What is the difference in efficacy between metformin (biguanide) and metformin ER (extended release biguanide) in lowering Hemoglobin A1c (HbA1c) levels?

From the Guidelines

Metformin and metformin extended-release (ER) have similar efficacy in lowering HbA1c levels, with the most recent and highest quality study suggesting no significant difference between the two formulations 1. The key difference lies not in their effectiveness but in their administration and side effect profile. Metformin immediate-release is usually taken 2-3 times daily with meals, while metformin ER is taken once daily, improving adherence for many patients. Some of the benefits of metformin ER include:

• Improved tolerability due to fewer gastrointestinal side effects like diarrhea, nausea, and abdominal discomfort
• Once daily dosing, which can improve medication adherence
• Similar mechanism of action as metformin immediate-release, reducing hepatic glucose production, improving insulin sensitivity, and decreasing intestinal glucose absorption Both formulations are effective and safe, and metformin is recommended as a first-line treatment for type 2 diabetes due to its beneficial effects on A1C, weight, and cardiovascular mortality 1. The choice between metformin and metformin ER should be based on individual patient factors, such as tolerance to side effects and ability to adhere to the medication regimen. It's worth noting that metformin use is associated with an increased risk of vitamin B12 deficiency and worsening of symptoms of neuropathy, suggesting periodic testing of vitamin B12 levels 1. Overall, metformin ER may be a better option for patients who have difficulty adhering to a multiple-dose regimen or experience gastrointestinal side effects with metformin immediate-release, as it can provide similar efficacy with improved tolerability 1.

From the FDA Drug Label

Table 11: Mean Changes from Baseline *in HbA1c and Fasting Plasma Glucose at Week 24 comparing Metformin Hydrochloride Tablets vs Metformin Hydrochloride Extended-Release Tablets in Patients with Type 2 Diabetes Mellitus †an=68 Metformin Hydrochloride Tablets 500 mg Twice Daily Metformin Hydrochloride Extended – release Tablets 1000 mg Once Daily 1500 mg Once Daily Hemoglobin A 1c (%) Baseline Change at FINAL VISIT (95% CI) (n=67) (n=72) (n=66) 7.06 6.99 7.02 0.14 a 0.27 0.13 (–0.04,0.31) (0.11,0.43) (–0.02,0.28)

The difference in efficacy between metformin and metformin ER in lowering Hemoglobin A1c (HbA1c) levels is not significantly different.

• The change in HbA1c at week 24 was 0.14% for metformin hydrochloride tablets 500 mg twice daily, 0.27% for metformin hydrochloride extended-release tablets 1000 mg once daily, and 0.13% for metformin hydrochloride extended-release tablets 1500 mg once daily.
• The confidence intervals for these changes overlap, indicating no significant difference in efficacy between the two formulations 2. Key points:
• Metformin and metformin ER have similar efficacy in lowering HbA1c levels.
• The choice between metformin and metformin ER should be based on individual patient factors, such as tolerance and preference.

From the Research

Efficacy of Metformin vs Metformin ER in Lowering HbA1c

• The efficacy of metformin and metformin ER (extended release) in lowering Hemoglobin A1c (HbA1c) levels has been studied in several clinical trials 3.
• A study published in Diabetes Care in 2006 found that significant decreases in mean HbA1c levels were observed in all treatment groups, including those receiving metformin ER and immediate-release metformin 3.
• The study found that the mean changes from baseline to end point in the two groups given 1,500 mg extended-release metformin were not significantly different from the change in the immediate-release metformin group, whereas the 2,000-mg extended-release metformin group showed a greater decrease in A1C levels [-1.06%; mean difference (2,000 mg extended-release metformin - immediate-release metformin): -0.36 (98.4% CI -0.65 to -0.06)] 3.
• Another study published in Diabetologia in 2017 noted that metformin is widely considered to be the optimal initial therapy for patients with type 2 diabetes mellitus, due to its efficacy, low cost, weight neutrality, and good safety profile 4.

Comparison of Metformin and Metformin ER

• Metformin ER is designed to provide a slower release of the medication, which can help to reduce gastrointestinal side effects and improve patient compliance 3.
• The study published in Diabetes Care in 2006 found that once- or twice-daily extended-release metformin was as safe and effective as twice-daily immediate-release metformin and provided continued glycemic control for up to 24 weeks of treatment 3.
• However, other studies have noted that metformin's established role as 'foundation therapy' in type 2 diabetes may be challenged by newer glucose-lowering drugs with more robust evidence for cardioprotection 4, 5, 6.

Clinical Use of Metformin and Metformin ER

• Metformin is generally well-tolerated with minimal side effects and is affordable, making it a popular choice for the treatment of type 2 diabetes mellitus 6.
• However, recent data from glucagon-like peptide-1 receptor agonist and sodium-glucose cotransporter-2 inhibitor cardiovascular and renal outcomes trials have demonstrated additional protection from diabetes complications for some high-risk patients, which has impacted the guidelines for diabetes management 6.
• The initiation of newer glycemic-lowering medications with cardiovascular benefits should be considered in high-risk patients regardless of glycemic control or target HbA1c, but cost remains a major factor in determining appropriate treatment 6.