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ACP Recommends SGLT2i, GLP1 RA After Metformin to Manage Cardiorenal Comorbidities in Adults with Type 2 Diabetes


Based on the classes' cardio- and renoprotective benefits, the ACP recommends SGLT2i and GLP1RA as second-line therapy in adults with T2D who are most likely to benefit.

The American College of Physicians (ACP) on April 19 released updated recommendations on use of newer classes of pharmacologic agents for adults with type 2 diabetes (T2D).1

The revised guidance amends the organization’s 2017 iteration and now supports the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) as second-line therapy after metformin based on the large body of evidence demonstrating their cardiovascular and renal protective benefits. The guideline also makes clear that given the current high cost of both classes of medication a careful cost-benefit analysis is warranted when considering adding them to a treatment regimen.1

ACP issues guidelines on newer pharmacologic treatment for adults with type 2 diabetes/ image credit: medication pens:©felipecaparros/stock.adobe.com

“In addition to improving glycemic control, these newer diabetes medications may have beneficial effects on mortality, cardiovascular outcomes, and renal outcomes,” the ACP Clinical Guidelines Committee wrote. “Hence, pharmacologic management decisions may now explicitly include not only glycemic control but also considerations of prevention of CVD, congestive heart failure (CHF), and chronic kidney disease (CKD).”2

In fact, in their review of evidence for the update, the Committee did not consider the effects of the newer agents on glycemic control, focusing the new guideline instead on the associated clinical benefits.

The guideline comprises 2 new recommendations:

The first, in adults with T2D and inadequate glycemic control while taking metformin and using lifestyle modifications, ACP recommends adding either a SGLT2i or a GLP1RA, the former to reduce risk for all-cause mortality, major adverse cardiovascular events, progression of chronic kidney disease, and hospitalization due to congestive heart failure and the latter to reduce the risk for all-cause mortality, major adverse cardiovascular events, and stroke. (Strong recommendation; high-certainty evidence).1

In recommendation 2 the ACP advises against adding a dipeptidyl peptidase-4 (DPP-4) inhibitor to metformin and lifestyle modifications in adults with T2D and inadequate glycemic control to reduce morbidity and all-cause mortality (Strong recommendation; high-certainty evidence).1

The updates are based on a systematic literature review and meta-analysis conducted to evaluate the effectiveness, comparative effectiveness, and harms of SGLT2i, GLP1RA, DPP-4 inhibitors, and long-acting insulins used as either monotherapy or in combination in adults with T2D.2 Reviewers conducted a search for randomized controlled trials (RCT) of at least 52 weeks duration published from 2010 through January 2023 with at least 500 adults participating. They identified 130 publications from 84 RCTs.2

ACP prioritized the following outcomes for the studies to be included, which were evaluated using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach: all-cause mortality, major adverse cardiovascular events, myocardial infarction, stroke, hospitalization for congestive heart failure, progression of chronic kidney disease, serious adverse events, and severe hypoglycemia.


Based on the cost effectiveness analysis conducted in conjunction with the literature review, the ACP concludes that GLP1RA and SGLT2i are of “low value” as first-line therapy for adults with T2D but may be of intermediate value when added to metformin or other therapies on board.3 The organization continues to support metformin as first-line therapy and considering additional therapies “only when glycemic goals are not met, or comorbidities warrant their use.”3

“As additional pharmacological treatments become available for the treatment of Type 2 diabetes, it’s critical for us to examine their effectiveness, the harms and benefits as well as costs in order to provide the best treatment for our patients,” Carolyn J Crandall, MD, MS, an internal medicine physician at the University of California Los Angeles School of Medicine and the chair of the Guidelines Committee said in an ACP statement.4 “Adding a second medication to metformin for patients with inadequate glycemic control may provide additional benefits but the added benefit on important clinical outcomes may be minimal in relation to the high cost, particularly for the more expensive, newer medications.”4

Among the clinical considerations enumerated as a summary of the guideline, ACP recommends shared decision making that individualizes treatment choices sensitive to patient preferences, glycemic targets, comorbidities, and risk for hypoglycemia.1 Collaborative care should include other specialties as needed and integrate dietary improvement, weight management, sleep health, and management of comorbidities and concomitant medications.1 The organization also calls for close attention to the impact on T2D of social determinants of health including racial and ethnic background and recommends linkage to community services.1

“This new evidence has expanded the treatment options and emboldened clinicians to use medications outside those commonly used as first-line therapy,” Fatima Z Syed, MD, MSc, a primary care internal medicine physician from Duke University Division of General Internal Medicine, wrote in an editorial accompanying the guideline.5 “The potential added benefits of these newer medications, including weight loss and cardiovascular and renal benefits, motivate their prescription, but cost and prior authorization hurdles can bar their use.”5

1. Qaseem A, Obley AJ, Shamliyan T, Hicks LA, Harrod CS, Crandall CJ. Newer pharmacologic treatments in adults with type 2 diabetes: A clinical guideline from the American College of Physicians. Ann Intern Med. Published online April 19, 2024. doi:10.7326/m23-2788
2. Drake T, Landsteiner A, Langsetmo L, et al. Newer pharmacologic treatments in adults with type 2 diabetes: A systematic review and network meta-analysis for the American College of Physicians. Ann Intern Med. Published online April 19, 2024. doi:10.7326/m23-1490
3. Schousboe JT, Landsteiner A, Drake T, et al. Cost-effectiveness of newer pharmacologic treatments in adults with type 2 diabetes: A systematic review of cost-effectiveness studies for the American College of Physicians. Ann Intern Med. Published online April 19, 2024. doi:10.7326/m23-1492
4. ACP issues clinical recommendations for newer pharmacological treatments of adults with type 2 diabetes. News release. American College of Physicians. April 19, 2024. Accessed April 19, 2024. https://www.acponline.org/acp-newsroom/acp-issues-clinical-recommendations-for-newer-pharmacological-treatments-of-adults-with-type-2
5. Syed FZ. Pharmacologic treatment of adults with type 2 diabetes: cost-effectiveness and comorbidity considertations. Ann Intern Med. Published online April 19, 2024. doi:10.7326/M24-0861

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