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Glucoregulatory Hormones and GLP-1/GIP Receptor Agonists

Steven V. Edelman, MD

Reviewed on August 08, 2024

Introduction

Incretins

GLP-1 Analogues

Ozempic (Semaglutide)

Rybelsus (Oral Semaglutide)

Mounjaro (Tirzepatide)

Fixed-Ratio Combination of a GLP-1 Agonist <br>and Basal Insulin

Amylin Analogue

References

Introduction

The quest for more physiologic approaches to augment insulin treatment prompted investigation of glucoregulatory hormones. These include the gut-derived hormones, such as the potent incretins glucagon-like polypeptide-1 (GLP-1) and gastric inhibitory peptide (GIP) and the β-cell hormone amylin.

Incretins

A potential role for intestinal peptides in the treatment of type 2 diabetes (T2D) was based on the observation that insulin responses to an oral glucose load exceeded those after IV glucose administration measured at the same blood glucose concentration. This so-called incretin effect is attributed to the insulinotropic action of gut hormones, particularly:

Glucose-dependent insulinotropic polypeptide (GIP)
Glucagon-like peptide 1 (GLP-1).

Since the glucose-lowering effects of GIP have been shown to be impaired in patients with T2D, interest has focused on developing antidiabetic therapies based upon the actions of GLP-1 and GIP, the response to which remains intact. Combination (dual) GLP-1 and GIP receptor agonism has recently emerged as a promising therapeutic avenue.

GLP-1 is produced by the tissue-specific cleavage of proglucagon into several smaller peptides in the L-cells of the intestinal mucosa and GIP is synthesized by K cells found in the intestinal mucosa (Figure 19-1). The insulinotropic functions of GLP-1 are mediated through interaction with GLP-1 receptors expressed on pancreatic β cells. The release of GLP-1 in response to a meal is rapid (within 10 minutes) and highly correlated with the release of insulin and amylin. In healthy subjects, postprandial levels of GLP-1 rise, whereas patients with T2D or impaired glucose tolerance (IGT) exhibit reduced levels of meal-stimulated circulating GLP-1.

Exogenous GLP-1 has the potential to normalize fasting and PPG levels in patients with T2D. One study in patients with T2D demonstrated that intravenously administered GLP-1 significantly reduced fasting blood glucose (FBG) and, in a glucose-dependent manner, both enhanced insulin secretion and suppressed glucagon secretion (Figure 19-2). Another study found that subcutaneously (SC) administered GLP-1 normalized postprandial glucose (PPG), enhanced glucose-mediated insulin secretion and delayed gastric emptying. Importantly, the insulinotropic and glucagonostatic actions of GLP-1 are strictly glucose dependent. Therefore, GLP-1 should not induce hypoglycemia when administered alone or with other antidiabetic agents that do not cause hypoglycemia, such as metformin (MET), thiazolidinediones (TZDs) and alpha-glucosidase inhibitors (AGIs). Dipeptidyl peptidase-4 (DPP-4) inhibitors do not cause hypoglycemia; however, they are not used concomitantly with GLP-1 receptor agonists (GLP-1 RAs).

Significant acute reductions in appetite and food intake were initially observed after intravenous (IV) administration of GLP-1 both in healthy individuals and in patients with T2D. The weight effects of GLP-1 therapy are potentially significant for the treatment of T2D, in which excessive caloric intake and weight management are important issues that are difficult to control.

In addition to these well-characterized metabolic activities, a number of novel biologic functions of GLP-1 have been shown to occur in animals and include:

Regulation of β-cell genes involved in glucose sensing and insulin biosynthesis and secretion
Expansion of β-cell mass through the proliferation and neogenesis of pancreatic cells
Potentiation of glucose uptake in peripheral tissues.

Several of these effects occur in humans treated with GLP-1 agonists or analogues, and studies that looked at surrogate markers of β-cell health are promising. The collective glucoregulatory actions of GLP1 make this peptide a potential powerful agent for the treatment of diabetes. Despite these features, the therapeutic potential of GLP1 has been limited by its rapid and extensive degradation. In humans, the half-life of GLP-1 is <2 minutes due to rapid degradation as a result of N-terminal cleavage by the ubiquitous enzyme, DPP-4. Elimination is principally via the kidneys.

Figure 19-1: Schematic Model of the Multihormonal Control of Glucose Homeostasis. The multihormonal control of glucose homeostasis is regulated by a complex interplay of several gut and islet hormones, including insulin, amylin, glucagon, and incretins.

Figure 19-2: Plasma Glucose, Insulin, and Glucagon Responses to the IV Administration of GLP-1 or Placebo in Patients with Type 2 Diabetes. Data are mean ± SE. <sup>a</sup> <em>P</em> <0.05. Source: Nauck MA, et al. <em>Diabetologia</em>. 1993;36:741-744. — Figure 19-2: Plasma Glucose, Insulin, and Glucagon Responses to the IV Administration of GLP-1 or Placebo in Patients with Type 2 Diabetes. Data are mean ± SE. ^a P <0.05. Source: Nauck MA, et al. *Diabetologia*. 1993;36:741-744.

GLP-1 Analogues

One approach to utilizing the therapeutic potential of GLP-1 has been the development of incretin mimetics. This has resulted in the production of GLP-1 analogues and GLP-1–like compounds that exhibit increased resistance to DPP-4 degradation. Several GLP-1 analogs and a GLP-receptor agonist that exhibit increased resistance to DPP-4 degradation, as well as DPP-4 inhibitors, have been developed. The GLP-1 receptor agonist exenatide (synthetic exendin-4) was the first agent of the incretin mimetic class to be approved by the Food and Drug Administration (FDA). More recently, the GLP-1 analogs liraglutide, dulaglutide, lixisenatide, semaglutide (oral and injectable formulations) and tirzepatide have also been approved.

Exenatide (Byetta)

Exendin-4 is a naturally occurring incretin mimetic that was originally isolated from the salivary secretions of the lizard Heloderma suspectum (Gila monster). Exendin-4 and mammalian GLP-1 have an approximately 50% amino acid sequence identity. However, exendin-4 and GLP-1 are transcribed from distinct genes and, therefore, the exendin-4 gene is not the Gila monster homologue of the mammalian proglucagon gene from which GLP-1 is expressed. In mammals, exendin-4 exhibits antidiabetic activities similar to those of native GLP-1 but is resistant to degradation by DPP-4, and this contributes to its longer half-life compared with GLP-1.

Exenatide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D.

Phase 3 Clinical Trials

Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of exenatide in patients with T2D unable to achieve adequate glycemic control with MET alone, an SFU alone, or MET in combination with an SFU. A total of 1446 patients were randomized in these three trials. The mean A1C values at baseline for the trials ranged from 8.2% to 8.7%. After a 4-week placebo lead-in period, patients were randomly assigned to receive exenatide 5 mcg bid, exenatide 10 mcg bid, or placebo before the morning and evening meals, in addition to their current oral antidiabetic agent. All patients randomized to exenatide began a treatment initiation period with 5 mcg bid for 4 weeks. After 4 weeks, those patients either continued to receive exenatide 5 mcg bid or had their dose increased to 10 mcg bid. Patients assigned to placebo received placebo bid throughout the study. The primary end point in each study was mean change from baseline A1C at 30 weeks. The results of the 30-week pivotal trials are summarized in Table 19-1.

The average reduction in A1C across the three phase 3 pivotal trials in patients completing the 30-week studies on the highest dose of exenatide (10 mg twice daily) approached 1%. Additionally, approximately 35% of these patients achieved A1C measurements ≤7%. On average, subjects in the phase 3 trials on the highest dose of exenatide also showed reductions in body weight of approximately 2 kg. Exenatide was generally well tolerated and the most common adverse event reported was mild-to-moderate nausea, which occurred most frequently early in the study. Patients taking exenatide in combination with an sulfonylurea (SFU) had an increased risk of hypoglycemia. When exenatide was used in combination with MET, no increase in hypoglycemia was seen over that of placebo in combination with MET. In general, hypoglycemia rates were consistent with the glucose-dependent action of exenatide, with no difference between the placebo and drug arms. In all three pivotal trials, observed antibody formation to exenatide was consistent with data reported to date. These data do not suggest an influence of antibody formation on exenatide’s glucose-lowering effect.

A randomized, placebo-controlled, double-blind trial was performed in 233 subjects with elevated A1C (in spite of therapy) with a TZD alone (20%) or with a TZD and MET (80%). Patients were randomized to receive subcutaneous (SC) injections of placebo or exenatide 5 mcg for 4 weeks then 10 mcg bid for 16 weeks in addition to their previous regimen (Figure 19-3). Exenatide therapy decreased A1C by -0.8 from a baseline of 7.9% (Figure 19-3-A). With exenatide, 62% of subjects achieved A1C ≤7% vs 16% with placebo (Figure 19-3-B). Fasting serum glucose with exenatide was -1.5 mmol/L (-27 mg/dL) lower than with placebo). Exenatide also significantly reduced body weight from baseline compared with placebo (-1.5 kg vs -0.2 kg respectively) (Figure 19-3-C). Nausea was the most frequent adverse event (40% vs 15%, exenatide vs placebo). There was no significant difference in the incidence of hypoglycemia between the two treatments.

