American Diabetes Association 78th Scientific Sessions:

Is Metformin Obsolete? Debating its Future in Managing Type 2 Diabetes

With Vanita R. Aroda, MD, and Alice YY. Cheng, MD

Making a very compelling argument in favor of maintaining the status quo, Vanita R. Aroda, MD, associate director of diabetes clinical research at Brigham and Women’s Hospital and on the faculty at Harvard Medical School in Boston, presented a strong rationale for keeping metformin as first-line therapy,1 in leading off the session—Should metformin remain the first-line therapy for type 2 diabetes?, at the 2018 American Diabetes Association (ADA) 78th annual meeting in Orlando, Florida.

In laying the groundwork for this debate, Dr. Aroda relied on the step-wise recommendations from the ADA Standards of Medical Care in Diabetes—2018 (See Figure 1),2 in which behavioral lifestyle intervention and metformin, as the “preferred initial pharmacologic agent” are the cornerstone of type 2 diabetes management.

Figure 1. Diabetes Care Recommendations

Step-wise approach to type 2 diabetes management remains the accepted practice.

Furthermore, Dr. Aroda presented "findings from a series of well-done studies, demonstrating the impact of current clinical care recommendations" in which metformin played a role.

Here is a quick overview of the trial findings:

  • UKPDS (n=5,102)3,4 and ADOPT (n=4,360)5 supported use of metformin as the preferred therapy for initial serum glucose reduction.
  • Look Ahead trial (n=5,145)6 showed the positive effects of intensive diet, exercise, and behavioral therapy focused on weight loss to address for next level care
  • STAMPEDE trial (n=150),7 indicated the benefits of surgery in people with obesity
  • Achieving more stringent Hemoglobin A1c goals in order to foster cardioprotective effects were offered in ACCORD (n=10,251),8 VADT (n=1,791)90 and ADVANCE (n=11,140).10
  • Finally, for patients with established cardiovascular disease, adding empagliflozin (EMPA-REG, n=7,020),11 and liraglutide (LEADER, n=9,341)12

Familiarity, Cost, and Guidelines to Justify Metformin Use

From level A evidence to application, 90% of the randomized control trials from 2003 to present supported the value of prescribing metformin at an initial diagnosis of diabetes.1 And, Dr. Aroda noted, “up to 80% of patients in cardiovascular disease (CVD) trials were taking metformin in the background.”

Probably two of the best reasons to support continued use of metformin is that a monthly prescription is likely to cost the patient about $4 a month,13 and it is weight neutral, unlike more intensive treatments, providing continued benefit for patients who are overweight,1 she said.

“The current standards and guidelines have recommended metformin as first-line pharmacotherapy since 2006.2,14 Current and future treatment strategies are limited by the lack of data evaluating long-term effects of newer medications started as initial therapy, whereas we have this longitudinal follow up and data with metformin,” said Dr. Aroda.

Let's Face It: There are More Effective Drugs to Consider 

Alice YY Cheng, MD, associate professor of medicine at the University of Toronto School of Medicine in Canada, argued against the continuing reliance on metformin.15 She was more forthright, making the case that change in medication management for type 2 diabetes is overdue given the availability of better therapeutic options.

To support this perspective, she offered “five reasons to break-up with metformin:”

  • It doesn’t meet core needs like the newer medications that also address several clinical endpoints and pathophysiology for the long-term.
  • Metformin falls short in improving glucose parameters for the majority of patients.
  • At best, metformin is weight neutral, but other indices such as blood pressure, lipids, and cardiovascular outcomes matter more.
  • While metformin may reduce CVD risk somewhat, that is so 1990s as there is no decreased in mortality attributed to metformin; yet, there are four medication classes with demonstrated cardioprotective effects. Primary outcomes data in Sustain 6 for primary outcomes,16 EMPA-REG for decreased hospitalizations/all-cause mortality,11 and CANVAS for a reduction in primary endpoints and hospitalizations.17
  • Most importantly, metformin does not reduce mortality while medications such as statins, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blocker (ARB), when added have been shown to achieve risk reductions in patients with type 2 diabetes.18,19

Metformin Been Eclipsed by News Medications

In effect, metformin has essentially been grandfathered in. A more realistic interpretation of therapeutic goals suggests that the role for metformin is narrowing,15 said Dr. Cheng. She made a case for viewing “the role of metformin in the bigger picture,” and challenged how we need to approach the use of metformin in the next decade.

The amassed evidence extends to new findings on novel mechanisms affecting the gut, brain, circulatory system, inflammation, and nervous system.15

To prevent or lessen long-term effects of diabetes, newer medications should be initiated earlier.Metformin has been eclipsed by newer medications aimed at reducing long-term effects of diabetes.

“Yes, there is still a place for metformin but other medications should take a more central role,” Dr. Cheng said acknowledging that it's not quite time to forgo metformin completely but the focus of diabetes management should be to initiate newer medications to prevent or slow the progress of micro- and macrovascular comorbidities much sooner.2,20

What we do therapeutically in early diabetes management will likely simplify the approach to care further into the course of the disease, said Dr. Aroda, “The critical opportunity presenting patients with diabetes now is that we can impact CVD morbidity and mortality sooner. That should become our primary management strategy.”

She added, “we must adapt trial designs to better account for the functions of the vast array of medications now available.”

Focus on Initiating Newer Interventions Earlier

“While all of the arguments put forth are valid, cheap is not always good and it’s more often true that you get what you pay for,” said Dr. Cheng with respect to the utility of metformin.

“The evidence basis for metformin as first-line therapy remains the strongest—for durability, long-term effects, and cardiovascular outcomes,” Dr. Aroda told EndocrineWeb. “Having said that, it is important to study newer medications in this population, and to better characterize long-term outcomes based on initial therapy.”  

It is just those outcomes, particularly the need to reduce co-morbidities and long-term risks that require more aggressive therapy,15 countered Dr. Cheng. And, she went a step further, “There is sufficient evidence to initiate combination treatment upfront and early on as the best strategy to provide the most efficacious diabetes management now.”

Next Summary:
Time to Rethink the Role of A1c in Patients with Diabetic Comorbidities
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