Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Clinical Guideline From the American College of Physicians

Abstract

Description: 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).

Figure 1.

Grading the certainty of evidence and strength of recommendations in ACP clinical guidelines using GRADE. ACP = American College of Physicians; GRADE = Grading of Recommendations Assessment, Development and Evaluation.

Figure 2.

Summary of CGC interpretation of evidence for newer diabetes medications compared with usual care or placebo. Favors intervention (green) or favors comparator (red; not present in this figure) indicates a statistically significant difference between the intervention and comparison or a meaningful difference in effect size (i.e., ≥25% increase or decrease) with 95% CIs not crossing both lower (0.75) and upper (1.25) bounds. Italicized interpretation text indicates statistically significant findings. Statistics are from the American College of Physicians (ACP)–funded systematic review and network meta-analysis (24) available in Supplement Tables 1 to 4 (available at Annals.org). Interpretation of findings was done by the CGC. CGC = Clinical Guidelines Committee; CHF = congestive heart failure; CKD = chronic kidney disease; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; MACE = major adverse cardiovascular events; MI = myocardial infarction; SAE = serious adverse event; SGLT-2 = sodium–glucose cotransporter-2. * SAEs were defined by investigators, varied, and were not always fully reported. In general, these SAEs included events considered fatal or life-threatening and incorporated events (e.g., stroke, MI) that could also be a clinical benefit (through a reduction) with type 2 diabetes treatment (24). Long-acting insulins and sulfonylureas directly cause hypoglycemia and were used either as a direct comparator or within usual care, which may distort findings.

Figure 3.

Summary of CGC interpretation of evidence for DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors compared with other active treatments. Favors intervention (green) or favors comparator (red) indicates a statistically significant difference between the intervention and comparison or a meaningful difference in effect size (i.e., ≥25% increase or decrease) with 95% CIs not crossing both lower (0.75) and upper (1.25) bounds. Italicized interpretation text indicates statistically significant findings. Statistics are from the American College of Physicians–funded systematic review and network meta-analysis (24) available in Supplement Tables 1 to 4 (available at Annals.org). Interpretation of findings was done by the CGC. CGC = Clinical Guidelines Committee; CHF = congestive heart failure; CKD = chronic kidney disease; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; MACE = major adverse cardiovascular events; MI = myocardial infarction; SAE = serious adverse event; SGLT-2, sodium–glucose cotransporter-2. * SAEs were defined by investigators, varied, and were not always fully reported. In general, these SAEs included events considered fatal or life-threatening and incorporated events (e.g., stroke, MI) that could also be a clinical benefit (through a reduction) with type 2 diabetes treatment (24). Long-acting insulins and sulfonylureas directly cause hypoglycemia and were used either as a direct comparator or within usual care, which may distort findings.

Figure 3.

Summary of CGC interpretation of evidence for DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors compared with other active treatments. Favors intervention (green) or favors comparator (red) indicates a statistically significant difference between the intervention and comparison or a meaningful difference in effect size (i.e., ≥25% increase or decrease) with 95% CIs not crossing both lower (0.75) and upper (1.25) bounds. Italicized interpretation text indicates statistically significant findings. Statistics are from the American College of Physicians–funded systematic review and network meta-analysis (24) available in Supplement Tables 1 to 4 (available at Annals.org). Interpretation of findings was done by the CGC. CGC = Clinical Guidelines Committee; CHF = congestive heart failure; CKD = chronic kidney disease; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; MACE = major adverse cardiovascular events; MI = myocardial infarction; SAE = serious adverse event; SGLT-2, sodium–glucose cotransporter-2. * SAEs were defined by investigators, varied, and were not always fully reported. In general, these SAEs included events considered fatal or life-threatening and incorporated events (e.g., stroke, MI) that could also be a clinical benefit (through a reduction) with type 2 diabetes treatment (24). Long-acting insulins and sulfonylureas directly cause hypoglycemia and were used either as a direct comparator or within usual care, which may distort findings.