GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS FOR TYPE 2 DIABETES: A COMPREHENSIVE

Transcription

1 ENDOCRINE PRACTICE Rapid Electronic Article in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Original Article EP GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS FOR TYPE 2 DIABETES: A COMPREHENSIVE REVIEW OF HOW TO WEIGH THE OPTIONS, SELECT THE RIGHT PATIENTS, AND MAXIMIZE BENEFITS Lawrence Blonde, MD 1, FACP, MACE; Vivian Fonseca, MD 2 Running Title: Review of GLP-1 Receptor Agonists From: 1 Director, Ochsner Diabetes Clinical Research Unit, Frank Riddick Diabetes Institute, Department of Endocrinology, Ochsner Medical Center; 2 Chief, Section of Endocrinology, Tulane University School of Medicine Corresponding address: Vivian Fonseca, MD Tullis Tulane Alumni Chair in Diabetes Professor of Medicine and Pharmacology Chief, Section of Endocrinology Tulane University School of Medicine 1430 Tulane Avenue - SL 53 New Orleans, LA vfonseca@tulane.edu

2 Word Count: 9817 Number of Tables: 2 Number of Figures: 4 Key words: diabetes, type 2 diabetes, GLP-1 receptor agonists, cardiovascular, antihyperglycemic Faculty Disclosures Vivian Fonseca, MD Contracted Research: Asahi Kasei Pharma; Bayer HealthCare Consulting: AstraZeneca; Eli Lilly and Company; Janssen Pharmaceuticals, Inc; Novo Nordisk, Inc.; sanofi-aventis U.S. LLC; Takeda Pharmaceutical Company Ltd Lawrence Blonde, MD, FACP, MACE Investigator: AstraZeneca; Janssen Pharmaceuticals, Inc; Lexicon Pharmaceuticals, Inc.; Merck & Co, Inc; Novo Nordisk, Inc.; sanofi-aventis U.S. LLC Speaker: AstraZeneca; Janssen Pharmaceuticals, Inc; Novo Nordisk, Inc.; sanofiaventis U.S. LLC Consultant: Intarcia Therapeutics, Inc.; Janssen Pharmaceuticals, Inc; Merck & Co, Inc.; Novo Nordisk, Inc.; sanofi-aventis U.S. LLC

3 ABSTRACT A growing body of data, guideline recommendations, algorithms, and position papers supports the use of glucagon-like peptide-1 (GLP-1) receptor agonists in type 2 diabetes (T2D), given their beneficial effects on glycemic control, weight, lipid parameters, and blood pressure, and low risk for hypoglycemia when used in patients who have not achieved glycemic goals with metformin and lifestyle interventions. Exciting new evidence continues to emerge, showing the utility of certain GLP-1 receptor agonists to decrease incident cardiovascular (CV) outcomes, and to bolster glycemic control when combined with other antihyperglycemic therapies, including basal insulin. The recent availability of fixed-ratio GLP-1 receptor agonist and basal insulin coformulations and a new, first-ever, indication for the use of a GLP-1 receptor agonist (liraglutide) to reduce the risk of major adverse CV events (MACE) in adults with T2D and established cardiovascular disease (CVD) increase options for improved care. In addition, semaglutide (another GLP-1 receptor agonist with positive CV outcomes data) received FDA approval in December 2017 with an indication to improve glycemic control in adults with T2D. These new developments and continuously emerging CV outcomes data should be considered in determining how GLP-1 receptor agonists may be best used in clinical practice. This Q&A presentation with 2 expert endocrinologists provides a pragmatic approach to inform the selection and use of GLP-1 receptor agonists based on the rapidly evolving evidence. RATIONALE FOR THE USE OF GLP-1 RECEPTOR AGONISTS EARLIER IN THE

