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Newer Pharmacologic Treatments in Adults With Type 2 Diabetes
abstract
This abstract is available on the publisher's site.
Access this abstract nowDESCRIPTION
The American College of Physicians (ACP) developed this clinical guideline to update recommendations on newer pharmacologic treatments of type 2 diabetes. This clinical guideline is based on the best available evidence for effectiveness, comparative benefits and harms, consideration of patients' values and preferences, and costs.
METHODS
This clinical guideline is based on a systematic review of the effectiveness and harms of newer pharmacologic treatments of type 2 diabetes, including glucagon-like peptide-1 (GLP-1) agonists, a GLP-1 agonist and glucose-dependent insulinotropic polypeptide agonist, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and long-acting insulins, used either as monotherapy or in combination with other medications. The Clinical Guidelines Committee prioritized the following outcomes, 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. Weight loss, as measured by percentage of participants who achieved at least 10% total body weight loss, was a prioritized outcome, but data were insufficient for network meta-analysis and were not rated with GRADE.
AUDIENCE AND PATIENT POPULATION
The audience for this clinical guideline is physicians and other clinicians. The population is nonpregnant adults with type 2 diabetes.
RECOMMENDATION 1
ACP recommends adding a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or glucagon-like peptide-1 (GLP-1) 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, progression of chronic kidney disease, and hospitalization due to congestive heart failure.
- Use a GLP-1 agonist to reduce the risk for all-cause mortality, major adverse cardiovascular events, and stroke.
RECOMMENDATION 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).
Additional Info
Disclosure statements are available on the authors' profiles:
Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Clinical Guideline From the American College of Physicians
Ann. Intern. Med 2024 Apr 19;[EPub Ahead of Print], A Qaseem, AJ Obley, T Shamliyan, LA Hicks, CS Harrod, CJ CrandallFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Benefits of GLP-1 agonists and SGLT-2 inhibitors
Two papers reviewed this week support the benefits of both GLP-1 agonists and SGLT-2 inhibitors. The first paper is the American College of Physicians Guidelines regarding the treatment of adults with type II Diabetes.1 The guidelines report strong evidence with high certainty for adding either a GLP-1 agonist or an SGLT-2 antagonist to lifestyle and metformin if needed.
GLP-1 agonists reduce the risk for all-cause mortality, major adverse cardiovascular events, and stroke.
SGLT-2 inhibitors reduce the risk for all-cause mortality, major adverse cardiovascular events, progression of chronic kidney disease, and hospitalization due to congestive heart failure.
The second was a population-based cohort study of patients with diabetes in the UK who were followed for 5 years.2 The researchers were able to compare the outcomes of patients receiving a GLP-1 agonist or an SGLT-2 inhibitor alone with those of patients receiving both. Compared with patients receiving either medication alone, those receiving both medications had improved outcomes. Specifically, the combination was associated with a 30% reduced risk of major adverse cardiovascular events and a 57% reduction of serious renal events when compared with using either drug alone. The confidence interval for renal events was broad (CI, 0.32–1.41).
In summary, these two studies provide evidence to support the use of an SGLT-2 inhibitor or a GLP-1 agonist after initiating lifestyle modifications and metformin therapy in patients with type II diabetes, and the use of a combination of both medications reduces the risk of major adverse cardiovascular events and renal events compared with using either alone.
References
Type 2 diabetes (T2D) has increased in prevalence worldwide, with higher risk for morbidity and mortality leading to an increased economic burden. The ADA/EASD 2022 consensus advocates a holistic person-centred approach to management, considering patients' preferences and highlighting three additional key components beyond glycaemic control: weight management, cardiorenal protection, and cardiovascular risk management.1 For cardiorenal protection, the ADA/EASD 2022 consensus suggests adding SGLT2 inhibitors (SGLT2i) or GLP-1 receptor agonists (GLP-1 RA) or a combination of these as needed, irrespective of metformin use. SGLT2i should be prioritised in patients with heart failure, risk of cardiovascular disease (CVD) or chronic kidney disease (CKD). GLP-1 RA should be prioritised in patients with risk of CVD or stroke. For weight management and maintenance, use of GLP-1 RA (semaglutide) or GIP/GLP-1 co-agonist (tirzepatide) are positioned early in management.
The recent publication of the American College of Physicians (ACP) clinical guideline consolidates what we know, but does not appear to make any new fundamental recommendations in what was suggested in the ADA/EASD 2022 consensus. Furthermore, the ACP continues to suggest metformin therapy as first-line treatment, followed by SGLT2i or GLP-1 RA as second-line treatment and does not recommend a combination of GLP-1 RA and SGLT2i. However, the current ACP guideline prioritises the use of SGLT2i or GLP-1 RA instead of DPP-4 inhibitors, sulfonylureas, and long-acting insulin due to their greater morbidity and mortality benefits. Moreover, the ACP has shed light on the similar cost-effectiveness of GLP-1 RA and SGLT2i, which is an essential area lacking in research. With regards to cost, the ACP makes a recommendation about use of future generic formulations once available. It is worth noting that there are formulations of GLP-1 RA and SGLT2i without positive cardiorenal outcomes; hence, prioritisation of formulations with proven cardiorenal outcomes in selected populations may be more appropriate. In contrast to the ADA/EASD 2022 consensus, tirzepatide has not been added to the ACP recommendations due to lack of cardiovascular outcome data, which are anticipated in 2025, despite the clinical trials demonstrating superior weight loss and glycaemic benefits compared with other comparators, including GLP-1 RA.
Although it may be challenging to incorporate the latest clinical trials into the guidelines, it is worth noting emerging studies that demonstrate the benefits of GLP-1 RA in 1) progression of CKD and 2) symptoms and physical function in people with heart failure with preserved ejection fraction, which may impact future recommendations.2,3 In summary, the ACP guideline targets patients with longstanding T2D, and escalation to second-line treatment is based on glycaemic control — conversely, an approach incorporating the four components of holistic care that the ADA/EASD 2022 consensus advocates may provide better overall outcomes for people with T2D.
References
Semaglutide 1.0 mg demonstrates 24% reduction in the risk of kidney disease-related events in people with type 2 diabetes and chronic kidney disease in the FLOW trial [company announcement]. Bagsværd, Denmark. Novo Nordisk; March 5, 2024. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=167028Butler J, Shah SJ, Petrie MC, et al. Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials. Lancet. 2024;403(10437):1635-1648. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)00469-0/abstract