Comparative and Long-Term Open-Label Trials
Exenatide vs Insulin Glargine

A 26-week, randomized, active-controlled noninferiority study was performed to determine if exenatide could be used safely and effectively as an alternative to basal insulin glargine in 551 patients being treated with MET and an SFU. Patients were randomized to receive exenatide (5 mcg bid for the first 4 weeks, then 10 mcg bid for the remainder of the study) or insulin glargine qd (one daily dose titrated to maintain FBG levels of 5.6 mmol/L [<100 mg/dL]). At end point, similar A1C reductions were achieved with exenatide and glargine (-1.1% and -1.1%, respectively) consistent with the noninferiority study design (Figure 19-4-A). As measured by 7-point glucose monitoring, exenatide reduced postprandial excursions following breakfast and dinner, whereas the predominant effect of glargine was a reduction of fasting glucose. Mean weight changes from baseline were -2.5 kg (5.5 lb) with exenatide and +1.8 kg (3.9 lb) with glargine (Figure 19-4-B). GI symptoms were more common in the exenatide group than in the insulin glargine group, including nausea (57.1% vs 8.6%), vomiting (17.4% vs 3.7%), and diarrhea (8.5% vs 3.0%). Nausea (57%), generally mild to moderate with a decreasing incidence during the study, was the most common adverse event with exenatide and resulted in a 6% discontinuation rate. The rates of symptomatic hypoglycemia were similar with the two treatments except that nocturnal hypoglycemia was significantly less common with exenatide (0.9 vs 2.4 mean events/patient/year).

The ability of exenatide to improve glycemic control with minimal weight gain in overweight patients with T2D compared with insulin glargine was assessed in the Helping Evaluate Exenatide in Overweight Patients With Diabetes Compared With Long-Acting Insulin (HEELA) study. Patients (mean BMI 34.1 kg/m²) inadequately controlled on two or three OADs and with elevated CV risk factors were randomized to open-label add-on treatment with exenatide 5-10 mcg bid (n = 118) or insulin glargine qd titrated to fasting plasma glucose ≤5.6 mmol/L [100.8 mg/dL] (n = 117). The primary outcome was a composite of A1C ≤7.4% and weight gain ≤1 kg. After 26 weeks, a significantly greater proportion of patients in the exenatide group achieved the composite end point compared with those in the insulin glargine group (53.4% vs 19.8%, respectively). Although there was no significant difference in the reductions in A1C with exenatide and insulin glargine (-1.25% and -1.26%, respectively), whereas mean body weight decreased in the exenatide group but increased in the insulin glargine group (-2.71 vs +2.98 kg, respectively). There were more treatment-related adverse events with exenatide but a lower incidence of nocturnal hypoglycemia, with no differences in overall or severe hypoglycemia.

A 1-year, randomized, open-label study in 69 MET-treated patients with T2D found that exenatide significantly improved β-cell function (as assessed by arginine-stimulated hyperglycemic clamp) during 1 year of treatment compared with titrated insulin glargine. After cessation of both exenatide and insulin glargine therapy, the β-cell function, A1C and body weight returned to pretreatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therapy.

82-Week Studies

Several published analyses reported the effects of exenatide on A1C and weight over 82 weeks in patients with T2D who had participated in prior 30-week phase 3 clinical trials and a subsequent 52-week open-label extension. One post hoc analysis examined changes in A1C and weight in 393 patients. During the open-label extensions, all patients received exenatide 5 mcg bid for 4 weeks followed by exenatide 10 mcg bid. All patients continued their MET, SFU, or MET plus SFU. In patients who were treated with exenatide 10 mcg bid for a total of 82 weeks, the reduction from baseline of A1C was -1.1% and the progressive reduction in weight was -4.5 kg or 9.9 lb (Figure 19-5). At week 82, patients who received placebo during the first 30 weeks prior to subsequent exenatide 10 mcg bid had reductions in A1C of -1.2% as well as reductions in weight of -3.3 kg from their 30-week baseline.

Another analysis examined pooled data from a larger cohort of 314 overweight patients (weight 99 ± 21 kg, BMI 34 ± 6 kg/m²) with T2D who received exenatide in addition to an SFU and/or MET in a 30-week placebo-controlled trial and subsequently in an additional 52-week open-label uncontrolled extension study. Patients continued their SFU and/or MET regimens throughout. In these 314 patients who completed 82 weeks of exenatide treatment, reduction in A1C from baseline to week 30 (-0.9%) was sustained to week 82 (-1.1%), with 48% of patients achieving A1C ≤7% at week 82. At week 30, exenatide reduced body weight from baseline (-2.1 kg), with progressive reduction at week 82 (-4.4 kg) (Figure 19-6). In addition, patients who completed 82 weeks of exenatide showed statistically significant improvement in some CV risk factors.

Dosage and Administration

Exenatide therapy should be initiated at 5 mcg administered twice daily at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart) (Table 19-2). Exenatide should not be administered after a meal. Based on clinical response, the dose of exenatide can be increased to 10 mcg twice daily after 1 month. Each dose should be administered as an SC injection in the thigh, abdomen, or upper arm. Exenatide is not recommended in patients with severe GI disease, ESRD, or severe renal impairment (CrCl <30mL/min).

Exenatide Extended-Release Formulation

An extended-release (ER) formulation of exenatide (Bydureon) was recently approved by the FDA as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with T2D in multiple clinical settings. Whereas the regular exenatide formulation is administered twice daily, this ER formulation is administered every 7 days.

ER exenatide has been studied as monotherapy and in combination with MET, an SFU, a TZD, a combination of MET and an SFU, or a combination of MET and a TZD. The concurrent use of ER exenatide with insulin has not been studied and cannot be recommended.

The efficacy and safety of ER exenatide 2 mg once every 7 days and regular exenatide 10 mcg twice daily were compared in a 24-week, randomized, open-label trial in 252 patients with T2D and inadequate glycemic control with diet and exercise alone (19%), a single OAD agent (47%), or a combination of OAD agents (35%). As shown in Table 19-3, the reductions in A1C and FPG were significantly greater with ER exenatide compared with regular exenatide. In addition, reductions from mean baseline (97/94 kg) in body weight were observed with both ER exenatide (-2.3 kg) and regular exenatide (-1.4 kg). In this study, the most common adverse events were nausea (ER exenatide 14.0%; regular exenatide 5.0%), diarrhea (ER exenatide 9.3%; regular exenatide 4.1%)cand injection site erythema (ER exenatide 5.4%; regular exenatide 2.4).

Prescribing Extended-Release Exenatide

ER exenatide (2 mg per dose) should be administered via SC injection once every 7 days (weekly). The dose can be administered at any time of day, with or without meals. Prior treatment with regular exenatide is not required when initiating the ER formulation. Patients changing from the ER to the immediate-release formulation of exenatide may experience transient (approximately 2 weeks) elevations in blood glucose concentrations. ER exenatide should not be used in patients with severe renal impairment (creatinine clearance (CrCl) <30 mL/min) or end-stage renal disease (ESRD). ER exenatide is contraindicated in patients with personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2.

Figure 19-3: Adjunctive Treatment With Exenatide or Placebo in Patients With Type 2 Diabetes Not Adequately Controlled With a Thiazolidinedione Alone or in Combination With Metformin. <sup>a</sup> ITT patient sample; mean + SE. <sup>b </sup>Per-protocol patient sample: randomized patients who had no protocol violations and either completed the protocol or received at least 16 weeks of treatment. Baseline A1C >7% or 6.5%. <sup>c </sup>Baseline body weight (mean ± SD): exenatide, 97.5 ± 18.9 kg; placebo, 96.9 ± 19.0 kg. Source: Zinman B, et al. <em>Ann Intern Med</em>. 2007;146:477-485. — Figure 19-3: Adjunctive Treatment With Exenatide or Placebo in Patients With Type 2 Diabetes Not Adequately Controlled With a Thiazolidinedione Alone or in Combination With Metformin. ^a ITT patient sample; mean + SE. ^bPer-protocol patient sample: randomized patients who had no protocol violations and either completed the protocol or received at least 16 weeks of treatment. Baseline A1C >7% or 6.5%. ^cBaseline body weight (mean ± SD): exenatide, 97.5 ± 18.9 kg; placebo, 96.9 ± 19.0 kg. Source: Zinman B, et al. *Ann Intern Med*. 2007;146:477-485.

Figure 19-4: Exenatide/Insulin Glargine Comparator Trial Intent-to-treat population; mean ± SE shown. <sup>a </sup><em>P</em> <0.0001, exenatide vs insulin glargine at same time point. Source: Heine RJ, et al. <em>Ann Intern Med</em>. 2005;143:559-569. — Figure 19-4: Exenatide/Insulin Glargine Comparator Trial Intent-to-treat population; mean ± SE shown. ^aP <0.0001, exenatide vs insulin glargine at same time point. Source: Heine RJ, et al. *Ann Intern Med*. 2005;143:559-569.

