Arlington, VA—The American Diabetes Association (ADA) generally hasn’t weighed in about what medication should be added to metformin as a second agent in patients with type 2 diabetes.

That stance generally continues in the 2020 Standards of Medical Care, published in Diabetes Care, with authors advising, “The choice of medication added to metformin is based on the clinical characteristics of the patient and their preferences.”

For the first time, however, the ADA made a strong recommendation for what drugs should be used in diabetes patients who have atherosclerotic cardiovascular disease (ASCVD) or are at high risk for it. The document urges strong consideration for the use of sodium-glucose transport protein 2 (SGLT-2) inhibitors or glucagon-like peptide-1 (GLP-1 RA) receptor agonists.

“For patients with established or indicators of high ASCVD risk (such as patients ≥55 years of age with coronary, carotid, or lower-extremity artery stenosis >50% or left ventricular hypertrophy), established kidney disease, or heart failure, an SGLT-2 inhibitor or GLP-1 RA with demonstrated CVD benefit is recommended as part of the glucose-lowering regimen independent of A1C and in consideration of patient-specific factors,” the ADA writes in the revised statement.

The standards point out that, despite numerous trials comparing dual therapy with metformin alone, there is little evidence to support one combination over another for patients without ASCVD or significant risk factors.

“A comparative effectiveness meta-analysis suggests that each new class of noninsulin agents added to initial therapy with metformin generally lowers A1C approximately 0.7–1.0%,” according to the document. “If the A1C target is not achieved after approximately three months, metformin can be combined with any one of the preferred six treatment options: sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 RA, or basal insulin; the choice of which agent to add is based on drug-specific effects and patient factors.”

The ADA also discusses the growing importance of combination therapy and raises the question of whether more than one medication should be used beginning at diagnosis.

“Because type 2 diabetes is a progressive disease in many patients, maintenance of glycemic targets with monotherapy is often possible for only a few years, after which combination therapy is necessary,” the authors write. “Current recommendations have been to use stepwise addition of medications to metformin to maintain A1C at target. This allows a clearer assessment of the positive and negative effects of new drugs and reduces patient risk and expense; based on these factors, sequential addition of oral agents to metformin has been the standard of care.”

Yet the new guidance points to data supporting initial combination therapy for more rapid attainment of glycemic goals. It also states that a recent clinical trial has demonstrated that the combination approach is superior to sequential addition of medications for extending time to primary and secondary failure.

In the VERIFY trial, the document notes, participants receiving the initial combination of metformin and the dipeptidyl peptidase 4 inhibitor vildagliptin had a slower decline of glycemic control, compared with metformin alone and to vildagliptin added sequentially to metformin.

“These results have not been generalized to oral agents other than vildagliptin, but they suggest that more intensive early treatment has some benefits and should be considered through a shared decision-making process with patients, as appropriate,” according to the 2020 Standards of Medical Care. “Moreover, since the absolute effectiveness of most oral medications rarely exceeds 1%, initial combination therapy should be considered in patients presenting with A1C levels 1.5–2.0% above target.”

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