What are key pharmacologic recommendations in the management type 2 diabetes based on updated 2023 American Association of Clinical Endocrinologists (AACE) type 2 diabetes algorithm and 2024 American Diabetes Association (ADA) guidelines?

Introduction
Type 2 diabetes (T2D) is a metabolic disorder characterized by insulin resistance and insulin secretion impairment, which results in uncontrolled hyperglycemia.¹ Insulin secretion declines over time, affecting fat, carbohydrate, and protein metabolism. Type 2 diabetes has a gradual onset and generally occurs after 30 years of age. Chronic complications that can occur include microvascular, macrovascular, and neuropathic disorders. Type 2 diabetes is a risk factor for heart disease and stroke and is also the leading cause of blindness and kidney failure. Nearly 38.4 million children and adults in the United States have T2D, and the disease was estimated to contribute to 399,401 deaths in 2021.² Approximately two-thirds of these deaths were due to cardiovascular events or complications. Risk factors for developing T2D include family history, obesity, ethnic groups other than European ancestry, physical inactivity, prediabetes, elevated triglycerides, low levels of high-density lipoprotein cholesterol, and a history of gestational diabetes.¹ Diagnosis of T2D is made based on glycated hemoglobin A1C (A1C) values, fasting plasma glucose (FPG), a 2-hour oral glucose tolerance test (OGTT), or the presence of symptoms (although T2D patients are often asymptomatic). One or more of the following laboratory values are diagnostic of diabetes: A1C ≥ 6.5%, FPG ≥ 126 mg/dL, plasma glucose ≥ 200 mg/dL during OGTT, or a random plasma glucose ≥ 200 mg/dL in patients with symptoms of hyperglycemia.

The treatment of T2D is aimed at preventing complications, reducing the risk for heart disease and stroke, decreasing mortality, and improving quality of life.¹ Goals are set for glycemic, blood pressure, and lipid control. Diet and lifestyle changes can help improve these metabolic parameters, but pharmacologic intervention is usually necessary for adequate control. The American Diabetes Association (ADA) goals for glycemic control for most nonpregnant adults are an A1C < 7%, with preprandial and postprandial plasma glucose of 80 to 130 mg/dL and < 180 mg/dL, respectively.³ The American Association of Clinical Endocrinologists (AACE) have set lower target values, with an A1C of ≤ 6.5%, for patients without concurrent serious illness and at low hypoglycemic risk, and preprandial and postprandial plasma glucose of < 110 mg/dL and < 140 mg/dL, respectively.⁴ A less stringent A1C goal of 7% to 8% is recommended by the AACE for patients with a history of severe hypoglycemia, hypoglycemia unawareness, a short life expectancy, advanced renal failure, several concomitant illnesses, or long-standing diabetes for which an optimal A1C goal has been difficult to attain.

Various agents are available for the treatment of T2D, including metformin, sulfonylureas, thiazolidinediones, incretin mimetics (glucagon-like peptide-1 [GLP-1] receptor agonists and dipeptidyl peptidase-4 [DPP-4] inhibitors), sodium-glucose cotransporter-2 (SGLT-2) inhibitors, alpha-glucosidase inhibitors, meglitinides, amylin mimetics, and insulin.^{4, 5} These agents vary in their effectiveness to achieve targeted glycemic control, effects on cardiovascular outcomes, risk of hypoglycemia and weight gain, and the potential for other adverse effects. The purpose of this article is to give a general overview of pharmacologic treatment recommendations for individuals with T2D based on the updated recommendations from the 2023 AACE T2D treatment algorithm and the 2024 ADA guidelines.

AACE Guideline Recommendations
The AACE updated their comprehensive diabetes management algorithm in 2023 to align with the 2022 AACE clinical practice guideline on diabetes.^4,6 Lifestyle optimization, with weight loss, increased physical activity and healthy dietary changes, is recommended for all patients with prediabetes and diabetes. Management of any comorbid conditions, such as hypertension or hyperlipidemia, is also stressed, and choice of antihyperglycemic therapy considers glycemic targets as well as comorbidities. Pharmacologic therapy is based on presenting A1C with goal A1C dependent on an individual patient’s risk of hypoglycemia and comorbid conditions. For many patients, metformin is generally used as the first-line therapy. Other medications may be appropriate as first-line or in addition to metformin to reduce blood glucose levels and/or address certain comorbidities (such as cardiovascular disease [CVD], heart failure, chronic kidney disease [CKD], obesity, or non-alcoholic fatty liver disease), independent of glucose-lowering effects. For patients not responding to monotherapy (those with an A1C > 6.5% after 3 months) or for patients with an initial A1C > 7.5%, dual therapy is recommended. Individuals with an initial A1C > 9% or 1.5% above goal, dual or triple therapy should be started concomitantly. Dual therapy typically includes metformin plus another agent based on efficacy and comorbidities.

The AACE ranks additional therapies in order of preference based on risk factors, access considerations, and comorbid diseases.⁴ The preferred agents may differ based on patient factors and a patient-centric and shared-decision making approach is recommended to choosing therapy. For example, in an overweight or obese patient, GLP-1 receptor agonists, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist combination, and SGLT-2 inhibitors are preferred. Those at high risk of hypoglycemia would benefit from addition of an agent associated with low risk of hypoglycemia, including GLP-1 receptor agonists, SGLT-2 inhibitors, dual GIP/GLP-1 receptor agonist, thiazolidinediones, or DPP-4 inhibitors. Individuals with newly diagnosed T2D and A1C ≥ 7.5% could be started concomitantly on metformin and an agent with low hypoglycemia risk, such as a GLP-1 receptor agonist, SGLT-2 inhibitor, or DPP-4 inhibitor. Clinicians should be cognizant of potential risks associated with medications, including weight gain or hypoglycemia. Triple therapy can be used for patients not responding to dual therapy. Insulin should be considered for patients with symptomatic hyperglycemia, an A1C > 10%, and/or basal glucose > 300 mg/dL, whether initially or while on dual or triple therapy. To accomplish a patient’s individualized A1C goal, antihyperglycemic drugs should be titrated to the maximally tolerated dose, and additional antihyperglycemic therapy should be considered if needed. Table 1 provides a summary of AACE pharmacologic recommendations for individuals with T2D and underlying cardiorenal risk factors based on individual comorbidities.

