Updated Diabetes Guidelines: Metformin Remains First-Choice Pharmaceutical

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By: Jessica Bussey

Recently updated guidelines for diabetes medication have confirmed that metformin remains the preferred choice for management of type 2 diabetes cases requiring oral medication. The American College of Physicians (ACP) made the recommendations based upon the development and introduction of new FDA-approved diabetes drugs, as well as further research into existing medications.

A systematic review of randomized control trials formed the basis for the ACP’s guidelines. The studies included in the review investigated the efficacy of multiple different classes of oral type 2 diabetes medications, including metformin, thiazolidinediones (TZDs), sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium–glucose cotransporter-2 (SGLT-2) inhibitors. These medications were evaluated based upon their effects on hemoglobin A1c (HbA1c), weight, and systolic blood pressure, among other factors, as well as their associated adverse reactions. (A brief review of each class of medication can be found at the end of this article.)

Although all of the medications reduced HbA1c, metformin and sulfonylureas produced the strongest effects. SGLT-2 inhibitors, however, were superior to metformin in both weight and blood pressure reduction. Furthermore, metformin and SGLT-2 inhibitors used in combination therapy produced results superior to either medication used alone.

With respect to adverse side effects, metformin monotherapy was associated with a lower risk of hypoglycemia than other medications. In contrast, sulfonylureas increased this risk. Additionally, sulfonylureas and TZDs both increased the risk of weight gain when compared to other oral diabetes treatments.

Based on these results of the studies, the ACP concluded that metformin is more effective, cheaper, and associated with fewer negative side effects than other oral type 2 diabetes treatment options. Therefore, unless contraindicated, metformin monotherapy should be the first recommendation for oral pharmacological treatment of type 2 diabetes. If a second medication is required, the ACP recommends adding a sulfonylurea, TZD, SGLT-2 inhibitor, or DPP-4 inhibitor, depending on the case, as combination therapy may provide additional benefits to the patient. However, increasing medications can also result in an increased cost to the patient, and it may not always be worth the added expense or potential adverse effects.

Oral Diabetes Medications: A Review           

Metformin, an insulin sensitizer, works by both diminishing excess glucose production by the liver and increasing muscular sensitivity to insulin without affecting insulin production by the pancreas. It is renally excreted and safe for use in combination with most other oral diabetes medications. Additionally, metformin is associated with weight loss, an added benefit for overweight or obese patients. However, metformin is not recommended for patients with heart failure, kidney or liver dysfunction, alcoholism, or those over 80 years of age. Additionally, the use of contrast dye in some patients taking metformin has led to acute renal failure. Therefore, it should be discontinued 48 hours before, and not resumed until 48 hours after, a contrast dye procedure takes place.

TZDs, another type of insulin sensitizer, works similarly to metformin, in it increases the insulin sensitivity of muscle and adipose tissues. TZDs have the added benefit of increasing high-density lipoproteins and reducing diastolic blood pressure.3 However, they do increase the risk of both congestive heart failure and hepatotoxicity, so frequent cardiovascular and liver function tests are recommended.

Sulfonylureas, a class of insulin secretagogues, works by stimulating additional insulin production by pancreatic beta cells. However, hypoglycemia can result when sulfonylureas are used in conjunction with NSAIDS, anticoagulants, and certain antidepressants. Conversely, hyperglycemia may occur when used in conjunction with certain diuretics, corticosteroids, thyroid agents, and calcium channel blockers, therefore blood glucose levels should be monitored accordingly.

DPP-4 inhibitors, a newer class of oral type 2 diabetes medication, block the action of dipeptidyl peptidase-4, which is responsible for degrading incretins, or hormones that stimulate insulin release. This process results in an increase in insulin and a resulting decrease in blood glucose. DPP-4 inhibitors are contraindicated in patients with pancreatitis, and providers should adjust dosage in patients with renal insufficiency to minimize the risk of hypoglycemia. Although these drugs have been approved for use, their long-term consequences have not yet been determined.

SGLT-2 inhibitors, the final class of oral type 2 diabetes medication examined in the studies, also represent a newer approach to oral diabetes treatment. These drugs block SGLT-2 receptors in the proximal tubules of the kidney, thereby decreasing the body’s reabsorption of glucose, as well as increasing renal glucose excretion. However, they can increase patients’ risks of ketoacidosis and urinary tract infections. Due to their newness in diabetes treatment, the long-term consequences of SGLT-2 inhibitor use are still being investigated.


1. Dotinga R. Metformin Still Best as First Type 2 Diabetes Treatment. Health Day News. https://consumer.healthday.com/diabetes-information-10/type-ii-diabetes-news-183/metformin-still-best-as-first-type-2-diabetes- treatment-718262.html Accessed February 15, 2017.

2. Qaseem A, Barry MJ, Humphrey LL, Forciea MA, for the Clinical Guidelines Committee of the American College of Physicians. Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline Update From the American College of Physicians. Ann Intern Med. [Epub ahead of print 3 January 2017] doi: 10.7326/M16-1860.

3. Lehman C and Charles CV. Oral Medications and Type II Diabetes. ARN Network. April/ May 2006; 10-11.

4. Pathak R, Bridgeman MB. Dipeptidyl Peptidase-4 (DPP-4) Inhibitors In the Management of Diabetes. Pharmacy and Therapeutics. 2010;35(9):509-513.

5. Food and Drug Administration website. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm446852.htm. Accessed February 15, 2017.

6. Food and Drug Administration website. http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm. Accessed February 15, 2017.


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