Figure 19-5: Open-Label Extension<sup>a</sup>: Sustained A1C Reductions and Progressive Body Weight Reductions With Exenatide Therapy Over 82 Weeks. Mean (SE); <em>N</em> = 393; completer population; 82-week data. <sup>a</sup> All subjects received exenatide 10 mcg bid. <sup>b</sup> Baseline A1C 8.3% in all three groups. <sup>c</sup> Weight change was a secondary end point. Baseline weight: placebo, 98 kg; 5 mcg, 98 kg; 10 mcg, 100 kg. Source: Data on file: Amylin Pharmaceuticals, Inc. — Figure 19-5: Open-Label Extension^a: Sustained A1C Reductions and Progressive Body Weight Reductions With Exenatide Therapy Over 82 Weeks. Mean (SE); N = 393; completer population; 82-week data. ^a All subjects received exenatide 10 mcg bid. ^b Baseline A1C 8.3% in all three groups. ^c Weight change was a secondary end point. Baseline weight: placebo, 98 kg; 5 mcg, 98 kg; 10 mcg, 100 kg. Source: Data on file: Amylin Pharmaceuticals, Inc.

Figure 19-6: Changes in Body Weight Over 82 Weeks of Treatment With Exenatide and Metformin, a Sulfonylurea, or Both in Patients Who Previously Participated in 30-Week Phase 3 Trials. Source: Blonde L, et al. <em>Diabetes Obes Metab</em>. 2006:8:436-447. — Figure 19-6: Changes in Body Weight Over 82 Weeks of Treatment With Exenatide and Metformin, a Sulfonylurea, or Both in Patients Who Previously Participated in 30-Week Phase 3 Trials. Source: Blonde L, et al. *Diabetes Obes Metab*. 2006:8:436-447.

Liraglutide (Victoza)

Liraglutide is an acylated GLP-1 analog that shares 97% amino acid sequence identity with native GLP-1. Liraglutide self-associates into a heptameric structure that delays absorption from the SC injection site and slows its metabolism, thereby resulting in a prolonged elimination half-life compared with native GLP-1. This structural modification also results in resistance to GLP-1 inactivation by DPP-4. This pharmacokinetic profile allows for once-daily administration. Liraglutide reduces both FPG and PPG levels, an effect that lasts throughout a 24-hour dosing interval. It increases insulin secretion, reduces postprandial glucagon secretion, delays gastric emptying and improved β-cell function. Its use has been associated with reductions in body weight and SBP.

Liraglutide is indicated as an adjunct to diet and exercise to improve glycemic control in patients 10 years and older with T2D. It is also indicated to reduce the risk of major adverse cardiovascular (CV) events in adults with T2D and established cardiovascular disease (CVD). This latter indication was the result of the positive cardiovascular outcomes trial (CVOT) discussed below. It is administered once daily at any time of day, independently of meals. It should be initiated at a dose of 0.6 mg per day for 1 week, following by a dose increase to 1.2 mg per day. Results from phase 3 clinical trials have demonstrated that liraglutide can be used as monotherapy, or in combination with one or two oral antidiabetic drugs (OADs), such as MET, SFUs, or TZDs. When using liraglutide with insulin, administer as separate injections in non-adjacent areas. The concurrent use of liraglutide and prandial insulin has not been studied although it is commonly employed. In addition, liraglutide and other GLP-1 RAs can be used with sodium glucose cotransporter type 2 (SGLT2) inhibitors.

Phase 3 Clinical Trials

The efficacy and safety of liraglutide were assessed in the Liraglutide Effect and Action in Diabetes (LEAD) phase 3 program consisting of six large, multicenter, randomized trials of 26- or 52-weeks in duration that enrolled >4000 adult patients with T2D (Table 19-4). Three of the trials included both placebo and active control groups, while others were either placebo- or active-controlled. Four of the trials used double-blind, double-dummy methodology; however, LEAD-6 was open-label and the insulin glargine arm in LEAD-5 was open-label since the basal insulin dose was individually titrated. LEAD-3 compared liraglutide monotherapy with glimepiride monotherapy in patients with early-stage diabetes who had not achieved adequate glycemic control with diet and exercise or a single OAD at up to half the maximum approved dose. Change from baseline in A1C was the primary efficacy end point in all LEAD trials. Secondary end points included change from baseline in fasting plasma glucose (FPG), postprandial glucose ( PPG) and body weight.

Monotherapy

In the LEAD-3 trial, both doses of liraglutide as monotherapy demonstrated significant improvements in glycemic control in comparison with glimepiride (Table 19-5). In addition, A1C reductions from baseline were significantly greater with liraglutide 1.8 mg than with liraglutide 1.2 mg (between-treatment difference of -0.29%). By week 52, significantly more patients in each of the liraglutide groups achieved the target A1C <7%. A1C levels tended to decrease over the first 8 to 12 weeks of treatment with liraglutide. They then remained stable until 52 weeks in the liraglutide 1.8-mg group but increased slightly between week 12 and week 52 with liraglutide 1.2 mg or glimepiride treatment. Patients previously treated with diet and exercise had greater decreases in A1C than did those who were switched from an OAD to liraglutide. Significantly greater reductions in body weight with both doses of liraglutide were also observed compared an increase with glimepiride.

The LEAD-3 trial was extended for an additional 52 weeks of open-label treatment during which 440 of the original study population entered the extension period of whom 321 completed the full 2 years of monotherapy with liraglutide. Of these patients, 110 received liraglutide 1.2 mg, 114 received liraglutide 1.8 mg and 97 received glimepiride. After 2 years, the mean reductions in A1C with both doses of liraglutide were significantly greater that those of glimepiride (-0.9% and -1.1% vs -0.6, respectively). The proportion of patients achieving A1C <7% were significantly greater with liraglutide 1.2 mg and 1.8 mg than with glimepiride (53% and 58% vs 37%). Reductions in FPG also were significantly greater with both doses of liraglutide than with glimepiride. Whereas there was a mean increase in body weight with glimepiride (+1.1 kg), body weight decreased with both doses of liraglutide (-2.1 and -2.7 kg).

In Combination With One OAD

Liraglutide in combination with either rosiglitazone or glimepiride was evaluated in two 26-week, double-dummy, placebo-controlled and active-controlled studies (Table 19-4). In LEAD-1, liraglutide used in combination with glimepiride reduced A1C to a significantly greater degree than placebo plus glimepiride or rosiglitazone plus glimepiride (Figure 19-7-A). The reductions in A1C were greater for patients previously treated with monotherapy compared with combination therapy. However, because the increase with placebo was higher for individuals entering from combination therapy (0.7% vs 0.23%), the differences between treatment groups in favor of liraglutide were similar irrespective of whether individuals were treated previously with monotherapy or combination therapy. A significantly greater proportion of patients treated with liraglutide 0.6, 1.2, or 1.8 mg (24%, 35% and 42%, respectively) achieved A1C <7% compared with 8% of those who received placebo with glimepiride. The proportions were also significantly greater with liraglutide 1.2 or 1.8 mg (35% and 42%, respectively) compared with that in the rosiglitazone plus glimepiride group (22%). At week 26, all doses of liraglutide decreased FPG significantly more than did placebo (Figure 19-7-B), while only liraglutide 1.2 or 1.8 mg produced greater reductions than rosiglitazone. Changes in body weight with liraglutide 0.6, 1.2 and 5 mg were significantly less than with rosiglitazone (liraglutide +0.7, +0.3, -0.2 kg vs rosiglitazone +2.1 kg, respectively).

In the LEAD-2 trial, reductions in A1C with all three doses of liraglutide plus MET and glimepiride plus MET were significantly greater than with placebo plus MET (Table 19-6). The reductions with liraglutide were similar to that with glimepiride; specifically, they were statistically noninferior to glimepiride. The proportions of patients reaching A1C <7% were significantly greater with all doses of liraglutide plus MET compared with placebo plus MET. The proportion of patients in the liraglutide 1.8 mg plus MET group was significantly greater than in the glimepiride plus MET group. Although the proportion of patients with A1C <7% in the glimepiride plus MET group was similar to those receiving liraglutide, the P value compared with placebo plus MET was not reported. FPG levels decreased from baseline in the liraglutide plus MET groups as well as in the glimepiride group, whereas FPG increased with placebo plus MET. While body weight decreased in the liraglutide plus MET and placebo plus MET groups, there was an increase in the glimepiride plus MET group.

In Combination With Two OADs

The LEAD-4 and LEAD-5 trials assessed the efficacy of liraglutide as add-on to two OADs: MET and rosiglitazone or MET and glimepiride, respectively (Table 19-4).

