ACP releases guideline, systematic reviews on newer type 2 diabetes medications

ACP released a clinical guideline updating its recommendations on newer pharmacologic treatments of type 2 diabetes on April 19. The guideline, which replaces a 2017 version, was published by Annals of Internal Medicine and includes the following two recommendations:

1. 1. ACP recommends adding a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control (strong recommendation; high-certainty evidence). Use an SGLT-2 inhibitor to reduce the risk for all-cause mortality, major adverse cardiovascular events (MACE), progression of chronic kidney disease, and hospitalization due to congestive heart failure. Use a GLP-1 receptor agonist to reduce the risk for all-cause mortality, MACE, and stroke.
2. 2. ACP recommends against adding a dipeptidyl peptidase-4 (DPP-4) inhibitor to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control to reduce morbidity and all-cause mortality (strong recommendation; high-certainty evidence).

The recommendations were based on a systematic review of the effectiveness, comparative effectiveness, and harms of SGLT-2 inhibitors, GLP-1 receptor agonists, combined GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, DPP-4 inhibitors, and long-acting insulins as monotherapy or combination therapy in adults with type 2 diabetes. A total of 130 publications from 84 randomized controlled trials were identified. The review found that compared with usual care, both SGLT-2 inhibitors and GLP-1 receptor agonists reduce all-cause mortality and MACE, SGLT-2 inhibitors reduce progression of chronic kidney disease and heart failure hospitalizations, and GLP-1 receptor agonists reduce stroke risk. Serious adverse events and severe hypoglycemia are also less frequent with SGLT-2 inhibitors and GLP-1 receptor agonists than with insulin or sulfonylureas, the review noted. The review found that insulin, tirzepatide, and DPP-4 inhibitors do not reduce all-cause mortality compared with usual care.

The guideline was also accompanied by a systematic review of the drugs' cost-effectiveness that included nine cost-effectiveness analyses. The review's only high-certainty conclusion was that GLP-1 receptor agonists and SGLT-2 inhibitors provide low value as first-line therapy. Lower-certainty evidence suggested that these two classes may be of intermediate value when added to metformin or other background therapy compared with adding nothing. Compared with adding sulfonylureas, GLP-1 receptor agonists, DPP-4 inhibitors, and long-acting insulin analogues may all be of low value. As third-line treatment, all of the newer agents may be of low value compared with neutral protamine Hagedorn (NPH) insulin. Insulin analogues may be similarly effective as NPH but are more expensive, the review noted.

The author of an accompanying editorial made the case for considering individual patient factors when choosing a type 2 diabetes medication. "What is missing from the evidence presented is the nuance of comorbid conditions, particularly obesity," the editorial said. It mentioned the promising preliminary reports of the clinical effectiveness of tirzepatide, the first GIP/GLP-1 receptor agonist. "For a patient with a new diagnosis of type 2 diabetes who would benefit from weight loss, a GLP1 agonist rather than metformin might be appropriate initial therapy. … The cost-effectiveness of GLP1 agonists and SGLT2 inhibitors as initial diabetes therapy in the setting of various comorbid conditions warrants careful exploration," the editorialist wrote.