Updates in Glucagon-like Peptide-1 Receptor Agonist Use for Patients with Type 2 Diabetes to Maximize Glycemic and Non-Glycemic Outcomes

INTRODUCTION

Approximately 37.3 million people live with diabetes mellitus (DM) in the United States according to current estimates from the Centers for Disease Control and Prevention (CDC), which equates to 11.3% of the population.¹ The majority of patients with diabetes (≈90%-95%) have type 2 diabetes (T2D).¹ For people living with T2D, optimization of glycemic control and cardiovascular (CV) risk factors (e.g., blood pressure, cholesterol, and smoking cessation) are components of standard-of-care management to avoid and/or delay the progression of DM-related complications.² Microvascular (e.g., nephropathy, retinopathy, and neuropathy) and macrovascular (e.g., CV and cerebrovascular disease) complications are associated with considerable morbidity and mortality in people with T2D, as well as a significant cost to the healthcare system.¹ Unfortunately, data from the CDC indicate that between 2015 to 2018 only 18.2% of adults aged 18 years and older met combined glycemic, blood pressure, cholesterol, and smoking cessation goals (hemoglobin A1C [A1C] <7.0%, blood pressure <140/90 mm Hg, non–high-density lipoprotein cholesterol <130 mg/dL, and being a non-smoker).¹ There is opportunity for improvement for many of our patients with T2D by facilitating blood glucose control and better managing modifiable risk factors to prevent the development of DM-related complications. Fortunately, recently completed trials have identified agents from the glucagon-like peptide-1 receptor agonist (GLP-1 RA) and sodium-glucose cotransporter 2 (SGLT2) inhibitor classes as having important benefits on CV and kidney outcomes in patients with T2D. In turn, agents from these medication classes are increasingly recommended in clinical practice guidelines to improve glycemic control; promote weight loss; and mitigate CV, cerebrovascular, and kidney risk in appropriate patients.

Given the increasingly important role of GLP-1 RAs in clinical practice, it is important that all members of the healthcare team, including pharmacy professionals, understand current recommendations and patient-specific considerations for use. This review begins with a brief overview of the mechanisms of action of GLP-1 RAs, discusses current guideline recommendations for their use, compares and contrasts currently available GLP-1 RAs and key clinical considerations for their use, and briefly discusses evolving clinical applications for GLP-1 RA use. A brief discussion of the new dual incretin agonist, tirzepatide, is also included.

GLP-1 RA Mechanisms of Action

The term “incretin effect” (INtestinal seCRETion of INsulin) was created to describe the observation that oral administration of glucose induces a more robust insulin response compared with that of intravenous insulin infusion.³ This observation led to the discovery of incretin hormones in the gut that stimulate insulin release in the prandial state. The first incretin hormone discovered was glucose-dependent insulinotropic polypeptide (GIP) in the 1970s, followed by GLP-1 in the 1980s.⁴ Together, GIP and GLP-1 are important physiologic mediators of prandial insulin release and help to maintain normal glucose homeostasis. Endogenous GLP-1 is secreted from intestinal L cells following a meal.⁵ The beneficial metabolic effects of GLP-1 receptor activation occur through multiple complementary mechanisms. GLP-1 receptor activation stimulates glucose-dependent insulin secretion from pancreatic β cells, suppresses inappropriately elevated glucagon secretion from α-cells of the pancreas, delays gastric emptying, and induces satiety via a direct action in the central nervous system (Figure 1).⁶ Because the therapeutic potential of natural GLP-1 is limited due to its rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-4), GLP-1 RAs have been developed that are resistant to the DPP-4 enzyme.⁶

Currently available GLP-1 RAs can be divided into 2 general pharmacokinetic categories: short- and long-acting agents. Exenatide and lixisenatide are considered short-acting GLP-1 RAs with relatively short half-lives. Short-acting agents, which are dosed before meals, demonstrate strong effects on gastric emptying and are associated with strong postprandial glucose effects and more prominent gastrointestinal (GI) side effects.⁵ Liraglutide, dulaglutide, exenatide extended-release (XR), and injectable and oral semaglutide are considered long-acting agents. Long-acting agents can be taken any time of day without regard to meals. Because these agents have longer half-lives, their use produces more consistent activation of GLP-1 receptors.⁵ Longer-acting GLP-1 RAs have a more balanced effect on both postprandial and fasting blood glucose when compared with short-acting agents.⁵

Additional discussion of efficacy and safety considerations with these agents is in the Comparative Review of Available GLP-1 RAs section below.

GLP-1 RAs: Place in Therapy for Patients With T2D

An important factor that drives selection of an antihyperglycemic agent is the desire to mitigate CV and/or kidney risk. In consideration of the recently reported CV outcome trial (CVOT) and kidney outcome data, multiple organizations have published updated guidance over the last several years regarding the use of glucose-lowering agents in patients with T2D for organ protection. The following sections summarize key guidance published since 2019 with an emphasis on recommendations pertaining to the use of GLP-1 RAs. The American Diabetes Association (ADA) 2022 Standards of Medical Care in Diabetes will be discussed in detail, followed by a brief synopsis of other key guidance documents to highlight areas of commonality and key differences. While the information below is current at the time of this writing, clinical practice guidelines are updated regularly to reflect rapidly evolving evidence with GLP-1 RAs and SGLT2 inhibitors.

