The relaxing of the guidelines for metformin use in patients with kidney disease and the advent of slow-release formulations have expanded the population of patients who can benefit from this old drug.
Diabetes organizations around the world recommend metformin as first-line antihyperglycemic therapy for the treatment of type 2 diabetes [1–3]. This is in large part due to data demonstrating improved microvascular and macrovascular outcomes in patients with type 2 diabetes [4]. Additionally, the American Diabetes Association recommends continuing metformin, as long as it is tolerated and renal function allows [1]. When combined with insulin, metformin is associated with improved glucose control, less hypoglycemia, lower insulin doses, and favorable weight profile [5].
Relaxing restrictions in kidney disease
In 2016, the US Food and Drug Administration (FDA) revised its recommendation for use of metformin in patients with chronic kidney disease. They recommend using estimated glomerular filtration rate (eGFR) as basis for treatment decisions, with the guidelines listed below [6].
- Measure eGFR before starting metformin and at least annually thereafter.
- Metformin should not be started in patients with eGFR <45 mL/min per 1.732.
- It remains contraindicated in patients with eGFR <30 mL/min per 1.732.
- Withhold metformin before iodinated contrast procedures if the eGFR is 30–60 mL/min per 1.732.
In addition to these FDA recommendations, Inzucchi and co-authors [7] endorse the UK National Institute for Health and Care Excellence guidelines, which suggest reducing the maximal dose of metformin to 1000 mg in patients with eGFR 30–45 mL/min per 1.732.
Exploiting metformin’s gastrointestinal effects
The history of metformin dates back to the early 1900s, when Galega officinalis was found to be rich in guanidine and was shown to lower blood glucose in animals. In 1957, the glucose-lowering properties of dimethylbiguanide were reported and metformin was approved in the UK the following year [7]. It was approved in the USA in 1994, as adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes [8]. In 60 years of human use, metformin has been shown to effectively improve glucose levels, is weight-neutral, and has been shown to reduce micro and macrovascular complications [4, 9].
Metformin is absorbed mainly in the proximal small intestine, is not bound to plasma proteins, is not metabolized, and is 100% excreted by the kidneys. A significant proportion is accumulated within the mucosa of the small intestine [7]. Metformin improves glycemic control by several mechanisms, primarily by activation of adenosine monophosphate-activated protein kinase (AMPK) signaling pathway in the liver, small intestine, and skeletal muscle. Additional mechanisms have been identified, some of which are described below.
- In the liver, metformin also inhibits gluconeogenesis by non-AMPK pathways, in part by inhibition of mitochondrial electron transport [10, 11]. This mechanism may also decrease conversion of lactate to glycerol. It also decreases selenoprotein P, which is a hepatokine associated with insulin resistance [12, 13].
- In the small intestine, metformin stimulates L-cells to increase plasma glucagon-like peptide-1 [14, 15] with possible involvement of the gut–brain–liver axis to decrease glucose production [16].
- In the skeletal muscle, metformin enhances glucose disposal [17].
- Metformin also affects the gut microbiome [18] and bile acid metabolism [19].
It has become evident that the effect of metformin is, in large part, related to its effects on the gastrointestinal (GI) tract. When metformin is given orally, it induces greater glucose-lowering than when given intravenously [20]. This finding led to development of metformin delayed release (DR), which is designed to release at the pH associated with the lower jejunum and ileum (6.5), thus bypassing the major sites of metformin absorption. It has 50% lower plasma concentrations than metformin immediate release (IR) or extended release (XR), but, at similar blood concentrations, metformin DR has a 40% higher potency for glucose-lowering compared with metformin XR [21]. This product might extend the use of metformin to patients with even lower levels of renal function.
GI side effects and the solutions
The primary failure rate for metformin averaged 55% in UK primary care [22] and 44% at Kaiser Permanente [23]. Of the latter cohort, 23% of patients either did not fill their first prescription or took it very sporadically. At Kaiser Permanente, secondary failure rate was 42% at mean of 27.6 months after initiation. The rate of secondary failure was higher in younger patients, patients started >3 months after diagnosis, and those with longer duration of disease [23]. Neither of these studies were able to address failure due to GI side effects, including diarrhea and nausea. These are reported to occur in between 12% to 24% of treated patients, is not dose dependent, tended to occur early after starting the medication and result in discontinuation in about 5% [24]. In the package insert for Glucophage® IR and XR, diarrhea was reported in 53.2% and 9.6% of patients, respectively. Discontinuation due to diarrhea was reported in 6% and 0.6%, respectively [8]. Many clinicians report higher discontinuation rates, especially with generic versions of metformin.
In order to overcome the GI side effects of metformin IR, several slow release formulations have been developed, including XR and gastric retention (GR). A DR formulation is currently under development. The XR version is associated with a slower rate of release by imbedding metformin into a polymer which swells in contact with water, and covering the tablet with a permeable membrane technology. The GR version (Glumetza®) is designed to remain in the stomach and deliver metformin slowly to the upper GI tract over a prolonged period of time. The time to peak concentration ranges from 3 hours with IR to 6–7 hours with XR and 7–8 hours with GR formulations, allowing for once-daily dosing. The first XR product in the US was Glucophage® XR. In the package inserts, diarrhea was reported in 53.2% of patients treated with Glucophage® IR and 9.6% of those treated with Glucophage® XR. This compares to reports of diarrhea of 16.7% with Fortamet® and 12.5% with Glumetza®. None of these medications have been evaluated in head to head studies. However, GI tolerability was improved in a study of patient switched from metformin IR to XR preparations [25], and metformin XR was associated with increased adherence over metformin IR [26].
Metformin has been included in several fixed-dose combination (FDC) products, including IR, XR, and GR formulations. In general, FDC products have been shown to be associated with improved adherence [27], and those with the slow-release metformin formulations may be better tolerated. Another advantage of the FDC with metformin is that the formulation will be consistent over time.
Implications in the clinic
Given the key role that metformin plays in improving outcomes for patients with type 2 diabetes, the new renal guidelines are very important. Additionally, the newer slow-release formulations of metformin, either as single agent or FDC, might improve tolerability in patients previously considered to be intolerant to metformin. Clinicians should evaluate any patient with type 2 diabetes who is not taking metformin and consider restarting it according to the new FDA recommendations for chronic kidney disease. If a patient reports GI intolerance in the past, consideration should be given for a rechallenge with a slow-release formulation. Finally, B12 deficiency has been reported in patients on long-term metformin therapy, with low/borderline-low levels seen in around 20% of metformin-treated patients in the Diabetes Prevention Program, and those treated with proton-pump inhibitors disproportionately affected [28]. This highlights the need for monitoring vitamin B12 levels in these patients.