In LEAD-4, A1C values decreased significantly more in the liraglutide 1.2 and 1.8 mg plus MET and rosiglitazone groups vs placebo plus MET and rosiglitazone. Mean A1C values with both doses of liraglutide decreased from baseline within the first 12 weeks of the study and thereafter remained steady throughout the rest of the trial (Figure 19-8-A). By week 26, 57.5% and 53.7% of patients in the 1.2- and 1.8-mg liraglutide groups, respectively, had an A1C of <7% compared with 28.1 % in the placebo group. FPG values decreased within 2 weeks of randomization with liraglutide and remained relatively stable thereafter, while there was a significantly smaller decrease with placebo (Figure 19-8-B). In addition, 90-minute PPG at the end of the study decreased from baseline in all treatment groups by -47 mg/dL for 1.2-mg liraglutide, -49 mg/dL 1.8-mg liraglutide and -14 mg/dL for placebo. Dose-dependent weight loss was observed with 1.2- and 1.8-mg liraglutide (-l.0 and -2.0 kg, respectively) compared with weight gain with placebo (+0.6 kg). The weight loss with liraglutide 1.8 mg was significantly greater than with liraglutide 1.2 mg.

The LEAD-5 trial compared liraglutide 1.8 mg qd, placebo, or open-label insulin glargine, all as add-on to MET and glimepiride. After 26 weeks, the addition of liraglutide 1.8 mg reduced A1C significantly compared with the addition of placebo or insulin glargine. Significantly more patients achieved an A1C <7% with liraglutide than with placebo. FPG levels decreased to a similar degree with liraglutide and insulin glargine, while they increased in the placebo group. There was greater weight loss with liraglutide vs placebo and insulin glargine.

Liraglutide Compared With Exenatide

Liraglutide 1.8 mg qd was compared with exenatide 10 mcg bid, both added to previous treatment with maximally tolerated, but inadequate, doses of MET, an SFU, or both, in a randomized, open-label trial (LEAD-6). By week 26, liraglutide reduced A1C significantly more than exenatide (1.0% vs 0.79%) (Figure 19-9-A), and more patients reached A1C <7% with liraglutide than with exenatide (54% vs 43%). Liraglutide treatment also resulted in a greater reduction in FPG than with exenatide (-1.61 mmol/L [-29.0 mg/dL] vs -0.60 mmol/L [-10.8 mg/dL]; P <0.0001) (Figure 19-9-B). Weight losses from baseline were similar with both liraglutide and exenatide (-3.24 kg and -2.87 kg).

Safety and Tolerability

Throughout the LEAD trials, liraglutide was generally well tolerated, with most adverse events reported to be mild to moderate in severity. GI events (eg, nausea, vomiting, diarrhea) were the most frequently reported adverse events with liraglutide monotherapy and combination therapy and were often dose related. For example, in the LEAD-3 trial with liraglutide monotherapy, 27%, 29% and 8% of patients who received liraglutide 1.2 mg, 1.8 mg, or glimepiride, respectively, reported treatment-emergent nausea. Nausea generally occurred early during treatment and <10% of patients in the liraglutide 1.8-mg group had experienced nausea by week 4. In the LEAD-4 trial in which liraglutide was added to MET and rosiglitazone, nausea was reported 29% and 40% in the liraglutide 1.2-mg and 1.8-mg groups. However, nausea tended to decrease in frequency over time; for example, there were 216 events during weeks 1 through 4 and 65 events during weeks 4 through 26. In general, serious adverse events were uncommon with liraglutide. In the LEAD-5 trial, patients treated with insulin glargine or placebo reported a 7% frequency of serious adverse events in comparison with a 4% frequency with liraglutide.

Few episodes of minor and major hypoglycemia were reported with liraglutide across the LEAD studies. In the LEAD-3 monotherapy trial, no major hypoglycemic episodes were reported and only 8% of patients treated with liraglutide 1.8 mg reported minor hypoglycemia compared with 24% of glimepiride-treated patients. There were no reports of major hypoglycemia in the LEAD-4 trial. The incidence of minor hypoglycemia also was low (9.0%, 4.9% and 5.1%) in patients who received liraglutide 1.8 mg, 1.2 mg combined with MET and rosiglitazone, or placebo and MET and rosiglitazone, respectively. Although data are limited, major hypoglycemia with liraglutide seems to occur only when liraglutide is used in combination with an SFU. This may be a result of both agents acting simultaneously to potentiate insulin secretion from β cells, and the fact that insulin secretion stimulated by an SFU is not glucose dependent. This phenomenon of increased hypoglycemic risk in combination with an SFU has also been reported with exenatide.

Cardiovascular Outcomes (LEADER)

Until the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial, the effects of liraglutide or any other GLP-1 RA on CV outcomes were unknown. This large trial randomized a total of 9340 patients with T2D and high CV risk to receive either liraglutide or placebo plus standard of care. Additional antihyperglycemic agents (with the exception of GLP-1 receptor agonists, DPP-4 inhibitors, or pramlintide) were available to patients who did not meet the glycemic control target of ≤7% after randomization. Patients were then followed for 3.5 to 5.0 years.

The primary endpoint was a composite of the first occurrence of death from CV causes, nonfatal MI, or nonfatal stroke. This outcome occurred in statistically fewer patients in the liraglutide group compared with the placebo group (hazard ratio [HR], 0.87; 95% CI, 0.78 to 0.97; P <0.001 for noninferiority; P = 0.01 for superiority) (Figure 19-10-A). In addition, death from CV causes (HR, 0.78; 95% CI, 0.66 to 0.93; P = 0.007) (Figure 19-10-B), death from any cause (HR, 0.85; 95% CI, 0.74 to 0.97; P = 0.02), and microvascular outcomes, as measured by a composite of renal or retinal microvascular events (HR, 0.84; 95% CI, 0.73 to 0.97; P = 0.02), were significantly reduced in the liraglutide group. Adverse events leading to permanent discontinuation of treatment were more common with liraglutide. Overall, among patients with T2D on standard therapy and at high risk of CV events, those administered liraglutide experienced lower rates of CV events and death from any cause compared with those receiving placebo.

In similar trials, other agents—including insulin, thiazolidinediones and DPP-4 inhibitors—have had comparable effects on glycemic control as liraglutide. However, these other agents have not demonstrated significant benefits with respect to rates of CV events or death. LEADER is the first trial to demonstrate CV risk reduction with a GLP-1 receptor agonist and the second of any antihyperglycemic agent, after empagliflozin, to show CV benefit.

Dosage and Administration

Liraglutide should be initiated at 0.6 mg qd for 1 week in order to reduce GI symptoms during initiation of treatment. However, this dose is not effective for glycemic control. After 1 week, the dose should be increased 1.2 mg qd. If the 1.2-mg dose does not result in acceptable glycemic control, the dose can be increased to 1.8 mg. Liraglutide can be injected SC in the abdomen, thigh, or upper arm at any time of day, independently of meals. The timing and site of injection can be changed without dosage adjustment. In order to reduce the risk of hypoglycemia, reduction in the dose of a concomitant insulin secretagogue (eg, an SFU) should be considered.

Since liraglutide is not a substitute for insulin, it should not be used in patients with T1D or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

It should be noted that since liraglutide causes thyroid C-cell tumors at clinically relevant exposures in rodents, it is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2.

Figure 19-7: LEAD-1 Trial: Change in Glycemic Parameters After 24 Weeks With Liraglutide or Rosiglitazone Added to Glimepiride.<sup>a </sup><em>P</em> <0.0001 vs PBO. <sup>b</sup> <em>P</em> <0.0001 vs RSG. <sup>c </sup><em>P</em> <0.01 vs RSG. Source: Modified from Marre M, et al. <em>Diabet Med</em>. 2009;26(3):268-278. — Figure 19-7: LEAD-1 Trial: Change in Glycemic Parameters After 24 Weeks With Liraglutide or Rosiglitazone Added to Glimepiride.^aP <0.0001 vs PBO. ^b P <0.0001 vs RSG. ^cP <0.01 vs RSG. Source: Modified from Marre M, et al. *Diabet Med*. 2009;26(3):268-278.

Figure 19-8: LEAD-4 Trial: Change in Glycemic Parameters After 24 Weeks With Liraglutide Added to Metformin and Rosiglitazone. <sup>a </sup><em>P</em> <0.0001 vs PBO. Source: Zinman B, et al. <em>Diabetes Care</em>. 2009;32(7):1224-1230. — Figure 19-8: LEAD-4 Trial: Change in Glycemic Parameters After 24 Weeks With Liraglutide Added to Metformin and Rosiglitazone. ^aP <0.0001 vs PBO. Source: Zinman B, et al. *Diabetes Care*. 2009;32(7):1224-1230.

Figure 19-9: LEAD-6 Trial: Change in Glycemic Parameter After 24 Weeks With Liraglutide or Exenatide, Both Added to Previous Treatment With MET, SFU, or Both. Source: Buse JB, et al. <em>Lancet</em>. 2009;374:39-47. — Figure 19-9: LEAD-6 Trial: Change in Glycemic Parameter After 24 Weeks With Liraglutide or Exenatide, Both Added to Previous Treatment With MET, SFU, or Both. Source: Buse JB, et al. *Lancet*. 2009;374:39-47.