ADA 2022 Standards of Medical Care in Diabetes

The ADA annually publishes its Standards of Medical Care in Diabetes, with Living Standards Updates published online as needed when major studies or position statements are published and/or when new treatments are approved that warrant a change to the ADA’s clinical practice recommendations.⁷ Important updates were made to the 2022 Standards of Medical Care in Diabetes. They continue to emphasize a shared decision-making approach, in which patients and caregivers are actively engaged in care decisions as central members of the care team.² The Standards note that the goal of provider-patient communication is to establish a collaborative relationship that allows for the assessment of self-management barriers without blaming patients for “noncompliance” or “nonadherence” when outcomes are less than optimal. To emphasize this approach, the 2022 Standards continue to include a “decision cycle for patient-centered glycemic management in type 2 diabetes.” The ADA recommends that the decision cycle be undertaken at least once or twice annually to reevaluate patient needs and avoid clinical inertia, with the central goals of preventing complications and optimizing quality of life.² Figure 2 provides a simplified summary of the decision cycle.²

New in 2022, the ADA no longer recommends metformin as the preferred first-line agent in all patients with T2D.² The ADA now states that first-line therapy depends on comorbidities, patient-centered treatment factors (including cost and access considerations), and management needs.² Recommendations for intensification of glucose-lowering therapy also includes careful consideration of patient- and medication-related factors.

The following subsections summarize the overall approach recommended by the ADA for intensification of glucose-lowering therapies in patients with T2D, with an emphasis on the role of GLP-1 RAs within the current intensification algorithm and evidence-rated practice recommendations. Figure 3 provides a simplified summary of the ADA’s 2022 algorithm for intensification to a dual glucose-lowering medication regimen in T2D.²

Patients With ASCVD/Indicators of High Risk, HF, or CKD

Based on outcome trial data with agents from the GLP-1 RA and SGLT2 inhibitor classes, the paradigm for the management of patients with T2D has shifted from a glucose-centric approach to one of multifactorial risk reduction. Table 1 provides a summary of key CVOT data with agents from the GLP-1 RA class.^8-13 When intensifying glucose-lowering therapy in patients with T2D, the ADA first recommends considering whether the patient has atherosclerotic CV disease (ASCVD) or indicators of high risk (such as patients aged ≥55 years with coronary, carotid, or lower-extremity artery stenosis >50% or left ventricular hypertrophy), heart failure (HF), or chronic kidney disease (CKD) (Figure 3).² If a patient has 1 or more of these comorbidities, it is recommended that addition of an agent with evidence for CV, HF, or kidney risk reduction be considered independent of the patient’s current A1C or A1C target. These recommendations are stated as actionable whenever these comorbidities become a new clinical consideration, regardless of the background glucose-lowering regimen. The following sections provide additional discussion of comorbidity-specific recommendations based on the presence of ASCVD (or high risk), HF, or CKD.

Established ASCVD or indicators of high risk: The ADA recommends use of either a GLP-1 RA with proven CV benefit or an SGLT2 inhibitor with proven CV benefit in individuals with a history of ASCVD or indicators of high ASCVD risk.² Importantly, the ADA does not give preference for one class or the other. Agents are functionally defined to have “proven CV benefit” if they carry a labeled indication for reducing CV events.² Liraglutide, dulaglutide, and injectable semaglutide all carry an indication to improve CV outcomes.^14-16 For patients receiving either a GLP-1 RA or an SGLT2 inhibitor for CV risk reduction, the ADA recommends considering the addition of the other class if benefits outweigh risks (e.g., if already on a GLP-1 RA, add an SGLT2 inhibitor with proven CV benefit or vice versa) in addition to optimizing other guideline-directed medical therapies for prevention (Figure 4).²

Heart failure: GLP-1 RAs have not demonstrated benefit on secondary HF outcomes in large CVOTs (Table 1).^8-13 SGLT2 inhibitors, in contrast, have consistently demonstrated benefit on HF outcomes in completed CVOTs and in dedicated HF trials.² Both dapagliflozin and empagliflozin carry indications to improve HF outcomes.^17,18 Accordingly, the ADA specifically recommends use of an agent from the SGLT2 inhibitor class with proven benefit in patients with comorbid HF.²

Chronic kidney disease: For patients with T2D with CKD and albuminuria (e.g., ≥200 mg/g creatinine), the ADA preferably recommends use of an SGLT2 inhibitor with primary evidence of reducing CKD progression.² Both canagliflozin and dapagliflozin have demonstrated benefit in patients with T2D and CKD in dedicated kidney outcome trials and carry an indication for improving CKD outcomes.^19,20 High-level results from the EMPA-KIDNEY trial with empagliflozin have also been released and reported benefit on primary kidney outcomes.²¹ If an SGLT2 inhibitor cannot be taken due to a contraindication or drug intolerance, the ADA recommends the addition of a GLP-1 RA with proven CV benefit.² For patients with T2D and CKD (estimated glomerular filtration rate <60 mL/min/1.73m²) who do not have albuminuria, the ADA states that an SGLT2 inhibitor or a GLP-1 RA with proven CV benefit can be used. This recommendation is based on the considerable CV-related morbidity and mortality risk present in the CKD population.²²

