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

Scope and Purpose

This ACP clinical guideline is an update to the 2017 version (19) with evidence about the effectiveness and harms of newer pharmacologic treatments to reduce the risk for all-cause mortality, cardiovascular morbidity, and progression of chronic kidney disease (CKD) in adults with type 2 diabetes. In addition to incorporating network meta-analyses (NMAs), this clinical guideline adds key questions on patient values and preferences and economic evidence.

Newer pharmacologic treatments include glucagon-like peptide-1 (GLP-1) agonists (dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide), a GLP-1 agonist and glucose-dependent insulinotropic polypeptide agonist (tirzepatide), sodium–glucose cotransporter-2 (SGLT-2) inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), dipeptidyl peptidase-4 (DPP-4) inhibitors (alogliptin, linagliptin, saxagliptin, and sitagliptin), and long-acting insulins (insulin glargine and insulin degludec). The CGC did not consider studies of hospitalized adults with type 2 diabetes; type 2 diabetes management in adults with acute comorbid conditions, including acute stroke and myocardial infarction (MI); or adults with type 2 diabetes undergoing surgery or active cancer treatment.

Population

The patient population is nonpregnant adults with type 2 diabetes.

Intended Audience

The intended audience is physicians and other clinicians caring for adults with type 2 diabetes.

Guideline Development Process

The CGC developed this clinical guideline according to ACP’s guideline development methods (20) and its policy on disclosure of interests and management of conflicts of interest (21). The CGC used the Evidence-to-Decision framework when reporting evidence (Supplement Tables 1 to 5, available at Annals.org) and rated the recommendations using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach (22) (Figure 1). The Appendix (available at Annals.org) lists the key questions for the supporting systematic reviews (Appendix Table 1, available at Annals.org), describes the selection and definition of critical and important clinical outcomes, and details the methods used for the clinical guideline and systematic reviews. Supplement Tables 1 to 5 incorporate evidence from systematic reviews alongside interpretation and judgements made by the CGC, which are briefly summarized in Figures 2 and 3. ACP completes a Guidelines International Network Guideline Standards (23) reporting form for each clinical guideline it publishes, which can be found in the Network’s International Guidelines Library or on ACP’s website (www.acponline.org/clinical-information/guidelines/guideline-process).

Systematic Review of Benefits and Harms and Summary of the Evidence

This clinical guideline is based on an accompanying systematic review and NMA of randomized controlled trials (RCTs) with at least 12 months of treatment and follow-up that examined the benefits and harms of newer pharmacologic treatments in adults with type 2 diabetes (24). The systematic review and NMA was completed by the ACP Center for Evidence Reviews at Minnesota and funded by ACP.

Although the systematic review was not limited to add-on therapy in which a newer pharmacologic treatment of type 2 diabetes was added to usual care in adults with inadequate glycemic control, that is how most included studies were designed. The most common usual care medication in the included trials was metformin. In assessing the applicability of the evidence, the CGC considered glycemic control and lifestyle modifications directed by study investigators and physicians, prior treatments, risk for cardiovascular diseases (CVDs), presence of CKD, and comorbid conditions at baseline.

Outcomes of Interest

Benefits and Harms

The CGC, CGC Public Panel, and members of the topic expert panel for the systematic review independently rated the importance of clinical outcomes as “critical,” “important,” or “less important” for decision making (Appendix Table 2, available at Annals.org). The CGC prioritized the following outcomes for decision making: all-cause mortality, congestive heart failure (CHF) requiring hospitalization, major adverse cardiovascular events (MACE; generally defined as the occurrence of cardiovascular death, a nonfatal MI, or a nonfatal stroke), MI alone, progression of CKD, serious adverse events (SAEs), severe hypoglycemia, stroke alone, and weight change (as measured by achieving ≥10% total body weight loss). However, the Center for Evidence Reviews did not appraise the certainty of evidence for total body weight loss of 10% or more because data were heterogeneous and insufficient to include in the NMA. Glycemic control was not a prioritized outcome because all eligible medications have been shown to improve this surrogate measure.

Public and Patient Values and Preferences

The CGC assessed the evidence in the systematic review about values and preferences for newer pharmacologic treatments in adults with type 2 diabetes (Supplement Table 6, available at Annals.org). Evidence about public and patient values and preferences was identified through 2 sources, the accompanying review of research evidence conducted by the Center for Evidence Reviews and consultation with the CGC Public Panel. The CGC Public Panel was engaged in rating the importance of clinical outcomes, as well as providing their views on the findings from the systematic review about the benefits and harms of treatment options. In addition, the CGC Public Panel provided feedback on treatment selection preferences and guideline recommendations.