Figure 19-10: LEADER Trial Cardiovascular Outcomes. Primary composite outcome is the first occurrence of death from CV causes, nonfatal myocardial infarction, or non-fatal stroke. The insets show the same data on an enlarged y axis. Cumulative incidences estimated using the Kaplan–Meier method and hazard ratios with the Cox proportional-hazard regression model. Source: Marso SP, et al. <em>N Engl J Med</em>. 2016;375(4):311-322. — Figure 19-10: LEADER Trial Cardiovascular Outcomes. Primary composite outcome is the first occurrence of death from CV causes, nonfatal myocardial infarction, or non-fatal stroke. The insets show the same data on an enlarged y axis. Cumulative incidences estimated using the Kaplan–Meier method and hazard ratios with the Cox proportional-hazard regression model. Source: Marso SP, et al. *N Engl J Med*. 2016;375(4):311-322.

Dulaglutide (Trulicity)

Dulaglutide has an amino acid sequence that is 90% homologous to endogenous human GLP-1 and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D. It is also indicated to reduce the risk of major adverse CV events in adults with T2D who have established CVD or multiple CV risk factors. Dulaglutide functions by lowering fasting glucose and reduces postprandial glucose concentrations in patients with T2D, the effect of which can be observed after a single dose. It also causes a delay in gastric motility, which subsides after the first dose with subsequent doses. Dulaglutide is administered as a once-weekly SC injection.

Efficacy

The efficacy of dulaglutide 0.75 mg and 1.5 mg once weekly has been studied as monotherapy and in combination with MET, MET and SFU, MET and TZD and prandial insulin with or without MET. The efficacy of dulaglutide 3.0 mg and 4.5 mg once weekly was assessed in combination with MET. In patients with T2D, dulaglutide produced reductions from baseline in A1C compared with placebo (Table 19.7). No overall differences in glycemic effectiveness were observed across demographic subgroups (age, gender, race/ethnicity, duration of diabetes).

Monotherapy

Monotherapy with dulaglutide was compared with MET-treated patients with T2D in a 52-week double-blind study which randomized patients to SC dulaglutide 1.5 mg, dulaglutide 0.75 mg, or MET. The primary objective compared change from baseline A1C at 26 weeks among treated groups.

At 26 weeks, changes from baseline A1C were greater in dulaglutide 1.5 and 0.75 mg vs MET (LS mean difference): -0.22% (-2.4 mmol/mol) and -0.15% (-1.6 mmol/mol) (one-sided P <0.025, both comparisons), respectively. Greater percentages reached A1C targets <7.0% with dulaglutide 1.5 and 0.75 mg compared with MET (P <0.05, all comparisons). No severe hypoglycemia was reported. Compared with MET, decrease in weight was similar with dulaglutide 1.5 mg and smaller with dulaglutide 0.75 mg.

When compared with sitagliptin, dulaglutide 0.75 mg and dulaglutide 1.5 mg were found to be superior in reducing the levels of A1C up to week 52 (P <0.001 for both comparisons). Mean weight changes to 52 weeks were greater with dulaglutide 1.5 mg (-3.03 ± 0.22 kg) and dulaglutide 0.75 mg (-2.60 ± 0.23 kg) compared with sitagliptin (-1.53 ± 0.22 kg) (P <0.001, both comparisons).

The safety and efficacy of dulaglutide was compared with that of liraglutide in MET-treated patients with uncontrolled T2D in a head-to-head phase 3 trial. 599 patients were randomized to receive once-weekly dulaglutide (1.5 mg) or once-daily liraglutide (1.8 mg). At 26 weeks, dulaglutide was noninferior to once-daily liraglutide for LS mean reduction in A1C, with a similar safety and tolerability profile. The LS mean reduction in A1C was -1·42% (SE 0.05) in the dulaglutide group and -1.36% (0.05) in the liraglutide group. Mean treatment difference in A1C was -0.06% (95% CI, -0.19, 0.07; P_{non-inferiority} <0.0001) between the two groups. (Figure 19-11)

In Combination With One OAD

The efficacy of dulaglutide 0.75 mg and 1.5 mg as an add-on to MET was assessed in a 104-week placebo-controlled, double-blind study, in which 972 patients were randomized to placebo, dulaglutide 0.75 mg once weekly, dulaglutide 1.5 mg once weekly, or sitagliptin 100 mg/day, all as add-on to MET. Treatment with dulaglutide 0.75 mg and 1.5 mg once weekly resulted in a statistically significant reduction in A1C compared with placebo (at 26 weeks) and compared with sitagliptin (at 26 and 52 weeks), all in combination with MET. At 26 weeks, the percentage of patients who achieved A1C <7.0% was 22%, 56%, 62%, 39% and a mean weight reduction of 1.4 kg, 2.7 kg, 3.0 kg and 1.4 kg was observed for placebo, dulaglutide 0.75 mg, dulaglutide 1.5 mg and sitagliptin, respectively. There was a mean reduction of fasting glucose of 9 mg/dL, 35 mg/dL, 41 mg/dL and 18 mg/dL for placebo, dulaglutide 0.75 mg, dulaglutide 1.5 mg and sitagliptin, respectively.

The efficacy of dulaglutide 3.0 mg and 4.5 mg as an add-on to MET was assessed in AWARD-11, a 52-week active-controlled, double-blind trial. A total of 1,842 patients were randomized to dulaglutide 1.5 mg once weekly, dulaglutide 3.0 mg once weekly, and dulaglutide 4.5 mg once weekly; patients continued with MET therapy in all three groups. Two estimands were used in the analysis of 36-week data: a treatment regimen estimand (included all baseline and end point data regardless of initiation of new antihyperglycemic therapy or premature treatment discontinuation) and an efficacy estimand (included data from all study visits before either initiation of a new antihyperglycemic drug for >14 days or premature treatment discontinuation).

With respect to the primary endpoint of A1C reduction from baseline, dulaglutide 4.5 mg was superior to the 1.5 mg dose at Week 36 under the treatment regimen estimand (mean change from baseline [mean baseline 8.6%]: dulaglutide 1.5 mg -1.54%, dulaglutide 4.5 mg -1.77%; estimated treatment difference [ETD]: -0.24%; P <0.001) and under the efficacy estimand (mean change from baseline: dulaglutide 1.5 mg -1.53%, dulaglutide 4.5 mg -1.87%; ETD: -0.34%; P <0.001). Dulaglutide 3.0 mg was also superior to the 1.5 mg dose under the efficacy estimand (mean change from baseline: dulaglutide 1.5 mg -1.53%, dulaglutide 4.5 mg -1.71%; estimated treatment difference [ETD]: -0.17%; P = 0.003) but was not superior under the treatment regimen estimand (mean change from baseline: dulaglutide 1.5 mg -1.54%, dulaglutide 4.5 mg -1.64%; estimated treatment difference [ETD]: -0.10%; P = 0.096).

Additionally, dulaglutide 4.5 mg demonstrated superiority to the 1.5 mg dose for weight loss at Week 36 under both the treatment regimen estimand (mean change from baseline [mean baseline 95.7 kg]: dulaglutide 1.5 mg -3.0 kg, dulaglutide 4.5 mg -4.6 kg; ETD: -1.6 kg; P <0.001) and the efficacy estimand (mean change from baseline: dulaglutide 1.5 mg -3.1 kg, dulaglutide 4.5 mg -4.7 kg; ETD: -1.6 kg; P <0.001).

In Combination With Two OADs

The addition of dulaglutide to MET and a TZD was examined in a 52-week placebo-controlled study, where 976 patients were randomized to placebo, dulaglutide 0.75 mg once weekly, dulaglutide 1.5 mg once weekly, or exenatide 10 mcg BID, all as add-on to maximally tolerated doses of MET (≥1500 mg per day) and pioglitazone (up to 45 mg per day).

After 26 weeks, patients in the placebo treatment group were randomized to either dulaglutide 0.75 mg once weekly or dulaglutide 1.5 mg once weekly. At 26 weeks, treatment with dulaglutide 0.75 mg and 1.5 mg once weekly resulted in a statistically significant reduction in A1C compared with placebo and compared with exenatide. Over the 52-week study period, the percentage of patients who required glycemic rescue was 8.9% in the dulaglutide 0.75 mg once weekly plus MET and pioglitazone treatment group, 3.2% in the dulaglutide 1.5 mg once weekly plus MET and pioglitazone treatment group, and 8.7% in the exenatide BID + MET and pioglitazone treatment group.

Treatment with dulaglutide once weekly resulted in similar reductions in A1C from baseline at 52 weeks when used in combination with MET and SFU, as well as with postprandial insulin injections with or without MET.

Safety and Tolerability

The most common side effects observed in patients treated with dulaglutide were nausea, diarrhea, vomiting, abdominal pain and decreased appetite.

