According to the American Diabetes Association (ADA), about 29 million Americans have diabetes mellitus (DM). Uncontrolled DM causes various microvascular and macrovascular complications and leads to significant mortality. In 2011, DM was the seventh leading cause of death.1 The ADA recommends setting a hemoglobin A1c (HbA1c) goal of < 7% to prevent microvascular and macrovascular complications.1
The treatment cost of DM continues to rise and accounts for about $245 billion annually.1 Given its effectiveness, low cost, and low adverse-event (AE) profile, metformin has been the cornerstone of therapy in DM over the past 20 years. The ADA recommends metformin as first-line therapy in type 2 DM (T2DM). In 2014, 14.4 million Americans were dispensed a metformin-containing product.2 Metformin exerts its effect mainly by decreasing hepatic glucose production and increasing insulin sensitivity. Study results suggest gluconeogenesis may be decreased up to 75% in these patients.3 Metformin is effective in reducing the level of HbA1c by an average of 1.5%.3
Background
Metformin-induced lactic acidosis is a rare concern in patients with renal impairment (0.03 case/1,000 patient-years).4 Much of this concern stems from the high incidence of lactic acidosis associated with the medication phenformin, which was approved in the 1950s but taken off the market because of its high incidence of lactic acidosis in patients with a serum creatinine (SCr) level > 1.4 mg/dL.
Although phenformin and metformin are both biguanide class medications, they vastly differ. Increased phenformin levels in the blood are correlated with decreased glucose oxidation and increased lactate production. Conversely, metformin may enhance glucose oxidation, and there seems to be no correlation between metformin levels with lactate levels. Lactic acidosis occurred 10 to 20 times more often with phenformin than it does with metformin.5 In studies in which patients with an estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m2 continued to use metformin, lactic acidosis was rare, even in the presence of comorbid conditions that may promote lactic acidosis, such as chronic obstructive pulmonary disease, congestive heart failure, and liver disease.6 In 2012, the National Kidney Foundation (NKF) suggested an eGFR cutoff be considered when prescribing metformin.7
When the present study was initiated, metformin was contraindicated in patients with renal dysfunction (SCr levels ≥ 1.5 mg/dL in males≥ 1.4 mg/dL in females).5 The estimated incidence of renal dysfunction in patients with T2DM is 12%. Under this labeling, metformin use is prohibited in at least 2.5 million people. Study results have shown that, when package insert guidelines were disregarded and metformin was given against renal recommendations, the rate of AEs was not increased, and patients benefited clinically.8 Data suggest that the rate of lactic acidosis may be increased in patients with advanced kidney disease.8
In April 2016, the FDA started requiring that manufacturers update their labeling to indicate metformin may be used safely in cases of mild-to-moderate renal impairment. The FDA also changed a recommendation: now, before starting metformin, health care professionals should obtain the patient’s eGFR, which provides a more accurate determination of kidney function by taking into account age, sex, and race. Metformin is contraindicated in patients with an eGFR < 30 mL/min/1.73 m2 and is not recommended to be initiated in patients with an eGFR of 30 to 45 mL/min/1.73 m2. The suggestion for patients already using metformin is to obtain eGFR at least annually. In addition, when eGFR drops to between 30 and 45 mL/min/1.73 m2, the risks and benefits of continuing metformin should be weighed on a patient-specific basis.2,4
Methods
The authors retrospectively reviewed the charts of 199 randomly selected patients at Huntington VAMC in West Virginia who had metformin discontinued because of elevated SCr (defined as ≥ 1.5 mg/dL) between September 1, 2009 and September 1, 2014. Clinician notes written at time of discontinuation were assessed for other reasons for discontinuation, and patients thus identified were excluded. Change in glycemic control was assessed by comparing first HbA1c level 60 to 365 days after discontinuation of metformin with the most recent HbA1c level before discontinuation. Other data analyzed included age, time to next recorded SCr level, reinitiation of metformin (yes or no), and change in diabetic medication regimen. Class of medication initiated was recorded but not dose or insulin type. Subgroup analysis was performed on patients initiated on insulin after discontinuation of metformin. Evaluations were made of most recent HbA1c level at time of discontinuation of metformin, first HbA1c level after discontinuation, and HbA1c level 1 year after discontinuation in patients on insulin.
The primary endpoint of the study was change in HbA1c after discontinuation of metformin. This was studied to justify the value of metformin in T2DM and to evaluate whether patients could remain on metformin with mild-to-moderate renal impairment without AEs. Secondary endpoints were time to next recorded SCr level after discontinuation of metformin, reinitiation of metformin (yes or no), when next recorded SCr level was < 1.5 mg/dL, change in medication regimen after discontinuation of metformin, and incidence of lactic acidosis. Study inclusion criteria were male sex, age between 18 and 89 years, discontinuation of metformin because of elevated SCr, and documented repeat HbA1c level 60 to 365 days after discontinuation of metformin. Exclusion criteria were insulin therapy at time of discontinuation of metformin and type 1 DM diagnosis. A 2-sided t test was used to compare change in HbA1c level.