Patients Without ASCVD/Indicators of High Risk, HF, or CKD

For patients without ASCVD/indicators of high risk, HF, or CKD, the addition of glucose-lowering agents is based on the need for additional glucose lowering to maintain glycemic goals. As illustrated in Figure 3, the decision of which agent(s) to add is based on 1 or more of 3 patient-centered considerations: (1) desire to minimize hypoglycemia; (2) desire to minimize weight gain or promote weight loss; and (3) consideration of cost and access barriers.² In consideration of their low risk of contributing to hypoglycemia and the potential for weight loss with treatment, GLP-1 RAs are recommended for consideration when it is desired to minimize hypoglycemia risk or minimize weight gain/promote weight loss.²

If selecting a GLP-1 RA preferentially for weight loss, the ADA recommends selecting an agent with good efficacy for weight loss.² Please see the section Comparative Review of Currently Available GLP-1 RAs for a discussion of weight loss effects within the class.

Patients Requiring Injectable Glucose-Lowering Therapy to Meet Individualized Glycemic Goals

Another key algorithm within the ADA 2022 Standards of CareMedical Care in Diabetes is related to intensification of injectable glucose-lowering agents in patients with T2D.² Notably, the ADA recommends that a GLP-1 RA be considered preferentially as the first injectable agent in most patients prior to insulin.² If patients are already on an injectable GLP-1 RA, or if insulin is preferred, it is recommended that patients initiate basal insulin. For patients requiring additional postprandial coverage, the ADA recommends considering the addition of a GLP-1 RA as an alternative to prandial insulin (assuming the patient is not yet using GLP-1 RA therapy).² Two fixed-ratio combination products (insulin glargine [U-100]/lixisenatide and insulin degludec [U-100]/liraglutide) are available commercially containing basal insulin plus a GLP-1 RA for patients who could benefit from this combination.^23,24

As illustrated above, GLP-1 RAs are prominently recommended within the ADA 2022 Standards of Medical Care in Diabetes for patients with T2D to meet individualized treatment goals—including glycemic and non-glycemic targets. Table 2 provides a summary of key ADA recommendations for use of GLP-1 RAs in patients with T2D.² For additional details and discussion regarding pharmacologic approaches to glycemic management, please refer to the full ADA 2022 Standards of Medical Care in Diabetes.²

AACE/ACE Comprehensive T2D Management Algorithm

The glycemic control algorithm recommended by the American Association of Clinical Endocrinology (AACE)/American College of Endocrinology (ACE) largely aligns with the ADA recommendations discussed above.²⁵ AACE/ACE similarly recommend a long-acting GLP-1 RA or SGLT2 inhibitor with proven efficacy in patients with T2D with established ASCVD or ASCVD risk factors, stage 3 CKD, or HF with reduced ejection fraction, independent of glycemic control.²⁵ AACE/ACE also recommend a GLP-1 RA or SGLT2 inhibitor with evidence of benefit as an option for monotherapy in patients with these compelling comorbidities.²⁵ Addition of a GLP-1 RA is likewise recommended as an alternative option to prandial insulin in patients requiring intensification of prandial control to meet individualized glycemic targets.²⁵

2022 DCRM Multidisciplinary Practice Recommendations

The 2022 DCRM (diabetes, cardiorenal, and/or metabolic) Multidisciplinary Practice Recommendations also stress the importance of GLP-1 RAs and SGLT2 inhibitors in mitigating CV and kidney risk in patients with T2D.²⁶ Similar to guidelines described above, the DCRM recommendations state that patients with T2D with established or at high risk for ASCVD, CKD, and/or HF should be prescribed agents with proven benefit independent of their effects on glucose. Figure 5 provides a summary of key recommendations related to use of glucose-lowering agents from the DCRM Multispecialty Practice Recommendations.²⁶

KDIGO 2020 Clinical Practice Guideline for Diabetes Management in CKD

The Kidney Disease: Improving Global Outcomes (KDIGO) 2020 Clinical Practice Guideline for Diabetes Management in CKD advocates for a multifaceted treatment approach targeting key modifiable risk factors associated with kidney and CV disease progression.²⁷ KDIGO recommends a first-line combination glucose-lowering regimen inclusive of metformin plus an SGLT2 inhibitor in patients with T2D and CKD if they do not have a contraindication to therapy. For patients not meeting individualized glycemic targets despite recommended first-line therapy, KDIGO recommends adding additional glucose-lowering therapies to improve glycemia.²⁷ In this situation, KDIGO preferentially recommends the addition of a long-acting GLP-1 RA. While evidence of GLP-1 RA benefit on kidney outcomes is currently limited to secondary outcome data, the ongoing FLOW trial is specifically testing the impact of injectable semaglutide therapy on primary kidney outcomes in patients with T2D and CKD.²⁸

The FLOW trial will provide additional insight into the role of GLP-1 RAs in the setting of T2D and CKD. Table 3 provides a summary of key recommendations and practice points from KDIGO regarding the use of GLP-1 RAs in patients with T2D and CKD.²⁷