As with other GLP-1 agonists, pancreatitis-related adverse reactions were reported in patients exposed to dulaglutide. Patients should be observed carefully for signs and symptoms of pancreatitis after initiation of treatment with dulaglutide, including persistent severe abdominal pain. If pancreatitis is suspected, dulaglutide should be discontinued and other anti-diabetic therapies considered. Dulaglutide has not been evaluated in patients with a prior history of pancreatitis. Similarly to other GLP-1 agents, the risk of hypoglycemia is increased when dulaglutide is used in combination with insulin secretagogues or insulin. Patients may require a lower dose of SFU or insulin to reduce the risk of hypoglycemia.

Although dulaglutide has been shown to cause a dose-related and treatment-duration–dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure in animal studies, it is unknown whether dulaglutide will cause thyroid C-cell tumors, including MTC in humans. Dulaglutide is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Dulaglutide should not be used to treat people with T1Ds, diabetic ketoacidosis, or severe abdominal or intestinal problems, or as first-line therapy for patients who cannot be managed with diet and exercise.

Cardiovascular Outcomes

The effect of dulaglutide on CV outcomes were investigated in REWIND, a large, international, double-blind trial. A total of 9,901 eligible patients (aged at least 50 years with T2D and a previous CV event or CV risk factors) were randomized (1:1) to receive either a weekly subcutaneous injection of dulaglutide 1.5 mg or placebo. The primary (composite) outcome was the first occurrence of non-fatal myocardial infarction, non-fatal stroke, or death from CV causes (including unknown causes).

The primary outcome occurred in 12.0% and 13.4% of patients in the dulaglutide and placebo groups, respectively (hazard ratio 0.88; P = 0.026), demonstrating the superiority of dulaglutide over placebo in reducing the incidence of a composite of CV outcomes (Figure 19-12). While the frequencies of prespecified adverse events remained comparable between the dulaglutide and placebo groups, gastrointestinal adverse events were significantly more frequent in the dulaglutide group (47.4% compared to 34.1% with the placebo; P <0.0001).

Dosage and Administration

The recommended initiating dose of dulaglutide is 0.75 mg once weekly, any time of day regardless of food intake. The dose may be increased to 1.5 mg once weekly for additional glycemic control. If further glycemic control is needed, the dose can be increased to 3 mg once weekly after at least 4 weeks on the 1.5 mg dose and further to the maximum dose of 4.5 mg once weekly after at least 4 weeks on the 3 mg dose. Dulaglutide is available as injectable solutions of 0.75 mg/0.5 mL,1.5 mg/0.5 mL, 3.0 mg/0.5 mL and 4.5 mg/0.5 mL. It should be injected subcutaneously in the abdomen, thigh, or upper arm using a single dose pen or prefilled syringe. Injection is rapid and takes <5 seconds.

Dulaglutide should not be used in patients with T1D or for the treatment of diabetic ketoacidosis. It is not a substitute for insulin. Dulaglutide has not been studied in patients with severe GI disease, including severe gastroparesis and is therefore not recommended in patients with pre-existing severe GI disease.

Figure 19-11: Change From Baseline in Glycemic Control and Body Weight at Week 26 for Dulaglutide vs Liraglutide. <sup>a </sup><em>P</em> <0.05. Source: Modified from Dungan KM, et al. <em>Lancet</em>. 2014;384(9951):1349-1357. — Figure 19-11: Change From Baseline in Glycemic Control and Body Weight at Week 26 for Dulaglutide vs Liraglutide. ^aP <0.05. Source: Modified from Dungan KM, et al. *Lancet*. 2014;384(9951):1349-1357.

Figure 19-12: Primary Cardiovascular Composite Outcome in REWIND. Source: Modified from Gerstein HC, et al. <em>Lancet</em>. 2019;394(10193):121-130. — Figure 19-12: Primary Cardiovascular Composite Outcome in REWIND. Source: Modified from Gerstein HC, et al. *Lancet*. 2019;394(10193):121-130.

Lixisenatide (Adlyxin)

Lixisenatide was approved by the FDA in 2016 and is used alone but also commonly in the fixed ratio combination with insulin glargine U-100 (Soliqua 100/33, see below). Lixisenatide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D. It functions by increasing glucose-dependent insulin release, decreasing glucagon secretion, and slowing gastric emptying.

Efficacy

The efficacy of lixisenatide once daily has been studied as monotherapy and in combination with MET, MET ± an SFU, an SFU ± MET, pioglitazone ± MET, and basal insulin ± OADs (Table 19-8). In patients with T2D, lixisenatide significantly reduced A1C from baseline compared with placebo. Treatment with lixisenatide also had weight neutral effects or lead to significant weight loss, an important finding considering that weight gain is commonly associated with treatment intensification.

Monotherapy

In a 12-week double-blind study, 241 patients with T2D inadequately controlled on diet and exercise were randomized to lixisenatide 20 mcg once daily or placebo. Compared with placebo, treatment with lixisenatide resulted in statistically significant reductions in A1C from baseline at Week 12 (treatment difference: -0.65% [P <0.0001]). A significant difference was not observed in adjusted mean weight change from baseline between trial arms.

In Combination With MET (Alone or in Combination With an SFU)

Three 24-week studies assessed the efficacy of lixisenatide 20 mcg once daily in patients with T2D. The first trial enrolled 323 patients inadequately controlled on diet, exercise and MET. The second trial enrolled 391 Asian patients inadequately controlled on diet, exercise and MET with or without an SFU. In both trials, treatment with lixisenatide resulted in statistically significant reductions in A1C from baseline at Week 24 compared with placebo (treatment difference: -0.46% [P <0.0001] and -0.27% [P = 0.0032], respectively).

In a third study, 634 patients with T2D inadequately controlled on diet, exercise and MET were randomized to lixisenatide 20 mcg once daily or exenatide 10 mcg twice daily. Lixisenatide met the prespecified noninferiority margin of 0.4% vs exenatide for the difference in A1C reduction from baseline; however, lixisenatide provided significantly less A1C reduction than exenatide (treatment difference: 0.17% [P = 0.0175]).

In Combination With an SFU or Pioglitazone (Alone or in Combination With MET)

The efficacy of lixisenatide 20 mcg once daily was assessed in combination with an SFU or pioglitazone, alone or in combination with MET, in two 24-week studies. The first study enrolled 859 patients with T2D inadequately controlled with diet, exercise and an SFU with or without MET. The second study enrolled 484 patients with T2D with inadequately controlled with diet, exercise and pioglitazone with or without MET. In both studies, treatment with lixisenatide resulted in statistically significant reductions in A1C from baseline at Week 24 compared with placebo (treatment difference: -0.58% [P <0.0001] and -0.48% [P <0.0001], respectively).

In Combination With Basal Insulin (Alone or in Combination With OADs)

The efficacy of lixisenatide in combination with basal insulin alone or in combination with OADs was assessed in four studies. The first study enrolled 496 patients with T2D inadequately controlled on diet, exercise and basal insulin with or without MET. The second study enrolled 311 Asian patients with T2D inadequately controlled on diet, exercise and basal insulin with or without an SFU. The third study enrolled 446 patients with T2D inadequately controlled on diet, exercise, insulin glargine and MET with or without TZDs. In all three studies, randomization to lixisenatide 20 mcg once daily resulted in statistically significant reductions in A1C from baseline at Week 24 compared with placebo (treatment difference: -0.36% [P = 0.0002], -0.76% [P <0.0001] and -0.28% [P = 0.0005], respectively).

A fourth study enrolled 894 patients with T2D inadequately controlled on diet, exercise and basal insulin combined with 1 to 3 OADs. In this 26-week open-label study, patients were randomized to lixisenatide 20 mcg once daily, insulin glulisine once daily, or insulin glulisine TID combined with insulin glargine with or without MET. Lixisenatide 20 mcg once daily met the prespecified noninferiority margin of 0.4% vs insulin glulisine QD and TID for the difference in A1C reduction from baseline. However, lixisenatide provided significantly less A1C reduction than insulin glulisine TID (treatment difference: 0.23% [P = 0.0002]).

Safety and Tolerability

Adverse reactions that were not present at baseline, occurred more commonly with lixisenatide than with placebo and occurred in ≥5% of patients treated with lixisenatide were nausea (25%), vomiting (10%), headache (9%), diarrhea (8%) and dizziness (7%). The majority of these adverse reactions occurred during the first 3 weeks after starting treatment.

As with other GLP-1 agonists, pancreatitis has been reported in patients exposed to lixisenatide. Patients should be observed carefully for signs and symptoms of pancreatitis after initiation of treatment with lixisenatide, including persistent severe abdominal pain. If pancreatitis is suspected, lixisenatide should be promptly discontinued and appropriate management initiated. Other antidiabetic therapies should be considered in patients with a history of pancreatitis, since lixisenatide has not been studied in patients with chronic pancreatitis or a history of unexplained pancreatitis.