Costs

The CGC considered costs and the economic burden of care when assessing the value of the treatments. The Center for Evidence Reviews completed a separate systematic review (funded by ACP) (25) on the economic value of treatments based on willingness-to-pay thresholds for incremental cost-effectiveness ratio per quality-adjusted life-year gained reported in high-quality cost-effectiveness analyses applicable to the United States (26, 27). Average annual Medicare spending per beneficiary for type 2 diabetes medications is reported in Supplement Tables 7 and 8 (available at Annals.org). A summary of findings for the systematic review on cost-effectiveness analyses is in Supplement Table 9 (available at Annals.org).

Recommendations

A visual clinical guideline for this topic displaying a visual summary of the recommendations, rationales, and clinical considerations, alongside an interactive data visualization, is available at Annals.org (28).

Figures 2 and 3 provide an overview of the CGC’s interpretation of the summary of findings from the systematic review. Full summary of findings tables can be found in Supplement Tables 1 to 5.

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.

The only newer pharmacologic treatments of type 2 diabetes that reduced all-cause mortality compared with placebo or usual care were SGLT-2 inhibitors and GLP-1 agonists. However, after evaluating the benefits and harms of these pharmacologic classes, the CGC could not determine the superiority of one over the other. In addition, the most common usual care medication in the included trials was metformin. High-certainty evidence indicates that adding an SGLT-2 inhibitor to usual care reduces the risk for all-cause mortality, hospitalization due to CHF, and progression of CKD, and moderate-certainty evidence indicates that it probably reduces the risk for MACE compared with usual care (that is, background pharmacologic treatment and life-style modifications) (Supplement Table 1) (24). High-certainty evidence indicates that adding a GLP-1 agonist to usual care reduces the risk for all-cause mortality, MACE, and stroke (Supplement Table 1) (24). The CGC Public Panel considered the benefits and harms of SGLT-2 inhibitors and GLP-1 agonists and supported their use, which was consistent with the conclusions in the systematic review of studies on patient values and preferences (24).

When SGLT-2 inhibitors and GLP-1 agonists are compared indirectly (NMA), SGLT-2 inhibitors probably reduce the risk for hospitalization due to CHF, whereas GLP-1 agonists probably reduce the risk for stroke (Supplement Table 3) (24). Neither pharmacologic class causes severe hypoglycemia, but both are associated with various harms and carry specific warnings (24). Sodium–glucose cotransporter-2 inhibitors are associated with bone fractures, lower-limb amputations, urogenital mycotic infections, Fournier gangrene, orthostatic hypotension, euglycemic ketoacidosis, and other harms (24). Glucagon-like peptide-1 agonists are associated with thyroid C-cell tumors (in rodents), pancreatitis, acute gallbladder disease, diabetic retinopathy, and other harms (24). The analysis of SAEs was limited by variation in definition across studies, but it also included events that could be considered effectiveness outcomes (such as stroke and MI). As a result, newer therapies, such as SGLT-2 inhibitors, resulted in a reduction in SAEs compared with usual care (24), but this was likely attributable to how the outcome was measured as opposed to the treatment actually reducing SAEs.

Over study periods, SGLT-2 inhibitors and GLP-1 agonists resulted in total body weight loss (24). Inconsistent reporting of clinically important total body weight loss of 10% or more precluded accurate comparative assessment of this outcome by pharmacologic class (24). However, individual RCTs suggested that a higher percentage of participants had total body weight loss exceeding 10% with GLP-1 agonists than with usual care or long-acting insulins (24). Although all examined medications are indicated for improvement in glycemic control, primary study designs allowing postrandomization treatments in response to inadequate glycemic control, at the discretion of study investigators and physicians, precluded accurate assessment of comparative glycemic control by pharmacologic class (24).

The comparative evidence among all evaluated pharmacologic classes suggests that the most favorable net benefit is derived from an add-on SGLT-2 inhibitor or GLP-1 agonist (Supplement Tables 2 to 5) (24). Compared with long-acting insulins, SGLT-2 inhibitors may reduce and GLP-1 agonists probably reduce all-cause mortality (24). Compared with DPP-4 inhibitors, GLP-1 agonists probably reduce all-cause mortality. Sodium–glucose cotransporter-2 inhibitors probably reduce MACE compared with DPP-4 inhibitors and reduce MACE compared with sulfonylureas (24). The risk for severe hypoglycemia is lower with SGLT-2 inhibitors and GLP-1 agonists than with sulfonylureas and long-acting insulins (Supplement Tables 2 to 5) (24).