AHA/ASA 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack

CVOTs completed with several GLP-1 RAs reported benefit on the secondary outcome of stroke (Table 1).^9,11 Adding to this evidence of potential benefit on cerebrovascular outcomes, a systematic review and meta-analysis of randomized trials with GLP-1 RAs reported an overall class benefit on fatal or non-fatal stroke (hazard ratio [HR] 0.83; 95% CI: 0.76-0.92; P = .0002).²⁹ Based on this evidence, the American Heart Association/American Stroke Association (AHA/ASA) 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack recommends that in patients with ischemic stroke or transient ischemic attack who have T2D, treatment should include glucose-lowering agents with proven CV benefit to reduce the risk for future major adverse cardiovascular events (MACE), such as stroke, myocardial infarction, and CV death.³⁰ The guideline emphasizes that when prevention of future vascular events is a treatment priority in patients with established ASCVD, including ischemic stroke, a GLP-1 RA should be added to background metformin therapy independent of A1C level.³⁰

Comparative Review of Currently Available GLP-1 RAs

There are currently 7 GLP-1 RA products available commercially in the United States: exenatide, lixisenatide, liraglutide, exenatide XR, dulaglutide, injectable semaglutide, and oral semaglutide.^14-16,31-34 The GLP-1 RA class is quite diverse with agents varying in terms of duration of action, frequency of administration, expanded indications, administration devices, efficacy (glycemia and weight), and route of administration. Product-specific factors should be considered when selecting the optimal GLP-1 RA for a given patient. Table 4 provides a summary of key product information for currently available individual GLP-1 RA products indicated for treatment of T2D.^14-16,31-34

Glycemic and Weight Effects

The GLP-1 RA class has been studied extensively with varying background therapies and in comparisons with various active comparator agents. Overall, studies have shown reductions in A1C ranging from 0.4% to 2.2%. A meta-analysis of 13 randomized controlled trials showed that treatment with GLP-1 RAs resulted in significantly greater mean reductions in A1C compared with DPP-4 inhibitors (-0.41% between groups; 95% CI: -0.53, -0.30).³⁵ Active comparator studies have also shown similar or better A1C lowering with GLP-1 RAs compared with sulfonylureas, thiazolidinediones, and basal insulin.^36-46 Despite the common misconception that basal insulin has no ceiling effect, a meta-analysis of head-to-head trials of GLP-1 RAs vs insulin showed that GLP-1 RAs reduced A1C more effectively than basal insulin (-0.12% between groups, P < .001),⁴⁷ thus supporting the ADA recommendation to initiate most patients who require the A1C-lowering potential of an injectable agent on a GLP-1 RA prior to insulin.

GLP-1 RAs also have the potential to contribute to weight loss. Studies with GLP-1 RAs have demonstrated body weight changes ranging from +0.3 to -6.5 kg in T2D treatment trials.^36-46 In comparison, SGLT2 inhibitors typically lead to a lesser degree of weight loss; DPP-4 inhibitors are generally considered to be weight neutral; and sulfonylureas, thiazolidinediones, and insulin cause weight gain.² Given the robust weight loss potential of GLP-1 RAs, both liraglutide and injectable semaglutide, at higher doses than used for diabetes, have been approved and marketed specifically for weight loss.^48,49

Tolerability and Safety

The most common side effects associated with GLP-1 RAs are GI-related. These side effects tend to be most prominent at the initiation of therapy or immediately following a dose increase and often improve with continued use. GI side effects can usually be reduced by initiating the medication at a low dose and titrating slowly. In addition, nausea may be reduced by eating smaller meal portions.⁵⁰

The risk of hypoglycemia with GLP-1 RAs is low when used as monotherapy. However, the risk of hypoglycemia increases when GLP-1 RAs are administered concomitantly with insulin or insulin secretagogues. The manufacturers of GLP1-RAs typically recommend considering dose reductions of background insulin secretagogues and/or insulin upon GLP-1 RA initiation to reduce the risk of additive hypoglycemia.^14-16,31-34The GLP-1 RA and insulin secretagogue/insulin doses can then be re-titrated based on patient response to achieve the desired level of glycemic control.

GLP-1 RAs have been associated with the development of pancreatitis. Causality has not been established, but these agents should be used cautiously in patients with a history of pancreatitis—particularly if the cause of the initial event is unknown.^14-16,31-34Preclinical studies in rodents also have shown a relationship between long-acting GLP-1 RAs and the development of thyroid c-cell tumors, including medullary thyroid carcinoma (MTC).⁵ Therefore, long-acting GLP-1 RAs are contraindicated in patients with a personal or family history of MTC and in patients with multiple endocrine neoplasia syndrome type 2. Concern has been raised regarding a risk of worsening diabetic retinopathy with GLP-1 RA use. The CVOT for injectable semaglutide (SUSTAIN-6) showed an increased risk of diabetic retinopathy complications primarily in patients with pre-existing retinopathy (HR 1.76; 95% CI: 1.11-2.78).¹⁰ A meta-analysis also showed an increased risk of worsening diabetic retinopathy in 4 major GLP-1 RA CVOTs (odds ratio 1.23; 95% CI: 1.05-1.44).⁵¹ In response, the ongoing FOCUS trial was designed to evaluate the impact of long-term effects of semaglutide on diabetic eye disease, including retinopathy, in adults with T2D.⁵² The FOCUS study will help clarify and guide the use of long-acting GLP-1 RAs in adults with T2D with and without a history of diabetic eye disease. Because chronic hyperglycemia, independent of prescribed antihyperglycemic therapy, may result in the development of retinopathy, patients with T2D should have a comprehensive eye examination at the time of T2D diagnosis and annually thereafter.²