4 COURSE OF T2D TREATMENT Q: When and why should you consider adding a GLP-1 receptor agonist to T2D treatment? Fonseca: Many patients with T2D would benefit from the addition of a GLP-1 receptor agonist when lifestyle modifications and metformin are insufficient to achieve glycemic goals. GLP-1 receptor agonists are exceptional in terms of glycemic efficacy. In comparative trials, they have proven superior to virtually all noninsulin agents, including dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors (network meta-analysis; no head-to-head trials), sulfonylureas, thiazolidinediones, and metformin.[1-6] In clinical trials, GLP-1 receptor agonists have reduced hemoglobin A1C (A1C) by 0.6% to 1.5% when added to metformin. Liraglutide, semaglutide, dulaglutide, and exenatide ER have each demonstrated statistically significant reductions in A1C relative to active comparators.[7-9] It is noteworthy that, in none of the head-to-head GLP-1 receptor agonist trials (AWARD-6 and DURATION-6), was the comparator agent able to produce a greater A1C reduction than liraglutide.[10 11] In head-to-head trials, semaglutide, the newest of the 7 available GLP-1 receptor agonists reduced A1C by 1.5% to 1.8% significantly more than active comparators oral sitagliptin, insulin glargine, basal insulin, exenatide ER, and dulaglutide (see Figure 1).[10-20] Furthermore, semaglutide was associated with significant weight loss (4.5 kg to 6.4 kg). Mild to moderate nausea, the most common side effect, was typically transient. Two doses of semaglutide (0.5 mg once weekly and 1.0 mg once weekly), available in prefilled pens, were approved in December 2017.[21]

5 Blonde: When patients are not at goal on 1 or more oral antihyperglycemic agents, certain GLP-1 receptor agonists have demonstrated greater or equal A1C lowering than basal insulin analogs, with (in most cases), weight loss and less hypoglycemia.[22-25] At least 5 head-to-head trials compared a basal insulin analog to a GLP-1 receptor agonist in people with baseline A1C of 8% to 8.5% receiving 1 or more oral antihyperglycemic agents.[ ] In none of them was the basal insulin analog better at lowering hyperglycemia; and, in 3 of them, GLP-1 receptor agonists resulted in better A1C lowering and, in most, a weight and hypoglycemia benefit. Fonseca: One of the great benefits of GLP-1 receptor agonists is that they can be combined with basal insulin to obviate the need for prandial insulin in many patients with T2D. Prandial insulin poses many problems for people with T2D because of the complexity of the injection regimen and the potential for weight gain and hypoglycemia. Having the opportunity to achieve better control without those problems is important in T2D care. In the HARMONY 6 trial, once-weekly albiglutide added-on to basal insulin glargine versus thrice-daily prandial insulin added-on to basal insulin glargine led to comparable improvements in glucose control. At week 26, A1c decreased from baseline by ± SE 0.06% (9.0 mmol/mol) with albiglutide and ± 0.06% (7.2 mmol/mol) with insulin lispro; treatment difference, 20.16% (95% CI to 0.00; 1.8 mmol/mol; P<.0001), meeting the noninferiority endpoint. Albiglutide had the added benefit of weight loss (-0.73 ± 0.19 kg) versus weight gain with insulin lispro (+0.81 ± 0.19 kg)

6 less hypoglycemia, and a low rate of gastrointestinal (GI) adverse events (<5%) throughout the study period.[29] The option of 1 injection per week versus 21 injections per week to achieve similar glycemic benefits and additional benefits is also appealing and convenient, and it aligns with the American Diabetes Association/European Foundation for the Study of Diabetes (ADA/EASD) position statement s call for a more patient-centered approach to diabetes treatment.[30] Blonde: The strategy of adding a GLP-1 receptor agonist to basal insulin offers the complementary mechanisms of action of the two classes of agents to help control both fasting and postprandial plasma glucose. Several key trials, including HARMONY 6 discussed by Dr. Fonseca above, and SUSTAIN 5, support adding a GLP-1 receptor agonist when basal insulin plus oral antihyperglycemic agents have not achieved glycemic control in appropriate patients, as do clinical guidelines and algorithms.[30-33] Although trial results are not yet published, the SUSTAIN 5 abstract presented at EASD 2016 demonstrates the superiority of semaglutide versus placebo in reducing A1C levels and body weight in patients taking basal insulin.[34] At 30 weeks, mean A1C was reduced by 1.4% and 1.8% with semaglutide 0.5 mg and 1.0 mg, respectively, versus 0.1% with placebo. In addition, mean body weight was reduced by -3.7 kg and -6.4 kg with semaglutide 0.5 mg and 1.0 mg, respectively, versus -1.4 kg with placebo. Combining basal insulin and a GLP-1 receptor agonist has become more convenient with the recent approval of two fixed-ratio coformulations (insulin glargine/lixisenatide 100/33 and insulin degludec/liraglutide 100/3.6) that can be

