Why Select Extended-Release Metformin?

Jenny A. Van Amburgh, PharmD, BCACP, CDE

Disclosures

June 04, 2015

Question

When should extended-release metformin be recommended over immediate-release metformin?

Response from Jenny A. Van Amburgh, PharmD, BCACP, CDE
Assistant Dean of Academic Affairs; Clinical Professor, School of Pharmacy, Northeastern University; Director, Clinical Pharmacy Services & Residency Program, Harbor Health Services, Inc., Boston, Massachusetts

As the incidence of type 2 diabetes (T2D) increases, so does the development of treatment options. Metformin has robust evidence to demonstrate efficacy for glucose lowering in addition to microvascular and macrovascular benefits.[1,2,3] In the treatment and prevention of T2D, metformin acts by suppressing hepatic glucose production, decreasing intestinal absorption of glucose, and improving insulin sensitivity via enhancing peripheral glucose uptake, without an increased risk for hypoglycemia. Unless contraindicated due to renal impairment, metformin is recommended as a first-line agent for treatment and prevention of T2D.

Adherence and tolerability are often limited by the gastrointestinal (GI) side effects of metformin, such as diarrhea, nausea, and bloating. GI tolerability may be improved by administration with food and a dosing titration schedule starting with 500 mg daily, with weekly increases of 500 mg to reach a maximum clinically effective dose of 2000 mg/day given in divided doses.[2] Even with these strategies, GI side effects may persist, and the twice-daily dosing may lead to poor medication adherence or discontinuation altogether.

In an effort to improve GI absorption and tolerability, extended-release (ER) formulations were developed. Pharmacokinetic studies demonstrate that maximum metformin concentrations are reached within about 7 hours after administration with ER formulations, while immediate-release (IR) maximum concentrations are seen within about 2-3 hours.[1] The slower absorption with ER formulations allows for convenient once-daily dosing, which can improve adherence, particularly in patients taking multiple medications.

Existing literature supports similar or superior clinical efficacy and tolerability with metformin ER vs IR.[2,4,5,6]

In a randomized, double-blind, active-controlled trial, patients newly diagnosed with T2D were assigned to receive 1500 mg IR metformin twice daily or one of three ER formulations (1500 mg daily, 1500 mg twice daily, or 2000 mg daily). Incidence of adverse events was similar for all groups, and glycated hemoglobin (A1c) reductions ranged from -0.73% to -1.06% in the ER groups vs -0.70% in the IR group.[4]

In another randomized, double-blind, parallel trial comparing metformin IR 500 mg twice daily vs ER 1000 mg or ER 1500 mg once daily, A1c changes were similar among all three groups at 24 weeks. However, a lower incidence of GI side effects was reported in the ER groups (29% and 32%, respectively) vs 39% in the IR group.[5]

Likewise, a multisite retrospective analysis study found that GI side effects were reduced in patients transitioned from IR to ER metformin (26.34% vs 11.71%, P = .0006).[6]

In a similar multisite analysis in the United Kingdom, about 90% of patients who found metformin IR intolerable due to adverse GI effects were able to tolerate an ER formulation instead.[7] Similar results demonstrating improvements in GI tolerability and adherence with metformin ER formulations were found in other trials as well.[8,9]

With evidence demonstrating microvascular and macrovascular benefits, metformin will continue to remain a cornerstone in the management of T2D. Clinicians should not immediately rule out metformin use in patients who do not initially tolerate it but should employ adherence counseling and/or consider transitioning to an ER formulation. Metformin ER has been proven to be safe, effective, and better tolerated than IR formulations. Extended-release formulations may help optimize the medication's benefits and long-term clinical outcomes.

The author wishes to acknowledge the assistance of Josephine Aranda, PharmD, RPh, Lisa Cillessen, PharmD, RPh, and Amy Thein, PharmD, RPh, PGY1 Residents, at Northeastern University—School of Pharmacy, in collaboration with Federally Qualified Health Centers & the Program of All-Inclusive Care for the Elderly, Boston, Massachusetts.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....