Table 5 provides a within class comparison of GLP-1 RA products on A1C reduction, weight loss, and GI-related adverse events based on head-to-head trials.⁵⁰ Please refer to the second monograph in this series, Understanding and Addressing Barriers to Glucagon-Like Peptide-1 Receptor Agonist Use in Patients With Type 2 Diabetes, for additional discussion of patient-centered considerations when using GLP-1 RAs in patients with T2D.

GLP-1 RAs: Additional Evolving Clinical Applications

In addition to our evolving understanding of the role of GLP-1 RAs in reducing CV and kidney risk, additional work is being done to increase their effectiveness through use of higher doses and exploring their clinical role in other conditions such as nonalcoholic fatty liver disease (NAFLD).

Added Benefit With Higher GLP-1 RA Doses

Higher doses of GLP-1 RAs have been studied for added glycemic and weight benefits in the treatment of T2D. Two studies were recently published evaluating the effects of higher doses of the GLP-1 RA agents, dulaglutide and semaglutide.

The AWARD-11 study evaluated weekly dulaglutide 3.0 mg and 4.5 mg vs weekly dulaglutide 1.5 mg in 1,842 patients with T2D taking metformin.⁵³ Change in A1C from baseline to 36 weeks was significantly better in the 4.5-mg and 3.0-mg groups compared with the 1.5-mg group (-1.77% vs -1.64% vs 1.54%, respectively; P < .001 for 4.5 mg vs 1.5 mg and P = .003 for 3.0 mg vs 1.5 mg). Weight was also incrementally improved with the 4.5-mg and 3.0-mg groups compared with the 1.5-mg group (-4.6 kg vs -3.8 kg vs -3.0 kg, respectively; P < .001 for 4.5 mg vs 1.5 mg and P < .05 for 3.0 mg vs 1.5 mg). GI adverse events were most common, including nausea (17.3% vs 16.1% vs 14.2%, respectively), diarrhea (11.6% vs 12.0% vs 7.7%, respectively), and vomiting (10.1% vs 9.1% vs 6.4%, respectively). Based on the results of this trial, the US Food and Drug Administration (FDA) approved both the 3.0-mg and 4.5-mg doses.⁵³ Dulaglutide should be initiated at 0.75 mg once weekly and increased to 1.5 mg once weekly for additional glycemic control. The dose can be increased to 3.0 mg if needed after at least 4 weeks on the 1.5-mg dose and increased again to 4.5 mg if needed after at least 4 weeks on the 3.0-mg dose.¹⁵

The SUSTAIN-FORTE study evaluated weekly semaglutide 2.0 mg versus weekly semaglutide 1 mg in 961 patients with T2D taking metformin with or without a sulfonylurea.⁵⁴ Change in A1C from baseline to 40 weeks was significantly better in the 2.0-mg group compared with the 1-mg group (-2.2% vs -1.9%; P = .003). Mean change in body weight was also significantly better in the 2.0-mg group (-6.9 kg vs -6.0 kg; P = .015). GI adverse events occurred in 34% of those taking 2.0-mg semaglutide and 31% in those taking 1-mg semaglutide.⁵⁴

Nonalcoholic Fatty Liver Disease

NAFLD, characterized by excess fat accumulation in the liver, is estimated to occur in approximately 24% of adults in the United States, making NAFLD one of the most common causes of liver disease in the country.^55,56 NAFLD is defined by the presence of hepatic steatosis (fatty liver) in the absence of heavy alcohol use, and thus differs from alcohol-associated liver disease.⁵⁶ While the pathogenesis of NAFLD is not entirely understood, insulin resistance is widely considered a key mechanism contributing to the development and progression of hepatic steatosis.⁵⁷ Insulin resistance, impaired lipid and glucose metabolism, and altered insulin secretion all play a role in both NAFLD and T2D progression and may be indicators as to why the 2 disease states are so intimately linked.⁵⁸ GLP-1 RAs are a growing class of glucose-lowering medications that offer a variety of benefits in T2D treatment. Notably, select agents from the GLP-1 RA class have been associated with CV disease risk reduction and robust weight loss—treatment benefits that have fueled particular interest in these agents for the treatment of NAFLD. The LEAN trial was a phase 2 study that enrolled 52 patients who were overweight with biopsy-confirmed nonalcoholic steatohepatitis (NASH).⁵⁹ After 48 weeks of treatment with either liraglutide 1.8 mg daily or placebo, 39% (9/23) of participants in the treatment group experienced resolution of definite NASH (via liver biopsy) compared with 9% (2/22) of the placebo group (P = .019). Adverse events were reported as mild and transient in both study groups. A recently published 72-week, placebo-controlled trial with subcutaneous semaglutide enrolled 320 participants with biopsy-confirmed NASH.⁶⁰ Overall, treatment with semaglutide resulted in a significantly higher percentage of patients experiencing NASH resolution compared with those who received placebo.⁶⁰ Another 24-week trial with dulaglutide showed that GLP-1 RA treatment significantly reduced liver fat content in patients with T2D and NAFLD.⁶¹ Overall, these findings are promising and support the continued investigation of GLP-1 RAs as a viable treatment for NAFLD. In addition, based on this evidence, current clinical practice guidelines from the AACE recommends the use of GLP-1 RA for people with T2D and biopsy-proven NASH.⁶² Similarly, a recently published Clinical Care Pathway preferentially recommends use of a GLP-1 RA (or pioglitazone) for treatment of diabetes in patients considered to have intermediate or high risk with NASH.⁶³