7 administered as a single injection. The fixed-ratio coformulation of insulin glargine/lixisenatide 100/33 was studied in the LixiLan-L and LixiLan-O trials. LixiLan-L included 736 patients with long-standing basal insulin-treated diabetes (mean diabetes duration 12 years, BMI 31 kg/m 2 ), randomized 1:1 to receive openlabel, once-daily iglarlixi or iglar, both titrated to fasting plasma glucose <100 mg/dl (<5.6 mmol/mol) up to a maximum dose of 60 units/day.[35] At 30 weeks, fixed-ratio insulin glargine/lixisenatide 100/33 showed greater reductions in A1C from baseline compared with insulin glargine ( 1.1% versus 0.6%, P<.0001), reaching a mean final A1C of 6.9% (52 mmol/mol) compared with 7.5% (58 mmol/mol) for iglar alone. Weight decreased with the coformulation and increased with the use of insulin glargine (1.4 kg difference; P<.0001). LixiLan-O studied the coformulation of insulin glargine/lixisenatide 100/33 versus each component separately, with similar results.[36] Participants (N=1170, mean diabetes duration 8.8 years, BMI 31.7 kg/m 2 ) were randomly assigned to open-label once-daily insulin glargine/lixisenatide 100/33 or insulin glargine, both titrated to fasting plasma glucose <100 mg/dl (<5.6 mmol/l) up to a maximum insulin dose of 60 units/day, or to once-daily lixisenatide (20 μg/day) while continuing with metformin. At 30 weeks, greater reductions in A1C from baseline (8.1% [65 mmol/mol]) were achieved with insulin glargine/lixisenatide 100/33 compared with insulin glargine or 2lixisenatide ( 1.6%, 1.3%, 0.9%, respectively), reaching mean final A1C levels of 6.5% (48 mmol/mol) for insulin glargine/lixisenatide 100/33 versus 6.8% (51 mmol/mol) and 7.3% (56 mmol/mol) for insulin glargine and lixisenatide, respectively (both P<.0001). The DUAL phase 3 clinical trial program demonstrates the role of fixed-ratio

8 insulin degludec 100 units/ml and liraglutide 3.6 mg/ml (IDegLira) as an efficacious intensification approach in patients with T2D who are inadequately controlled on oral agents, basal insulin or GLP-1 receptor agonists. IDegLira consistently achieved an average A1C below 7% at 26 weeks, across all clinical trials, whether patients were converted from basal insulin (DUAL II and DUAL V) or GLP-1 receptor agonist (DUAL III).[37-39] or had IDegLira added to oral antidiabetes drugs.[40 41] DUAL II, which evaluated IDegLira in an insulin-experienced population, showed that IDegLira-treated patients achieved superior glycemic control versus those on insulin degludec (both capped at 50 U/d).[37] DUAL V, conducted in patients who were inadequately controlled on units of insulin glargine, compared IDegLira with the uptitration of insulin glargine 100 units/ml. IDegLira resulted in superior lowering of A1C, a lower rate of hypoglycemia, and weight loss, versus insulin glargine 100 units/ml.[38] DUAL III confirmed the superiority of IDegLira compared with maximum-dose GLP-1 receptor agonist therapy and oral antihyperglycemic medication in insulin-naïve patients.[39] Mean A1C reduced from 7.8% to 6.4% (61.5 to 46.9 mmol/mol) with IDegLira and from 7.7 to 7.4% (60.8 to 57.1 mmol/mol) with unchanged GLP-1 receptor agonist therapy. Furthermore, 75% and 63% of patients receiving IDegLira achieved A1C <7% and 6.5%, respectively, compared with 36% and 23% of those on unchanged GLP-1 receptor agonist therapy.[39] The DUAL VII phase 3b trial randomized patients with A1C >7% on insulin glargine U100 plus metformin to basal bolus therapy (combining insulin glargine U100 and premeal insulin aspart) or IDegLira. Similar A1C reduction occurred with both

