Metformin

Introduction

Metformin (MET) is a biguanide that works by:

• Mainly suppressing excessive hepatic glucose production
• Increasing glucose utilization in peripheral tissues to a lesser degree.

MET may also improve glucose levels by reducing intestinal glucose absorption. Because MET does not stimulate endogenous insulin secretion, hypoglycemia does not usually occur when this drug is used alone, although hypoglycemia may occur if MET is taken with insulin, an sulfonylurea (SFU), or an excessive amount of alcohol. MET is not metabolized and is excreted unchanged by the kidneys.

MET has been used to treat patients with type 2 diabetes (T2D) for more than 60 years and is currently recommended as initial pharmacologic therapy in newly diagnosed patients concurrent with lifestyle intervention. Its antihyperglycemic properties are well established in preventing progression from prediabetes to frank T2D. The best evidence for this was demonstrated in the Diabetes Prevention Program (DPP) trial), which found that metformin therapy alone (with minimal lifestyle intervention) could reduce progression to diabetes by 31%. The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that the benefits of metformin extended beyond its antihyperglycemic properties: metformin-treated patients exhibited a risk reduction of 32% in any diabetes-related endpoint (P = 0.0002), 36% for all-cause mortality (P = 0.011) and 42% for diabetes-related death (P = 0.017) compared with placebo-treated patients.

Treatment with MET also has beneficial effects on plasma lipids that are greater than expected from improved glucose control alone: it lowers triglyceride and low-density lipoprotein (LDL) cholesterol levels while increasing high-density lipoprotein (HDL) cholesterol. In addition, MET therapy is associated with weight loss or less weight gain than other OADs; this may be particularly helpful in obese patients with T2D.

The effectiveness of metformin in reducing glycosylated hemoglobin (A1C) was assessed in a meta-analysis of 35 trials enrolling a total of 7960 patients with T2D and body mass index (BMI) ranging from 26.9 kg/m² to 34.5 kg/m². Metformin monotherapy reduced glycosylated hemoglobin (A1C) by 1.12% (95% confidence interval (CI), 0.92 to 1.32; P <0.00001). When added to other OADs or insulin, metformin reduced A1C by an additional 0.95% (95% CI, 0.77 to 1.13; P <0.00001) or 0.60% (95% CI, 0.30 to 0.91; P=0.0001), respectively, compared with comparator therapy (oral therapy or insulin therapy alone).

Side Effects of Metformin

The major side effects of MET are:

• Gastrointestinal (GI) effects, consisting mainly of mild diarrhea or loose stools
• Anorexia
• Nausea
• Abdominal discomfort.

For most patients, these side effects:

• Are transient
• Are dose-related
• Tend to decrease with chronic therapy.

Side effects can be minimized by:

• Slow dosage titration
• Decreasing the dosage (sometimes only temporarily)
• Taking MET with meals
• Switching to an extended-release formulation.

Lactic acidosis is a rare complication of MET therapy but has a high mortality rate. Most of the cases of MET-associated lactic acidosis occurred in patients for whom the drug was contraindicated (i.e., patients with renal dysfunction). In 2016, the Food and Drug Administration (FDA) concluded that metformin can be used safely in patients with mild kidney impairment and in some patients with moderate impairment. Based on this information, the FDA is requiring labeling changes for metformin-containing medicines to expand metformin’s use. When assessing kidney function, the FDA recommends that it be based on estimated glomerular filtration rate (eGFR) rather than measures based on a single laboratory parameter (e.g., blood creatinine concentration). Metformin is now contraindicated in patients with an eGFR of <30 mL/minute/1.73 m², and starting metformin is not recommended in patients with an eGFR between 30 and 45 mL/minute/1.73 m².

MET is also contraindicated in patients with significant hepatic disease, cardiac insufficiency, alcohol abuse and any hypoxic condition or history of lactic acidosis. MET should not be used in any patient with CHF (compensated or uncompensated) who is currently on a loop diuretic and/or digoxin. MET should be temporarily discontinued at the time of or prior to any dye studies so that serum MET levels are low if the patient develops renal failure from the dye. MET should be withheld for 48 hours subsequent to dye studies and reinstated only after renal function has been evaluated and found to be normal. In any patient who is hospitalized with an acute severe illness, MET should be temporarily discontinued until the condition improves. During such circumstances, insulin is generally the preferred form of therapy.

Prescribing Metformin

The recommended starting dosage of MET is 500 mg twice a day or 850 mg once a day given with meals. However, we suggest an initial dosage of 500 mg/day with dinner for 1 week, then twice daily with breakfast and dinner to improve tolerability. The dosage should be titrated slowly, as needed, toward a maximum daily dose of 2,550 mg. A third dose can be safely added at bedtime instead of at noon; compliance tends to be better. MET at bedtime works well to suppress hepatic glucose production overnight. Several weeks are required to observe the maximum effect of MET once a stable dosage is achieved.

MET is also available in an extended-release form (Glucophage XR, Fortamet, Glumetza). It can be taken once a day with equal efficacy compared with the short-acting form.

If the target A1C level is not met after 3 months of MET monotherapy, the ADA recommends initiation of dual therapy. In cases where the initial A1C level is 1.5-2% above goal, the ADA recommends considering combination therapy from the outset. Several types of drugs are available as second-line options when metformin monotherapy fails, including SFUs, TZDs, DDP4s, SGLT2s, GLP-1 receptor agonists, or basal insulin. None of these options have been established as the ideal choice; they all lower A1C when added to maximally tolerated metformin therapy but have differing hypoglycemic risks and effects on weight gain. If the target A1C level is not met after 3 months of dual therapy, a third antidiabetic drug of another class can be added to the treatment regimen.

MET/SFU Combination Therapy

A combination of MET/SFU is one type of dual therapy available. MET can be added to the regimen of patients who have not initially responded to SFUs (primary treatment failure), or to regimens of patients who initially responded to SFUs but who subsequently experienced a deterioration of glycemic control (secondary treatment failure). SFUs can also be added to the regimens of patients in whom MET therapy has failed. When MET is added to an SFU, the dose of the SFU should be maintained. Two MET/SFU combination drugs, Glucovance and Metaglip, are available on the market.

Metformin/Glyburide Combination (Glucovance)

A combination pill (Glucovance) is available that consists of MET and glyburide (glyburide 1.25 mg combined with MET 250 mg and glyburide 2.5 mg or 5.0 mg combined with MET 500 mg) (Glucovance, Table 8-1). In the monotherapy pivotal trials, Glucovance was more effective at lowering the A1C and fasting and PPG values when compared with MET or glyburide alone. Even though Glucovance combines two medications that have been available for many years, early combination therapy with two different drugs that have different mechanisms of action have shown advantages.

Metformin/Glipizide Combination (Metaglip)

A combination pill (Metaglip) is available that consists of MET and glipizide in various dosages (Table 8-1). Glipizide has a shorter duration of action and the metabolites have minimal hypoglycemic activity, leading to a lower rate of hypoglycemia compared with that which occurs with longer-acting SFUs.

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