Tirzepatide: A Dual GLP-1/GIP Receptor Agonist

Tirzepatide is a novel dual agonist at both GIP and GLP-1 receptors that received approval for the treatment of T2D in 2022.⁶⁴ Currently available GLP-1 RAs affect only GLP-1 receptors, but as previously mentioned, GIP is another incretin hormone that plays an important role in stimulating meal-time insulin secretion, which is diminished in T2D.⁶⁴ The combined GLP and GIP effect may also have improved weight loss effects.

The phase 3 SURPASS clinical study program evaluates once-weekly injected tirzepatide against a variety of comparators including placebo, semaglutide, dulaglutide, insulin degludec, and insulin glargine, as well as includes CV outcome data. SURPASS-1 compared 3 doses of tirzepatide (5 mg, 10 mg, and 15 mg) with placebo in 478 adults with T2D that was inadequately controlled with diet and exercise and who were naive to injectable therapy.⁶⁵ After 40 weeks, all doses of tirzepatide lowered A1C, fasting glucose levels, and weight. The most common adverse events were nausea (12%-18% vs 6%), diarrhea (12%-14% vs 8%), and vomiting (2%-6% vs 2%) and were described as mild to moderate and transient.⁶⁵

SURPASS-2 compared 3 doses of tirzepatide with semaglutide 1 mg in 1,879 adults with T2D that was inadequately controlled on metformin.⁶⁶ After 40 weeks, all doses of tirzepatide (5 mg, 10 mg, and 15 mg) were non-inferior and superior to semaglutide for change in A1C from baseline (-2.01%, -2.24%, -2.3%, and -1.86%, respectively; P < .001). Weight loss was also significantly better with all doses of tirzepatide compared with semaglutide (-7.6 kg, -9.3 kg, -11.2 kg, and -5.7 kg, respectively; P < .001). The most common adverse events with tirzepatide and semaglutide were GI related (nausea 17%-22% vs 18%, diarrhea 13%-16% vs 12%, and vomiting 6%-10% vs 8%, respectively).⁶⁶

SURPASS-3 compared 3 doses of tirzepatide with insulin degludec in 1,437 adults with T2D that was inadequately controlled on metformin with or without an SGLT2 inhibitor.⁶⁷ After 40 weeks, all 3 doses of tirzepatide were superior to titrated insulin degludec for change in A1C from baseline (-1.93%, -2.2%, -2.37%, and -1.34%, respectively; P < .0001). Weight loss was also significantly better with all doses of tirzepatide compared with insulin degludec (-7.5 kg, -10.7 kg, -12.9 kg, and +2.3 kg, respectively; P < .0001). Tirzepatide led to higher rates of GI adverse events (nausea 12%-24% vs 2%, diarrhea 15%-17% vs 4%, and vomiting 6%-10% vs 1%) but lower rates of hypoglycemia (1%-2% vs 7%).⁶⁷

A pre-specified CV meta-analysis was recently published using data from the SURPASS program.⁶⁸ The primary outcome of the meta-analysis was to compare the time to first occurrence of confirmed 4-component MACEs. Events included within this primary outcome included CV death, myocardial infarction, stroke, and hospitalization for unstable angina. The meta-analysis included SURPASS trials in which participants received tirzepatide for at least 26 weeks. The HR for the comparison between tirzepatide and control was 0.80 (95% CI: 0.57-1.11).⁶⁸ Overall, tirzepatide was not found to increase risk for MACE in patients with T2D, thus supporting FDA approval of the medication. SURPASS-CVOT is a large ongoing CVOT comparing CV outcomes in patients receiving tirzepatide with dulaglutide.⁶⁹ SURPASS-CVOT is expected to complete in late 2024.

Collectively, the results of the SURPASS trials indicate A1C and weight-lowering effects of tirzepatide are superior to semaglutide and insulin degludec.

Conclusions

GLP-1 RAs represent an important tool to achieve individualized patient goals. GLP-1 RAs are capable of robust A1C reduction, dramatic weight loss, and low hypoglycemia risk. Current evidence also suggests a potential benefit of GLP-1 RA therapy for NAFLD. The dual GLP/GIP agonist tirzepatide also provides a new incretin-based therapy with impressive glycemic efficacy and weight loss effects. The expanding selection of glucose-lowering agents and our evolving understanding of the impact of these medications on CV, cerebrovascular, and kidney outcomes provide an opportunity for pharmacy professionals to make important contributions to individualized patient care. Pharmacists are well suited to advocate for optimal patient care by recommending appropriate agents based on patient- and medication-specific considerations and providing appropriate education to people living with T2D.