9 therapies but those receiving IDegLira had significantly lower rates of hypoglycemia and a decrease in weight (rather than weight gain).[32 42] The IDegLira group also needed a lower total daily insulin dose compared with the basal-bolus treatment group (40 vs 84 units; P<.0001). Other adverse events were similar across both treatment groups. To summarize, fixed-ratio GLP-1 receptor agonist basal insulin analog coformulations improved overall glycemic control with less weight gain (or weight reduction), and low rate of hypoglycemia compared with basal insulin but with higher rates of hypoglycemia than GLP-1 receptor agonists alone. Many T2D patients have not achieved target glycemia on basal insulin plus oral antihyperglycemic agents. Switching from basal insulin to one of the coformulations may help many patients achieve improved glycemia without increasing the number of daily injections. Fonseca: We need to put these clinical trials into context for application in practice. Most patients in the trials had failed on insulin, though they were receiving a modest dose. A few patients had failed GLP-1 receptor agonist therapy, and a few others were receiving oral agents alone. For the latter, the fixed-ratio GLP-1 receptor agonist/basal insulin coformulation becomes the first injectable therapy. However, not enough patients have been tested, and the FDA has only approved this coformulation in patients who have failed either component alone. Ongoing trials should provide data on the larger number of patients who have never used injectable antihyperglycemic medication. Another practical limitation is the dose of prior injectable therapy, since the fixedratio coformulation requires a potentially large dose reduction. Further, there is a limit to the maximum insulin dose in fixed-ratio coformulations (60 units with iglarlixi and 50

10 units with IDegLira).[43 44] The dosing of the fixed-ratio coformulation relies on the dose of insulin. For example, the starting dose of iglarlixi is 15 units: 15 units/ml of insulin glargine and 5 mg/ml of lixisenatide. The maximum dose of iglarlixi is 60 units: 60 units/ml of insulin glargine and 20 mg/ml of lixisenatide.[43] For IDegLira, the concentrations are 3.6 mg/ml of liraglutide and 100 units/ml of insulin degludec. The recommended starting dose is 16 units: 16 units/ml of insulin degludec and 0.58 mg/ml of liraglutide. The maximum daily dose is 50 units (50 units/ml of insulin degludec and 1.8 mg/ml of liraglutide).[44] Q: What are the professional recommendations on when to incorporate GLP-1 receptor agonist therapy? Blonde: Although GLP-1 receptor agonists have often been used later in the course of T2D, they are also recommended as potential early treatment options. Earlier use may allow more patients to achieve glycemic targets sooner, with added benefits, as discussed below. The ADA Standards of Medical Care in Diabetes emphasizes that treatment intensification, including consideration of insulin, should not be delayed in patients who are not achieving glycemic goals.[32] And the American Association of Clinical Endocrinologists/American College of Endocrinology/ (AACE/ACE) algorithm notes that combination therapy is usually required to achieve A1C targets in patients with T2D, and that therapies with complementary mechanisms of action are preferable.[33] Numerous guidelines and algorithms agree that treatment selection should be based on individual patient preference and characteristics, with the goal of

11 safely reducing A1C with minimal adverse events, particularly hypoglycemia and weight gain.[ ] According to several guidelines, position papers, and algorithms, a GLP-1 receptor agonist may be considered for treatment intensification in 3 common scenarios: 1) As dual therapy with metformin in patients who have not reached A1C target after about 3 months of treatment with the maximally tolerated dose. a. Because many patients with T2D do not achieve adequate glycemic control with monotherapy, combining antihyperglycemic agents is often necessary.[45] b. The 2018 update of the ADA Standards of Medical Care in Diabetes recommends that people with atherosclerotic CVD (ASCVD) should begin with lifestyle management and metformin and subsequently incorporate an antihyperglycemic agent proven to reduce major adverse CV events and/or CV mortality. At present this would mean adding either liraglutide or empagliflozin (based on their indications and evidence of improving heart health), after weighing drug and patient-specific factors. Considerations in the choice of agent include efficacy, hypoglycemia risk, impact on weight, potential side effects, renal effects, delivery method (oral formulation versus subcutaneous injection), cost, and patient preferences.[32] c. The AACE/ACE algorithm preferentially lists GLP-1 receptor agonists as the first recommended treatment choice after metformin, based on its robust A1C-lowering properties and typical association with weight loss