Similar to other GLP-1 agents, the risk of hypoglycemia is increased when lixisenatide is used in combination with basal insulin or an SFU. Patients may require a lower dose of SFU or insulin to reduce the risk of hypoglycemia. Acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis, has been reported in patients exposed to GLP-1 receptor agonists. Monitor renal function when initiating or escalating doses of lixisenatide in patients with renal impairment and in patients reporting severe gastrointestinal reactions.

Clinical studies have not shown macrovascular risk reduction with lixisenatide.

Dosage and Administration

The recommended starting dose of lixisenatide is 10 mcg SC once daily for 14 days. On Day 15, the dose should be increased to the maintenance dose of 20 mcg once daily. Lixisenatide is administered by SC injection in the abdomen, thigh, or upper arm 1 hour prior to the first meal of the deal, preferably at the same time each day. If a dose is missed, lixisenatide should be administered within 1 hour prior to the next meal. Lixisenatide is available as solutions for SC injection in single-patient use prefilled pens as:

50 mcg/mL in 3 mL of solution, for 14 doses at 10 mcg/dose
100 mcg/mL in 3 mL solution, for 14 doses at 20 mcg/dose.

Lixisenatide is not a substitute for insulin and is not indicated for use in patients with T1D or for the treatment of diabetic ketoacidosis. The concurrent use of lixisenatide with short-acting insulin has not been studied and is not recommended.

Ozempic (Semaglutide)

Semaglutide was approved by the FDA in 2017 as an adjunct to diet and exercise to improve glycemic control in adults with T2D. It has also received approval to reduce the risk of major adverse CV events in adults with T2D mellitus and established CVD.

Efficacy

The safety and efficacy of semaglutide has been evaluated in eleven clinical trials (SUSTAIN-1 to -11) in patients with T2D as monotherapy or in combination with metformin, metformin and sulfonylureas, metformin and/or thiazolidinedione, basal insulin, or metformin and basal insulin. In these trials, treatment with semaglutide had clinically relevant effects on reducing A1C, FPG, and weight from baseline (Table 19-9).

Monotherapy

SUSTAIN-1 was a 30-week trial than enrolled 388 patients with T2D inadequately controlled with diet and exercise. Eligible patients were randomized to 0.5 mg semaglutide or 1.0 mg semaglutide once weekly or placebo. Monotherapy with 0.5 mg or 1.0 mg semaglutide resulted in statistically significantly reductions in A1C compared with placebo (baseline mean A1C level: placebo group 8.0%, semaglutide 0.5 mg group 8.1%, semaglutide 1.0 mg group 8.1%; change: placebo -0.1%, semaglutide 0.5 mg -1.4%, semaglutide 1.0 mg -1.6%; difference from placebo: semaglutide 0.5 mg -1.2%, semaglutide 1.0 mg -1.4%; P <0.0001 for both).

Combination With Metformin and/or Thiazolidinediones

SUSTAIN-2 was a 56-week trial that randomized 1,231 patients with T2D to 0.5 mg semaglutide or 1.0 mg semaglutide once weekly or sitagliptin 100 mg once daily, all in combination with metformin and/or thiazolidinediones. Treatment with semaglutide 0.5 mg or 1.0 mg once weekly resulted in a significant reduction in A1C compared to sitagliptin (baseline mean A1C level: sitagliptin group 8.2%, semaglutide 0.5 mg group 8.0%, semaglutide 1.0 mg group 8.0%; change: sitagliptin -0.7%, semaglutide 0.5 mg -1.3%, semaglutide 1.0 mg -1.5%; difference from sitagliptin: semaglutide 0.5 mg -0.6%, semaglutide 1.0 mg -0.8%; P <0.0001 for both).

Combination With Metformin or Metformin With Sulfonylurea

SUSTAIN-3 was a 56-week open-label trial that enrolled 813 patients with T2D, with the majority (96%) of patients on metformin alone or metformin with sulfonylurea. Eligible patients were randomized to receive 1.0 mg semaglutide or 2.0 mg exenatide once weekly. Treatment with semaglutide resulted in a significant reduction in A1C compared to exenatide (baseline mean A1C level: exenatide group 8.3%, semaglutide group 8.4%; change: exenatide -0.9%, semaglutide -1.4%; difference from exenatide: -0.5%; P <0.0001).

SUSTAIN-4 was a 30-week trial of 1089 patients with T2D randomized to receive 0.5 mg semaglutide or 1.0 mg semaglutide once weekly or insulin glargine once daily. All patients received background metformin or metformin and sulfonylurea. Patients who received insulin glargine started at a dose of 10U once daily, with dose adjustments being made throughout the trial period based on self-measured fasting plasma glucose before breakfast, with a target of 71 mg/dL to <100 mg/dL. Insulin glargine could also be titrated between study visits at the discretion of the investigator. Treatment with 0.5 mg or 1.0 mg semaglutide resulted in a significant reduction in A1C compared with insulin glargine (baseline mean A1C level: insulin glargine group 8.1%, semaglutide 0.5 mg group 8.1%, semaglutide 1.0 mg group 8.2%; change: insulin glargine -0.9%, semaglutide 0.5 mg -1.2%, semaglutide 1.0 mg -1.5%; difference from insulin glargine: semaglutide 0.5 mg -0.3%, semaglutide 1.0 mg -0.6%; P <0.0001 for both).

SUSTAIN-FORTE was a 40-week randomized, active-controlled, double-blind trial involving a total of 961 patients with T2D inadequately controlled on metformin with or without sulfonylurea. The goal of SUSTAIN-FORTE was to assess the safety and efficacy of a higher semaglutide dose compared to the maximum then-approved weekly dose. Participants were randomized (1:1) to receive either semaglutide 1.0 mg weekly or semaglutide 2.0 mg weekly. The 2.0 mg weekly dose was superior to the led to a significantly lower A1C level at 40 weeks (baseline mean A1C level: semaglutide 1.0 mg group 8.8%, semaglutide 2.0 mg group 8.9%; mean change: semaglutide 1.0 mg -1.9%, semaglutide 2.0 mg -2.1%; difference in favor of semaglutide 2.0 mg: -0.2%; P <0.01).

Combination With Basal Insulin

SUSTAIN-5 was a 30-week trial of 397 patients with T2D inadequately controlled with basal insulin, with or without metformin. Enrolled patients were randomized to 0.5 mg semaglutide or 1.0 mg semaglutide once weekly or placebo. To reduce the risk of hypoglycemia, those patients with A1C <8.0% at screening reduced their insulin dose by 20% at trial initiation. Treatment with semaglutide resulted in a significant reduction in A1C after 30 weeks compared to placebo (baseline mean A1C level: placebo group 8.4%, semaglutide 0.5 mg group 8.4%, semaglutide 1.0 mg group 8.3%; change: placebo -0.2%, semaglutide 0.5 mg -1.3%, semaglutide 1.0 mg -1.7%; difference from placebo: semaglutide 0.5 mg, -1.1%; semaglutide 1.0 mg, -1.6%; P <0.0001).

Combination With Metformin: Semaglutide vs Dulaglutide

SUSTAIN-7 was a 40-week, head-to-head, open-label, parallel-group trial that compared the safety and efficacy of semaglutide and dulaglutide in T2D treatment. A total of 1201 eligible patients (adults with T2D uncontrolled [A1C 7.0–10.5%] on metformin monotherapy) were randomized (1:1:1:1) to one of the following once-weekly regimens: 1) semaglutide 0.5 mg; 2) dulaglutide 0.75 mg; 3) semaglutide 1.0 mg; or 4) dulaglutide 1.5 mg. Semaglutide demonstrated superiority over dulaglutide with respect to the primary endpoint of A1C change from baseline (mean baseline: semaglutide 0.5 mg group 8.3%, dulaglutide 0.75 mg group 8.2%, semaglutide 1.0 mg group 8.2%, dulaglutide 1.5 mg group 8.2%; mean change: semaglutide 0.5 mg -1.5%, dulaglutide 0.75 mg -1.1%, semaglutide 1.0 mg -1.8%, dulaglutide 1.5 mg -1.4%; ETD in favor of semaglutide 0.5 mg over dulaglutide 0.75 mg: -0.40%; ETD in favor of semaglutide 1.0 mg over dulaglutide 1.5 mg: -0.41%; P <0.0001 for both). Semaglutide was also superior to dulaglutide in reducing bodyweight (mean baseline: semaglutide 0.5 mg group 96.4 kg, dulaglutide 0.75 mg group 95.6 kg, semaglutide 1.0 mg group 95.5 kg, dulaglutide 1.5 mg group 93.4 kg; mean change: semaglutide 0.5 mg -4.6 kg, dulaglutide 0.75 mg -2.3 kg, semaglutide 1.0 mg -6.5 kg, dulaglutide 1.5 mg -3.0 kg; ETD in favor of semaglutide 0.5 mg over dulaglutide 0.75 mg: -2.26 kg; ETD in favor of semaglutide 1.0 mg over dulaglutide 1.5 mg: -3.55 kg; P <0.0001 for both).