Beyond benefits and harms, a systematic review of cost-effectiveness analyses (25) did not demonstrate substantial enough differences between SGLT-2 inhibitors and GLP-1 agonists to warrant prioritizing one pharmacologic class over the other (Supplement Table 9). The systematic review found low-certainty evidence that both drug classes may have intermediate value (that is, an incremental cost-effectiveness ratio of $50000 to $150 000 per quality-adjusted life-year gained) compared with usual care consisting of metformin (25). Low-certainty evidence also suggests that a GLP-1 agonist (oral semaglutide) may be of low value (incremental cost-effectiveness ratio, >$150 000 per quality-adjusted life-year gained) compared with an SGLT-2 inhibitor (empagliflozin) (Supplement Table 9) (25).

Annual Medicare spending for brand formulations differs among individual treatments within and between pharmacologic classes (Supplement Tables 7 and 8). The cheapest brand formulation of an SGLT-2 inhibitor had lower annual per beneficiary spending in 2021 than the cheapest brand formulation of a GLP-1 agonist ($1480 vs. $2313) (Supplement Table 7). The CGC considered only Medicare annual spending data on each drug and recognized that injectable formulations may have additional costs.

In the systematic review of values and preferences and feedback from the CGC Public Panel, medication cost was also an important consideration for patients when making choices about pharmacologic treatments of type 2 diabetes. No generic SGLT-2 inhibitors or GLP-1 agonists currently exist, but these formulations may become available (Supplement Table 7).

Recommendation 2

ACP recommends against adding a dipeptidyl peptidase-4 (DPP-4) inhibitor to metformin and life-style modifications in adults with type 2 diabetes and inadequate glycemic control to reduce morbidity and all-cause mortality (strong recommendation; high-certainty evidence).

High-certainty evidence showed that add-on DPP-4 inhibitors, compared with usual care, result in no differences in all-cause mortality, MACE, MI, stroke, CHF hospitalization, CKD progression, or severe hypoglycemia (Supplement Table 1) (24). Evidence from the NMA suggests that DPP-4 inhibitors may increase hospitalization due to CHF and probably increase the risk for MACE and progression of CKD compared with SGLT-2 inhibitors (Figure 3). Compared with GLP-1 agonists, DPP-4 inhibitors probably increase all-cause mortality and hospitalization due to CHF and the risk for MACE (Figure 3) (24). The most common usual care medication in the included trials was metformin. In addition, the CGC Public Panel expressed a preference for not using DPP-4 inhibitors primarily because of a lack of benefits compared with SGLT-2 inhibitors or GLP-1 agonists. Low-certainty evidence from a cost-effectiveness analysis also suggested that DPP-4 inhibitors may be more expensive and less effective than sulfonylureas when added to metformin to treat type 2 diabetes (Supplement Table 9) (25).

Applicability

These recommendations apply to adults who have long-standing type 2 diabetes with an HbA1c level around 8% (mean range in included primary RCTs, 7.2% to 9.5%) despite use of usual care with such treatments as metformin and lifestyle modifications (24). The most common usual care medication in the included trials was metformin. Social risk factor data were infrequently reported (24). Limited data were reported in specific subgroup populations. Three RCTs required participants to have CKD, 4 required existing CVD or acute coronary syndrome, 3 required overweight or obesity, and 11 required participants to be “at risk for CVD” with varying definitions (24). Most individuals with type 2 diabetes had additional CVD risk factors, including obesity, hypertension, or a history of tobacco use (24). Evidence ultimately did not allow evaluation of differences in treatment effects in patients with established CVD or CKD (secondary prevention) compared with those who did not have these diseases (primary prevention) (24). Therefore, our recommendations apply to patients with type 2 diabetes with and without established CVD or CKD.