In individuals with T2D without established ASCVD or associated high-risk factors, a glucose-centric algorithm is provided, with metformin recommended as the first-line agent if no contraindications. Instead of a focus on comorbidities based on risk factors, there is a focus on individualization of glycemic target, with a hemoglobin A1c ≤6.5% appropriate for most patients or 7% to 8% if high risk for adverse effects from hypoglycemia and/or limited life expectancy. Table 2 provides a summary of AACE recommendations for medications if patients do not reach glycemic targets with metformin (or in place of metformin if contraindicated), for individuals with T2D but without high-risk factors for CVD, heart failure, stroke or transient ischemic attack, or CKD.

ADA Guideline Recommendations
Similar to the AACE guidelines, recommendations from the ADA stress a patient-centered approach, and pharmacologic intervention depends on whether the treatment goal for a specific patient is to reduce cardiorenal risk (in addition to complete cardiovascular management), or to achieve and maintain glycemic and weight loss goals.⁵ Typically, higher efficacy approaches have a greater likelihood of achieving glycemic goals. Agents with very high efficacy for glucose lowering include dulaglutide (high dose), semaglutide, tirzepatide, insulin, combination oral regimens, or combination injectable regimens. The other GLP-1 receptor agonists not included in very high efficacy, along with metformin, SGLT-2 inhibitors, sulfonylurea, and thiazolidinedione agents, are considered to have high efficacy for glucose lowering. Recommended below these, are the DPP-4 inhibitors, which have intermediate efficacy for glucose lowering. If A1C is still above target, triple therapy, followed by more complex injectable medication regimens, are recommended.

Notably, the 2024 guidelines specifically recommend inclusion of therapies that have demonstrated CVD risk reduction in individuals with T2D and established CVD or at high risk of CVD, which include SGLT-2 inhibitors canagliflozin, dapagliflozin, and empagliflozin, and GLP-1 receptor agonists dulaglutide, liraglutide, and semaglutide, in glucose-lowering regimens, regardless of metformin use or glycemic control.⁵ In patients with T2D and heart failure, an SGLT-2 inhibitor with proven heart failure benefits (canagliflozin, dapagliflozin, empagliflozin) is recommended. Additionally, in individuals with CKD and T2D on a maximally tolerated angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, an SGLT-2 inhibitor with evidence of reducing CKD progression (canagliflozin, dapagliflozin, empagliflozin) or a GLP-1 receptor agonist with proven CVD benefit (dulaglutide, liraglutide, semaglutide) if an SGLT-2 inhibitor is not tolerated or contraindicated, should be incorporated into glucose-lowering treatment. Table 3 provides a summary of ADA pharmacologic recommendations based on associated risk factors.

Conclusion
In conclusion, both the AACE and ADA guidelines for T2D stress a patient-centered approach based on glycemic goals, comorbidities, and cardiorenal risk. While metformin has traditionally been considered a first-line agent for all patients with T2D, it is generally used as the first-line therapy in individuals without cardiorenal risk factors or comorbidities. Other medications may be appropriate as first-line therapy to reduce blood glucose levels and/or address certain comorbidities (such as CVD, heart failure, CKD), independent of glucose-lowering effects. In patients without cardiorenal comorbidities or risk factors, other medications can be considered in a stepwise approach if glycemic targets are not reached with metformin alone, based on other considerations. The guidelines state that GLP-1 receptor agonists and SGLT-2 inhibitors with proven cardiorenal benefit should be used for patients with T2D at high risk of CVD, heart failure, and CKD.

References

1. Trujillo J, Haines S. Diabetes mellitus. In: Dipiro JT, Yee GC, Haines S, Nolin T, Ellingrod V, Posey LM, eds. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach. 12th ed. McGraw Hill; 2023. Accessed February 23, 2024. https://accesspharmacy.mhmedical.com/content.aspx?sectionid=269398080&bookid=3097&Resultclick=2
2. Centers for Disease Control and Prevention. National diabetes statistics report. Centers for Disease Control and Prevention. Updated November 29, 2023. Accessed February 23, 2024. https://www.cdc.gov/diabetes/data/statistics-report/index.html
3. American Diabetes Association. 6. Glycemic goals and hypoglycemia. Diabetes Care. 2023;47(Suppl 1):S111-S125. doi:10.2337/dc24-S006
4. Samson SL, Vellanki P, Blonde L, et al. American Association of Clinical Endocrinology Consensus Statement: Comprehensive Type 2 Diabetes Management Algorithm – 2023 Update. Endocr Pract. 2023;29(5):305-340. doi:10.1016/j.eprac.2023.02.001
5. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2023;47(Suppl 1):S158-S178. doi:10.2337/dc24-S009
6. Blonde L, Umpierrez GE, Reddy SS, et al. American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. Endocr Pract. 2022;28(10):923-1049. doi:10.1016/j.eprac.2022.08.002

Prepared by:
Rachel Brunner, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

March 2024

The information presented is current as February 23, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.