12 and lipid and blood pressure reductions, as well as low risk of hypoglycemia.[33] The algorithm also notes that liraglutide has received FDA approval to reduce the risk of CV death, nonfatal myocardial infarction, and nonfatal stroke in adults with T2D and established CVD,[33] and that empagliflozin has received FDA approval for indication of reducing cardiac mortality in adults with T2D and established CVD. 2) As triple therapy in patients who have not reached their A1C target after approximately 3 months of dual therapy. The AACE/ACE algorithm notes that many patients receiving GLP-1 receptor agonist therapy will still eventually require insulin.[33] 3) When patients have not achieved glycemic target after approximately 3 months of basal insulin treatment (usually in combination with metformin +/- other noninsulin agents]. When basal insulin has been titrated to an acceptable fasting blood glucose level (or if the dose is 0.5 units/kg/d), and A1C remains above target, both ADA and AACE/ACE recommend advancing to combination injectable therapy by adding a GLP-1 receptor agonist.[32 33] a. The combination of basal insulin with a GLP-1 receptor agonist may offer greater efficacy than the oral agents, according to the AACE/ACE algorithm.[33] EXTRAGLYCEMIC BENEFITS OF GLP-1 RECEPTOR AGONISTS Q: What extraglycemic benefits are associated with GLP-1 receptor agonist therapy?

13 Blonde: GLP-1 receptor agonists have numerous extraglycemic effects, including (but not limited to) weight loss, blood pressure, and lipid lowering. Most people lose a mean of 2-3 kg while receiving GLP-1 receptor agonist therapy.[46] But the range is wide, and some patients lose no weight. It is important to emphasize that even patients who do not lose weight are still likely to have significant glycemic improvement and a lower risk of hypoglycemia compared with insulin therapy.[47] Several clinical trials have shown that GLP-1 receptor agonists may improve lipid profiles in patients with T2D through reductions in LDL cholesterol, total cholesterol, triglyceride, and free fatty acid levels.[48 49] Fonseca: In clinical trials, liraglutide and exenatide have modestly, but consistently, reduced both systolic and diastolic blood pressure compared with placebo and active comparators.[ ] In SUSTAIN 6, blood pressure reductions were more modest. At week 104, mean systolic blood pressure was 2.6 mm Hg lower in those receiving semaglutide 1.0 mg versus placebo (P<.001).[52] Q: What may account for the extraglycemic benefits observed with the use of GLP-1 receptor agonists? Fonseca: Because GLP-1 receptor agonists stimulate insulin secretion only in the presence of hyperglycemia, rates of hypoglycemia are low when these agents are used alone or in combination with metformin or other agents that also do not promote hypoglycemia.[22 53] Because GLP-1 receptors are expressed not only in the pancreas, but also in the GI, CV, renal, and central nervous systems, it is logical to

14 assume that GLP-1 receptor agonists mediate numerous effects, independent of improvements in glycemic control and weight.[54] But the mechanisms are complex and not all are fully understood (see Figure 2).[54] We need to first look at the pathophysiologic processes that contribute to the development of hyperglycemia decreased insulin secretion, increased glucagon secretion, increased hepatic glucose production, neurotransmitter dysfunction, decreased glucose uptake into tissues, especially muscle, increased glucose reabsorption from renal tubules, increased lipolysis, and decreased incretin effect and how GLP-1 receptor agonists intervene.[55] GLP-1 receptor agonists mimic the effects of the incretin hormone GLP-1, which is released from the intestine in response to food intake. The primary effects of GLP-1 receptor agonists include glucose dependent increased insulin secretion from beta cells, decreased glucagon secretion (also glucose dependent), slowing of gastric emptying, and increased satiety. These mechanisms help explain the beneficial effects of GLP-1 receptor agonists, including glycemic control, low rates of hypoglycemia, weight loss, and lipid lowering.[ ] The blood pressure benefits we discussed may result from natriuretic and diuretic effects of these agents on the kidney also conferring renoprotective benefits, such as lowering albuminuria.[56] CARDIOVASCULAR OUTCOMES TRIALS IN T2D Q: Do the GLP-1 receptor agonists differ in CV outcomes according to study results reported to date?

