Love Affair With Metformin: Still Strong, or Time to Move On?

June 23, 2018

ORLANDO — A light-hearted debate on whether metformin should remain the first-line therapy for type 2 diabetes drew plenty of smiles and giggles from the audience here during the opening afternoon at the American Diabetes Association (ADA) 2018 Scientific Sessions.

One of the debating physicians, Alice Cheng, MD, of the University of Toronto, Ontario, argued against the motion, described metformin as being like "a first love in your teenage years — you believe first love never dies." But then, "you realize there are plenty of other fish in the sea and it's time to move on."

She then presented "five reasons to break up with metformin."

Arguing the opposite motion, Vanita R. Aroda, MD, of Brigham and Williams Hospital, Boston, Massachusetts, said simply: "Metformin has stayed tried and true in first-line therapy," and she pointed to numerous diabetes, endocrinology, and medical society guidelines from all over the world that all still state metformin therapy should be the first port of call for treating this disease.

Metformin Is Effective, Cheap, Safe, and Still Recommended as First-Line

Presenting first, Aroda displayed a host of slides illustrating the history of trials with metformin, demonstrating its efficacy, safety, and the fact that its role as initial therapy is "well established."

And "at $4 a month," it's hard to argue with the economics, she noted.

Newer drugs that have shown benefit in cardiovascular outcomes trials include the SGLT-2 inhibitors empagliflozin (Jardiance, Boehringer Ingelheim) in EMPA-REG OUTCOME and canagliflozin (Invokana, Johnson & Johnson) in CANVAS, and the GLP-1 agonists liraglutide (Victoza, Novo Nordisk) in LEADER and semaglutide (Ozempic, Novo Nordisk) in SUSTAIN-6.

But these studies were mainly conducted in patients with high-risk type 2 diabetes who had a long duration of disease and already had cardiovascular disease (CVD) or a number of risk factors for it.

"So these data do not directly translate to 87% of our population," requiring first-line therapy for type 2 diabetes, Aroda argued.

She also pointed to safety, acknowledging, "We all know the potential for gastrointestinal disturbances with metformin and B12 deficiency," but this pales in comparison to the numerous safety warnings issued for newer drugs over the past few years, she said.

And very recently, new research has shown that metformin can be used safely in patients with much more advanced renal disease than previously thought, she added

"Metformin monotherapy should be started at diagnosis of type 2 diabetes unless there are contraindications. Metformin is effective, safe, and inexpensive, and may reduce risk of cardiovascular events and death."

These were the conclusions of the most recent ADA 2018 Standards of Care, said Aroda as she rested her case.

Five Reasons Why: You Can't Save My Kidneys, My Heart, or My Life

In beginning her argument against metformin as first-line therapy, Cheng stressed: "I love metformin, the diabetes community loves metformin; indeed, the EASD last year dedicated a whole issue of Diabetologia to the drug, a kind of love letter."

But likening this relationship to a teenage romance, she then went on to cite all the reasons why she believes this love affair should end.

Firstly, metformin does not address many of the core pathophysiologies of type 2 diabetes, she argued, and secondly, "you do not improve metabolic parameters as well as other [drugs] can." Although metformin lowers HbA1c, it is fairly neutral when it comes to any benefits on weight, blood pressure, and lipids, for example.

Next, "you can't save my kidneys like other [drugs] potentially can," she noted, pointing to benefits on renal outcomes seen in many of the cardiovascular outcomes trials with the newer agents.

And "you cannot save my heart like the others can," she stressed.

Studies with these four newer medications [empagliflozin, canagliflozin, liraglutide, and semaglutide] have been able to demonstrate cardiovascular protection, with reductions in a primary composite cardiovascular outcome as well as some that showed reductions in other cardiac outcomes, such as hospitalization for heart failure, she detailed.

"These are claims that metformin cannot make in this day and age," Cheng argued.

And lastly, "You can't save my life like others can," she posited, citing reductions in mortality seen with empagliflozin and liraglutide.

"The numbers needed to treat [NNT] to prevent one death across landmark trials in patients with high cardiovascular risk are staggering," Cheng said, showing that with empagliflozin, the NNT is only 39 over 3 years and for liraglutide it is 72 over 3.8 years. This compares to an NNT of 30 over 5 years for simvastatin and 56 over 5 years for the antihypertensive ACE inhibitor ramipril.

And although Cheng acknowledged that many of the impressive results with newer agents have been seen in secondary prevention populations (patients with type 2 diabetes at high risk for or with existing CVD), she noted that some real-world trials (such as CVD-Real) have a more than 80% primary prevention population and "we are all eagerly awaiting the results from the primary prevention population of DECLARE with dapagliflozin."

"These agents may prevent death in a primary prevention we need to reconsider whether we should be using these agents earlier on," she urged.

In contrast, metformin “has shown no proven mortality benefit,” she concluded.

But We Can Still Be Friends...

Cheng noted however the numerous combination therapies that include metformin already on the market, including a number with the newer agents, such as metformin/SGLT-2 inhibitor combinations.

"So you are already playing the field," she joked. "But we can still be friends. Move on. It's just a chapter in the past. But don't close the book, just turn the page."

In rebuttal, Aroda pointed out the 50:50 vote in the audience as to whether to support the motion that metformin should remain first-line therapy or not, which didn't really change after hearing both sides of the argument.

"Why is there so much angst?" she wondered. The truth, she says, is that "the evidence is strongest for metformin right now."

Responding, Cheng picked up on the cost issue with regard to metformin. While it's true that "you can't beat $4 a month for metformin," the "true cost saving is changing the course of the disease itself," she stressed, by preventing or reducing, down the line, the microvascular and macrovascular complications of diabetes.

"While the best things in life are free, cheap is not always good, and you get what you pay for. Ask yourself: Which medication would you give your mother? And which one would you give your mother-in-law?" she concluded.

The debate ended on an amicable note, however, as both doctors agreed that it is more than likely that combination therapy will come to the fore very soon, with more and more patients being started on more than one diabetes drug concomitantly as more data emerge to show that this is likely the way to go.

Aroda is a consultant for Adocia, Astra Zeneca, Novo Nordisk, Sanofi, and had received research support from Astra Zeneca/BMS, Calibra, Eisai, Janssen, Novo Nordisk, Sanofi, Theracos. Cheng has participated in speakers bureaus, advisory boards, and/or acted as a consultant for Abbott, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, Servier, Takeda. She has received research support from Boehringer Ingelheim and Sanofi.

Follow Lisa Nainggolan on Twitter: @lisanainggolan1.  For more diabetes and endocrinology news, follow us on Twitter and on Facebook.


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