Metformin: From Obscurity to Ubiquity

Thumb through or scroll down the print or online editions of Diabetes Care,JCEM, the New England Journal of Medicine, click on your inbox, or turn on your TV, and you’re bound to run across numerous articles or ads for one or more of the latest medications in our armamentarium against diabetes. From degludec to dulaglutide, we’ve come a long way from the many years when there was only one option: insulin.  

What about one of the oldest and most ubiquitous antidiabetes medications, metformin (Glucophage)? It’s the first-line therapeutic agent for many with type 2 diabetes mellitus (T2DM), it’s inexpensive, easy to dose, and has been around so long that you could say we slightly take it for granted.

To obscurity and back

Metformin has a history of fading into, only to rally from, obscurity. It arose from an herb, Galega officinalis (image above), which contains guanidine, an agent that can lower glucose. Synthetic derivatives were placed on the back shelf, as insulin was discovered, and the toxicity of the earlier forms was high. Interestingly, in the 1940s, these derivatives were revived during a quest for antimalarial agents. In 1957, Dr Jean Sterne reported the first use of metformin in diabetes. The FDA approved metformin for this indication in 1994, and it was first introduced in the US the following year.

As Cliff Bailey, MD, noted in a review of this agent in Diabetologia, “Metformin is unusual amongst pharmacotherapies as it does not appear to have a single mechanistic target: rather it counters insulin resistance and impacts metabolic, vascular and other physiological functions through multiple effects that are individually modest but collectively substantial.”¹

A few pearls about metformin
Here are some clinical pearls to keep in mind:

1. Start slowly.
Gastrointestinal adverse effects develop in approximately 10% of patients who take metformin. How can you minimize the potential for these effects, which include nausea, diarrhea, and stomach upset? Remember the adage, “Start low, go slow”? For patients who are new to metformin, recommend that they begin at 500 mg at dinner only for 7 days, then increase to 500 mg BID (breakfast and dinner).

While many patients may find that these adverse effects fade with time, what can you offer to those who may not tolerate the immediate-release form? Consider the extended-release (XR) version; the patient takes metformin only once a day.

2. Remember the new renal dose adjustment guidelines.
We were taught this absolute contraindication: to avoid metformin in men with a serum creatinine (SCr) level > 1.5 mg/dL, and in women with a level > 1.4 mg/dL. This advice was intended to lower the risk of lactic acidosis. Yet, this recommendation was based on clinical trial data of another agent in the biguanide class, phenformin, which had been removed from the market in 1977, as it demonstrated a higher risk of lactic acidosis and death.

In 2016, the FDA recommendations changed, based on data, including a large, observational study of 51,675 patients with T2DM that examined the effect of metformin on outcomes, such as all-cause mortality and cardiovascular disease, at different levels of renal function.² The FDA suggested using the estimated glomerular filtration rate (eGFR), rather than the SCr, as a more comprehensive gauge of renal function.

Here are the eGFR-based recommendations:
• < 30 mL/min/1.73 m²: Metformin is contraindicated.
• 30 - 45 mL/min/1.73 m²: Do not start metformin. Patients who are already taking this medication may continue with close monitoring, and you may consider reducing the dose by half.
• 45 - 60 mL/min/1.73 m²: Continue treatment; monitor renal function every 3 to 6 months.
• > 60 mL/min/1.73 m²: Patients can continue metformin without dose adjustments.

3. What about weight gain?
Among the many advantages of metformin-due to its effect on gluconeogenesis, and not on the insulin-secreting pathway-it is weight-neutral in most patients. In some, it may even yield a modest weight loss, of anywhere from 2 to 6.5 lb.

Dr Bailey captures this intriguing medication the best: “The awesome voyage of metformin from herbal beginnings to respected therapeutic agent has been turbulent. It was discovered, forgotten, rediscovered, repurposed, rejected, rescued, exonerated and may have further secrets to reveal.”

References:

1. Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60:1566-1576.

2. Ekström N, Schiöler L, Svensson AM, et al. Effectiveness and safety of metformin in 51,675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open. 2012;2.pii:e001076.