References

1. Centers for Disease Control and Prevention. National Diabetes Statistics Report. Reviewed January 18, 2022. Accessed August 20, 2022. https://www.cdc.gov/diabetes/data/statistics-report/index.html
2. American Diabetes Association Professional Practice Committee. Standards of Medical Care in Diabetes – 2022. Diabetes Care. 2022;45(suppl 1):S1-S264.
3. Elrick H, Stimmler L, Hlad CJ Jr, Arai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964;24:1076-1082.
4. Neumiller JJ. Incretin pharmacology: a review of the incretin effect and current incretin-based therapies. Cardiovasc Hematol Agents Med Chem. 2012;10(4):276-288.
5. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8(12):728-742.
6. Alicic RZ, Cox EJ, Neumiller JJ, Tuttle KR. Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence. Nat Rev Nephrol. 2021;17(4):227-244.
7. American Diabetes Association. Living standards update. Accessed August 20, 2022.https://professional.diabetes.org/content-page/living-standards-update
8. Pfeffer MA, Claggett B, Diaz R, et al; ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247-2257.
9. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322.
10. Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844.
11. Holman RR, Bethel MA, Mentz RJ, et al; EXSCEL Study Group. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228-1239.
12. Gerstein HC, Colhoun HM, Dagenais GR, et al; REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121-130.
13. Husain M, Birkenfeld AL, Donsmark M, et al; PIONEER 6 Investigators. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019;381(9):841-851.
14. Victoza [product information]. Plainsboro, NJ: Novo Nordisk Inc.; 2022.
15. Trulicity [product information]. Indianapolis, IN: Eli Lilly and Co; 2022.
16. Ozempic [product information]. Plainsboro, NJ: Novo Nordisk, Inc.; 2022.
17. Farxiga [product information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2022.
18. Jardiance [product information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2022.
19. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-2306.
20. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436-1446.
21. EMPA-KIDNEY: the study of heart and kidney protection with empagliflozin. August 21, 2022. https://www.empakidney.org
22. Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: challenges, progress, and possibilities. Clin J Am Soc Nephrol. 2017;12(12):2032-2045.
23. Soliqua [product information]. Bridgewater, NJ: Sanofi-aventis U.S.;2022.
24. Xultophy [product information]. Plainsboro, NJ: Novo Nordisk, Inc.;2022.
25. Garber AJ, Handelsman Y, Grunberger G, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm – 2020 Execute Summary. Endocr Pract. 2020;26(1):107-139.
26. Handelsman Y, Anderson JE, Bakris GL, et al. DCRM Multispecialty Practice Recommendations for the management of diabetes, cardiorenal, and metabolic diseases. J Diabetes Complications. 2022;36(2):108101.
27. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2020;98(4S):S1-S115.
28. A research study to see how semaglutide works compared to placebo in people with type 2 diabetes and chronic kidney disease (FLOW). ClinicalTrials.gov identifier: NCT03819153. Updated January 27, 2022. Accessed August 22, 2022. https://clinicaltrials.gov/ct2/show/NCT03819153?term=semaglutide+FLOW&draw=2&rank=1. A
29. Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 2021;9(10):653-662.
30. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 guideline for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline from the American Heart Association/American Stroke Association. Stroke. 2021;52(7):e364-e467.
31. Byetta [product information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2021.
32. Adlyxin [product information]. Bridgewater, NJ: sanofi-aventis U.S. LLC.; 2019.
33. Bydureon [product information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020.
34. Rybelsus [product information]. Plainsboro, NJ: Novo Nordisk, Inc.; 2021.
35. Tran S, Retnakaran R, Zinman B, Kramer CK. Efficacy of glucagon-like peptide-1 receptor agonists compared to dipeptidyl peptidase-4 inhibitors for the management of type 2 diabetes: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2018;20(suppl 1):68-76.
36. Yoo BK, Triller DM, Yoo DJ. Exenatide: a new option for the treatment of type 2 diabetes. Ann Pharmacother. 2006;40(10):1777-1784.
37. Trujillo JM, Goldman J. Lixisenatide, a once-daily prandial glucagon-like peptide-1 receptor agonist for the treatment of adults with type 2 diabetes. Pharmacotherapy. 2017;37(8):927-943.
38. Trujillo JM, Nuffer W. GLP-1 receptor agonists for type 2 diabetes mellitus: recent developments and emerging agents. Pharmacotherapy. 2014;34(11):1174-1186.
39. Montanya E, Sesti G. A review of efficacy and safety data regarding the use of liraglutide, a once-daily human glucagon-like peptide 1 analogue, in the treatment of type 2 diabetes. Clin Ther. 2009;31(11):2472-2488.