Clinical Considerations

Metformin (unless contraindicated) and lifestyle modifications are the first steps in managing type 2 diabetes in most patients (19, 29). When selecting an additional therapy, clinicians should consider the evidence of benefits, harms, patient burden, and cost of medications in addition to performing an individualized assessment of each patient’s preferences, glycemic control target, comorbid conditions, and risk for symptomatic hypoglycemia. Clinicians should prioritize adding SGLT-2 inhibitors in patients with type 2 diabetes and CHF or CKD.Clinicians should prioritize adding GLP-1 agonists in patients with type 2 diabetes and an increased risk for stroke or for whom total body weight loss is an important treatment goal.

Clinicians should prioritize adding SGLT-2 inhibitors in patients with type 2 diabetes and CHF or CKD.

Clinicians should prioritize adding GLP-1 agonists in patients with type 2 diabetes and an increased risk for stroke or for whom total body weight loss is an important treatment goal.

Clinicians should aim to achieve HbA1c levels between 7% and 8% in most adults with type 2 diabetes and deintensify pharmacologic treatments in adults with HbA1c levels less than 6.5% (29). An individualized glycemic goal should be based on risk for hypoglycemia, life expectancy, diabetes duration, established vascular complications, major comorbidities, patient preferences and access to resources, capacity for adequate monitoring of hypoglycemia, and other harms.

Self-monitoring of blood glucose might be unnecessary in patients receiving metformin combined with either an SGLT-2 inhibitor or a GLP-1 agonist.

When adding an SGLT-2 inhibitor or a GLP-1 agonist results in adequate glycemic control, clinicians should reduce or discontinue existing treatment with sulfonylureas or long-acting insulins due to increased risk for severe hypoglycemia.

Sulfonylureas and long-acting insulins are inferior to SGLT-2 inhibitors and GLP-1 agonists in reducing all-cause mortality and morbidity but may still have some limited value for glycemic control.

Benefits and harms of additional pharmacologic treatment beyond the initial add-on treatment are unknown (for example, a patient who receives metformin plus an SGLT-2 inhibitor but in the future receives an additional GLP-1 agonist). Further, clinical evidence on patient mortality, morbidity, and hospitalizations and economic evidence are lacking for use of SGLT-2 inhibitors and GLP-1 agonists as initial treatment for patients with type 2 diabetes.

Collaborative care plans should include integrated efforts with dietary improvement and weight management, sleep health, physical activity, stress management, and management of comorbidities and concomitant medications.

Type 2 diabetes management should be based on collaborative communication and goal setting among all team members, including clinical pharmacists, to reduce the risk for polypharmacy and associated harms.

Health systems should have a process in place to assess social risk factors. All relevant entities and stakeholders should intervene to connect adults with type 2 diabetes and adverse social risk factors to social and community services.

There are currently no generic SGLT-2 inhibitors or GLP-1 agonists, but these formulations may become available. Clinicians should prescribe generic medications when they are available rather than more expensive brand-name medications (30).

Clinicians and patients should discuss the cost of an add-on SGLT-2 inhibitor or GLP-1 agonist when selecting a medication from either drug class.

Clinicians should be attentive to patient race and ethnicity as a social risk factor for diabetes. Worse health outcomes for type 2 diabetes may be mediated by such factors as social determinants of health.

Interventions With No Recommendations

Evidence was inconclusive to develop recommendations for both add-on tirzepatide and add-on long-acting insulins to metformin and lifestyle modifications.

Evidence Gaps and Research Needs

Areas of Insufficient Evidence

Most included studies had shorter-term follow-up (treatment and follow-up range, 52 to 329 weeks), highlighting the need for longer-term studies to better understand the benefits and harms of newer treatments of type 2 diabetes. The evidence was very uncertain regarding predefined subgroups of interest, including demographic subgroups, treatment-naive patients, and patients with established CVD or CKD (24).

Evidence was insufficient or had low certainty regarding cost-effectiveness analyses directly comparing newer type 2 diabetes medications or pharmacologic classes (Supplement Table 9) (25).

Areas of No Evidence

For newer type 2 diabetes medications compared with usual care, evidence was not available on the effects of GLP-1 agonists for the progression of CKD and effects of tirzepatide on MI, stroke, hospitalizations for CHF, and progression of CKD. Evidence was not available on the effects of tirzepatide compared with other medications on MI, stroke, hospitalizations for CHF, and progression of CKD.

Evidence from RCTs was lacking for examined newer diabetes pharmacologic classes in patients with type 2 diabetes who have not been previously treated (24). The net benefit and cost-effectiveness of combined formulations or combined treatments with newer pharmacologic classes beyond glycemic control are currently unknown.

Supplementary Material