Combination With Metformin: Semaglutide vs Canagliflozin

In SUSTAIN-8, a 52-week, head-to-head, double-blind trial, the safety and efficacy of semaglutide 1.0 mg once weekly in patients with T2D uncontrolled on metformin was compared to that of canagliflozin 300 mg once daily. A total of 788 eligible patients was randomized (1:1) to either semaglutide 1.0 mg weekly or canagliflozin 300 mg daily. Patients receiving semaglutide had a significantly greater reduction in A1C at Week 52 (mean baseline: canagliflozin group 8.2%, semaglutide group 8.3%; mean change: canagliflozin -1.0%, semaglutide -1.5%; ETD: -0.49%; P <0.0001), the primary endpoint of the trial. Semaglutide also led to a significantly greater reduction in bodyweight compared to canagliflozin (mean baseline: canagliflozin group 89.8 kg, semaglutide group 90.6 kg; mean change: canagliflozin -4.2 kg, semaglutide -5.3 kg; ETD: -1.06 kg; P = 0.0029).

Combination With SGLT2 Inhibitor

SUSTAIN-9 was a 30-week trial that compared to safety and efficacy of semaglutide to a placebo in patients with T2D uncontrolled despite existing SGLT2 inhibitor therapy. A total of 302 patients were randomized (1:1) to semaglutide 1.0 mg or a volume-matched placebo and continued taking existing therapy. Patients in the semaglutide group achieved greater reductions in A1C (mean baseline: placebo group 8.1%, semaglutide group 8.0%; mean change: placebo -0.1%, semaglutide -1.5%; ETD: -1.42%; P <0.0001) at Week 30, the primary endpoint of the trial. Semaglutide was also superior to the placebo with regard to mean change in bodyweight (mean baseline: placebo group 93.8 kg, semaglutide group 89.6 kg; mean change: placebo -0.9 kg, semaglutide -4.7 kg; ETD: -3.81 kg; P <0.0001).

Combination With Metformin, Sulfonylurea, or SGLT Inhibitor: Semaglutide vs Liraglutide

The objective of SUSTAIN-10, a 30-week, head-to-head, open-label European trial was to compare the efficacy of semaglutide to liraglutide in their most frequently prescribed doses (reflecting real-world clinical practice). A total of 577 eligible patients (with T2D uncontrolled on 1-3 oral antidiabetic drugs) were randomized (1:1) to either semaglutide 1.0 mg once weekly or liraglutide 1.2 mg. Patients receiving semaglutide had significantly reduced A1C levels at Week 30 (the primary endpoint) compared to those receiving liraglutide (mean baseline: liraglutide group 8.3%, semaglutide group 8.2%; mean change: liraglutide -1.0%, semaglutide -1.7%; ETD: -0.69%; P <0.0001). Semaglutide also demonstrated superior results in mean bodyweight change (mean baseline: liraglutide group 97.2 kg, semaglutide group 96.6 kg; mean change: liraglutide -1.9 kg, semaglutide -5.8 kg; ETD: -3.83 kg; P <0.0001).

Combination With Metformin and Basal Insulin: Semaglutide vs Insulin Aspart

In SUSTAIN-11, a 52-week, parallel, open-label trial, 1748 adult patients with T2D uncontrolled on insulin glargine 100 units/mL and metformin were randomized (1:1) to semaglutide 1.0 mg once a week or insulin aspart 100 units/mL three times a day. At treatment initiation, insulin aspart was distributed at 4 units/mL three times a day. Both insulin glargine and insulin aspart doses were adjusted based on self-measured plasma glucose and individualized treatment goals. At week 52, semaglutide demonstrated a greater improvement in A1C levels compared to insulin aspart (mean baseline: 8.6% in both semaglutide and insulin aspart groups; mean change: -1.5% for semaglutide, and -1.2% for insulin aspart; ETD: -0.29%; P<0.0001). Additionally, semaglutide provided greater weight loss than insulin aspart (mean baseline: 87.9 kg for both groups; mean change: -4.1 kg for semaglutide, and +2.8 kg for insulin aspart; ETD: -6.99 kg).

Safety and Tolerability

The prescribing information for semaglutide includes a boxed warning for risk of thyroid C-cell tumors. Although semaglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma, in rodents, the relevance of this risk in humans has not been determined. Regardless, semaglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2. The prescribing information for semaglutide also contains warnings and precautions for pancreatitis, diabetic retinopathy complications, hypoglycemia, acute kidney injury and hypersensitivity.

The most common adverse reactions, excluding hypoglycemia, associated with the use of 1.0 mg semaglutide and occurring in ≥5% of semaglutide-treated patients include nausea (20.3%), vomiting (9.2%), diarrhea (8.8%), abdominal pain (5.7%) and constipation (3.1%).

Cardiovascular Outcome Trial of Semaglutide (SUSTAIN-6)

SUSTAIN-6 was a 104-week trial that enrolled 3297 patients with T2D at a high risk for CV events. Eligible patients were randomized to 0.5 mg semaglutide once weekly, 1.0 mg semaglutide once weekly, or placebo in addition to standard-of-care. Eighty-three percent of patients had a history of CV disease and 17% were at high risk, but without known CV disease. The composite primary endpoint was the first occurrence of death from CV causes, nonfatal MI, or nonfatal stroke.

The composite primary outcome occurred in 6.6% of semaglutide-treated patients compared to 8.9% of the placebo group (HR=0.74; P <0.001 for noninferiority; P = 0.02 for superiority; Figure 19-13-A). Of the individual composite components, only nonfatal stroke occurred significantly less frequently in semaglutide-treated patients compared to placebo (1.6% vs 2.7%; HR=0.61; P = 0.04; Figure 19-13-B). No significant differences were observed between treatment groups for components of nonfatal MI or CV death. Similar results were observed for both doses of semaglutide.

Complications of diabetic retinopathy occurred more frequently in semaglutide-treated patients compared to the placebo group (3.0% vs 1.8%; HR=1.76; P = 0.02), whereas new or worsening nephropathy occurred less frequently in semaglutide-treated patients (3.8% vs 6.1%; HR=0.64; P = 0.005).

Figure 19-13: Primary Composite Outcome and Nonfatal Stroke Component of the SUSTAIN-6 Trial. Source: Modified from Marso SP, et al. <em>N Engl J Med</em>. 2016;375:1834-1844. — Figure 19-13: Primary Composite Outcome and Nonfatal Stroke Component of the SUSTAIN-6 Trial. Source: Modified from Marso SP, et al. *N Engl J Med*. 2016;375:1834-1844.

Dosage and Administration

Semaglutide should be initiated with a 0.25 mg SC injection once weekly for 4 weeks, followed by an increase to 0.5 mg once weekly. The 0.25 mg dose is not effective for glycemic control and is only intended for treatment initiation. Dosage may be increased to 1.0 mg once weekly if additional glycemic control is needed after at least 4 weeks on the 0.5 mg dose, and to a maximum of 2.0 mg once weekly if additional glycemic control is required after at least 4 weeks on the 1.0 mg dose.

Semaglutide should be administered on the same day each week, at any time of day, with or without food. The day of weekly administration can be changed, but the time between two consecutive doses should be at least 48 hours. If a patient misses a dose, they should administer their dose as soon as soon as possible, but within 5 days of the missed dose. If more than 5 days have passed, the patient should skip the missed dose and resume the next dose on the next scheduled day. If the patient is also receiving insulin, injections should not be administered adjacent to one another.

Switching from Injectable to Oral Semaglutide

Patients treated with SC semaglutide 0.5 mg once weekly can be transitioned to a once daily dose of oral semaglutide (7 mg or 14 mg; see the Oral Semaglutide section below). Patients can start taking oral semaglutide 7 days after the last dose of injectable semaglutide. There is no equivalent dose of oral semaglutide for SC semaglutide 1 mg or 2 mg.

Summary

The introduction of GLP-1 receptor agonists represents a significant advance in the treatment of T2D. Not only are they effective in improving overall glycemic control as indicated by the FBG and PPG values and A1C, but at the same time they lead to weight loss. These effects on weight are very important since weight gain associated with intensification of therapy in an effort to normalize or near normalize A1C is a significant challenge in clinical practice. The positive effects on ASCVD also adds another important clinical dimension to this class of agents. The combination of GLP-1 RAs with MET appears to be not only effective in terms of metabolic outcomes but also safe in terms of a lower risk of hypoglycemia. It also appears that the weight gain seen with SFUs, TZDs and insulin is blunted when these agents are combined with these new classes of antidiabetic agents. Finally, activation of the GLP-1 receptors by these agents may also present the potential to improve β-cell function and, therefore, result in slowing down or halting the natural history of T2D. Thus, these novel medications have an important role in the prevention of T2D if used early in the course of glucose intolerance.

Rybelsus (Oral Semaglutide)

The oral (tablet) formulation of semaglutide received FDA approval in 2019 as an adjunct to diet and exercise to improve glycemic control in adults with T2D. This marks the first approval of an oral GLP-1 receptor agonist.