40. Genovese S, Mannucci E, Ceriello A. A review of the long-term efficacy, tolerability, and safety of exenatide once weekly for type 2 diabetes. Adv Ther. 2017;34(8):1791-1814.
41. Thompson AM, Trujillo JM. Advances in the treatment of type 2 diabetes: impact of dulaglutide. Diabetes Metab Syndr Obes. 2016;9:125-136.
42. Tuchscherer RM, Thompson AM, Trujillo JM. Semaglutide: the newest once-weekly GLP-1 RA for type 2 diabetes. Ann Pharmacother. 2018;52(12):1224-1232.
43. Bucheit JD, Pamulapati LG, Carter N, et al. Oral semaglutide: a review of the first oral glucagon-like peptide-1 receptor agonist. Diabetes Technol Ther. 2020;22(1):10-18.
44. Anderson SL, Beutel TR, Trujillo JM. Oral semaglutide in type 2 diabetes. J Diabetes Complications. 2020;34(4):107520.
45. Tran KL, Park YI, Pandya S, et al. Overview of glucagon-like peptide-1 receptor agonists for the treatment of patients with type 2 diabetes. Am Health Drug Benefits. 2017;10(4):178-188.
46. Prasad-Reddy L, Isaacs D. A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond. Drugs Context. 2015;4:212283.
47. Abd El Aziz MS, Kahle M, Meier JJ, Nauck MA. A meta-analysis comparing clinical effects of short- or long-acting GLP-1 receptor agonists versus insulin treatment from head-to-head studies in type 2 diabetic patients. Diabetes Obes Metab. 2017;19(2):216-227.
48. Saxenda [product information]. Plainsboro, NJ: Novo Nodisk, Inc.; 2022.
49. Wegovy [product information]. Plainsboro, NJ: Novo Nodisk, Inc.; 2021.
50. Trujillo JM, Nuffer W, Smith BA. GLP-1 receptor agonists: an updated review of head-to-head clinical studies. Ther Adv Endocrinol Metab. 2021;12:20420188821997320.
51. Yoshida Y, Joshi P, Barri S, et al. Progression of retinopathy with glucagon-like peptide-1 receptor agonists with cardiovascular benefits in type 2 diabetes – a systemic review and meta-analysis. J Diabetes Complications. 2022;36(8):108255.
52. A research study to look at how semaglutide compared to placebo affects diabetic eye disease in people with type 2 diabetes (FOCUS). ClinicalTrials.gov identifier: NCT03811561. Updated August 11, 2022. Accessed August 23, 2022. https://clinicaltrials.gov/ct2/show/NCT03811561
53. Frias JP, Bonora E, Ruiz LN, et al. Efficacy and safety of dulaglutide 3.0 mg and 4.5 mg versus dulaglutide 1.5 mg in metformin-treated patients with type 2 diabetes in a randomized controlled trial (AWARD-11). Diabetes Care. 2021;44(3):765-773.
54. Frías JP, Auerbach P, Bajaj HS, et al. Efficacy and safety of once-weekly semaglutide 2.0 mg versus 1.0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial. Lancet Diabetes Endocrinol. 2021;9(9):563-574.
55. Spengler EK, Loomba R. Recommendations for diagnosis, referral for liver biopsy, and treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mayo Clin Proc. 2015;90(9):1233-1246.
56. National Institute of Diabetes and Digestive and Kidney Diseases. Definition & facts of NAFLD & NASH. Reviewed April 2021. Accessed August 15, 2022. https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash/definition-facts
57. Tomah S, Alkhouri N, Hamdy O. Nonalcoholic fatty liver disease and type 2 diabetes: where do diabetologists stand? Clin Diabetes Endocrinol. 2020;6:9.
58. Saponaro C, Gaggini M, Gastaldelli A. Nonalcoholic fatty liver disease and type 2 diabetes: common pathophysiologic mechanisms. Curr Diab Rep. 2015;15(6):607.
59. Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, andomized, placebo-controlled phase 2 study. Lancet. 2016;387(10019):679-690.
60. Newsome PN, Buchholtz K, Cusi K, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;384(12):1113-1124.
61. Kuchay MS, Krishan S, Mishra SK, et al. Effect of dulaglutide on liver fat in patients with type 2 diabetes and NAFLD: randomised controlled trial (D-LIFT trial). Diabetologia. 2020;63(11):2434-2445.
62. Cusi K, Isaacs S, Barb D, et al. American Association of Clinical Endocrinology clinical practice guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings: co-sponsored by the American Association for the Study of Liver Diseases (AASLD). Endocr Pract. 2022;28(5):528-562.
63. Kanwal F, Shubrook JH, Adams LA, et al. Clinical care pathway for the risk stratification and management of patients with nonalcoholic fatty liver disease. Gastroenterology. 2021;161(5):1657-1669.
64. Mounjaro [product information]. Indianapolis, IN: Lilly USA, LLC; 2022.
65. Rosenstock J, Wysham C, Frias JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. 2021;398(10295):143-155.
66. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6):503-515.
67. Ludvik B, Giorgino F, Jódar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet. 2021;398(10300):583-598.
68. Sattar N, McGuire DK, Pavo I, et al. Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat Med. 2022;28(3):591-598.
69. A study of tirzepatide (LY3298176) compared with dulaglutide on major cardiovascular events in participants with type 2 diabetes (SURPASS-CVOT). ClinicalTrials.gov identifier: NCT04255433. Updated September 9, 2022. Accessed September 21, 2022. https://www.clinicaltrials.gov/ct2/show/NCT04255433

Back to Top