6.9 percent, the patient should proceed to a fasting blood glucose test or an OGTT**,” explained Dr Kevin Tan, president of Diabetes Singapore and a consultant endocrinologist at Kevin Tan Clinic for Diabetes Thyroid & Hormones Pte Ltd, Mt Elizabeth Medical Centre, Singapore.
He pointed out that a fasting blood glucose levels of ≥7 mmol/L indicates diabetes while levels between 6–7 mmol/L indicates impaired fasting glycaemia, in which case the patient should proceed to an OGTT if not already done.
Strong data for prevention in high-risk subjects
“Overall, the current report from the DPP/DPPOS group provides strong support for further discussion of using metformin early in the evolution from dysglycaemia to T2D,” wrote Drs William Cefalu and Matthew Riddle of the ADA in Arlington, Virginia and Oregon Health & Science University in Portland, Oregon, US, respectively in an accompanying commentary. [Diabetes Care 2019;42:499-501]
“It supports the view that HbA1c values higher than 6.0 percent but not yet 6.5 percent or higher should prompt reconsideration of treatment strategies, potentially including pharmacotherapy. It also supports further discussion and heightened awareness of the need for postpartum screening of women with prior GDM,” they highlighted.
The ADA*** has endorsed the use of metformin in individuals with prediabetes, in particular “those with BMI ≥35 kg/m2, those aged <60 years, women with prior GDM, and/or those with rising A1C despite lifestyle intervention”. [Diabetes Care 2017;40(Suppl. 1):S44–S47] The recommendations were made based on data from the original DPP trial which demonstrated that metformin protects participants from developing diabetes after 10 years of follow-up.
Metformin over lifestyle changes?
DPP randomized 3,234 individuals at high risk for T2D to intensive lifestyle modification, metformin 850 mg twice daily, or placebo. An initial analysis after 3 years of intervention showed that both lifestyle modification and metformin were effective in delaying progression to diabetes. At the end of DPP, all participants were offered lifestyle intervention of lower intensity and those in the original metformin group continued taking the drug during the observational follow-up in DPPOS.
“We realize that lifestyle modification remains the cornerstone of diabetes prevention … However, it is clear that translation of lifestyle intervention is not always easy or effective,” Cefalu and Matthew Riddle noted. “A major and lingering concern is how to maintain lifestyle changes and their beneficial effects over extended periods of time on a community basis.”
Tan agreed, recommending that intensive lifestyle modification should be the first step for individuals with prediabetes as they have an increased risk of developing diabetes. “In order to prevent future diabetes, they need to adopt an intensive lifestyle modification with at least 5-10 percent loss of weight and moderate intensity physical activity of at least 30 minutes daily. This is able to reduce their future risk of T2D by more than half,” he said.
Nonetheless, he also recognized the challenges of maintaining lifestyle changes in the long term. “Human will or the lack of, combined with the demands of work and life on one’s time are the universal barriers to long-term adherence,” said Tan.
“In order to be successful for diabetes prevention efforts, we need to continue to address these hurdles for successful lifestyle modification in a real-world setting,” Cefalu and Matthew stated.
Time ripe for a prevention indication?
“There is continued interest in preventive pharmacotherapy as an adjunct to lifestyle modification, and metformin continues to be the leading candidate. Its long-term efficacy and safety are well established,” the editorialists noted.
The same sentiment was echoed by Tan, who said “It is the drug of choice when pharmacologic management is warranted in [people with] prediabetes.” Also, he noted that generic metformin costs only a few cents a tablet, which means a wide access for patients.
According to Tan, he would consider initiating metformin in individuals with prediabetes who are unable to adopt intensive lifestyle modification due to, for example, physical infirmities, who have failed to attain the goals of intensive lifestyle modification within a pre-agreed time frame, whose blood glucose and/or HbA1c is trending upwards despite intensive lifestyle modification, or as an adjunct to intensive lifestyle modification in high-risk individuals as outlined in ADA’s position paper.
“Despite a clear need for better means of preventing diabetes, the lack of a formal prevention-related indication for metformin is and will remain a significant barrier to more widespread use,” lamented Cefalu and Matthew. “[These latest findings] further support the rationale for metformin as the most likely candidate for preventive strategies.”
“There is always resistance to starting pharmacologic treatment especially when prediabetes is regarded not as a disease-state but as a risk factor. It helps to overcome the resistance with a healthy fear of the condition we are trying to prevent - diabetes, the acknowledgement that it can be hard to achieve and maintain lifestyle modification and that the medicine advocated is time-tried and tested for over 60 years,” Tan added.