15 Blonde: Yes. The reported CV outcomes trials with GLP-1 receptor agonists demonstrated some result differences. All of the reported studies demonstrated noninferiority of the respective GLP-1 receptor agonist (lixisenatide, exenatide extended-release, liraglutide, semaglutide, and investigational ITCA-650) to placebo for their primary CV composite end point. Thus, they all met the primary endpoint of CV safety in their respective CV outcomes trials (see Table 1).[ ] However, liraglutide and semaglutide not only met the noninferiority safety endpoints but also demonstrated improvement in CV outcomes compared with placebo (see Figure 3).[ ] Whether the different outcomes among agents represent inherent differences among the agents or are a function of different study design and/or patient population is not presently known. In the LEADER trial, liraglutide significantly reduced MACE by 13% compared with placebo (P=.01) with an absolute risk reduction of 1.9%.[57] Furthermore, liraglutide reduced CV deaths by 22%, and time to all-cause deaths by 15%. Based on CV benefits demonstrated in the LEADER trial, liraglutide received an expanded indication in August 2017 to reduce the risk of MACE (CV death, nonfatal myocardial infarction, or nonfatal stroke) in adults with T2D and established CVD.[63] Fonseca: In the SUSTAIN 6 trial, once-weekly semaglutide reduced the risk of the same composite endpoint (MACE) by 26% (P=.02 for superiority to placebo) in 3297 patients with T2D and either established CVD, kidney disease, or high CV risk who were treated for 2.1 years.[52]

16 Q: How do these CV outcomes trials compare to those of other antihyperglycemic drug classes? Fonseca: Two SGLT2 inhibitors empagliflozin and canagliflozin have also had positive effects on CV outcomes. EMPA-REG was a long-term, multicenter, randomized, double-blind, placebocontrolled trial of 7020 patients with T2D and established CV disease.[64] It assessed the effect of empagliflozin (10 mg or 25 mg once daily) added to standard of care compared with placebo added to standard of care. Over a median of 3.1 years, empagliflozin significantly reduced the risk of CV death, nonfatal heart attack, or nonfatal stroke by 14% versus placebo. Risk of CV mortality was reduced by 38%, and risk of all-cause mortality was reduced by 32%, with no significant difference in risk of nonfatal heart attack or nonfatal stroke. The benefit on mortality and hospitalization for heart failure started almost immediately. A heart failure benefit has not been shown in GLP-1 receptor agonist trials. However, empagliflozin increased stroke risk (though not significantly), whereas liraglutide reduced stroke risk in LEADER.[57] The two CANVAS trials studied canagliflozin in patients with T2D and an elevated risk of CVD.[65] More than 65% of patients had a history of CVD. The studies found that patients treated with canagliflozin had a lower risk of CV events than those treated with placebo (primary outcome occurred in 26.9 versus 31.5 participants per 1000 patient-years; HR, 0.86; 95% CI, 0.75 to 0.97; P<.001 for noninferiority; P=.02 for superiority). However, patients treated with canagliflozin had a significantly greater risk of amputation (mainly toe or metatarsal) than those in the placebo group (6.3 versus 3.4

17 participants per 1000 patient-years; HR, 1.97; 95% CI, 1.41 to 2.75). Both GLP-1 receptor agonists and SGLT2 inhibitors are associated with mortality benefits compared with DPP-4 inhibitors, according to a network meta-analysis that indirectly compared these 3 drug classes.[66] Compared with control groups, GLP-1 agonists were associated with reduced all-cause mortality (HR, 0.88; 95% CI, 0.81 to 0.94), as were SGLT2 inhibitors (HR, 0.80; 95% CI, 0.71 to 0.89); DPP-4 inhibitors were not (HR, 1.02; 95% CI, 0.94 to 1.11). However, because no CV outcomes trials have directly compared the efficacy of these drug classes, causality cannot be inferred. Blonde: It is possible that, since liraglutide reduced all components of MACE, it may have a more anti-atherothrombotic effect, which requires some time to become manifest. In contrast, the CV benefits of SGLT2 inhibition with empagliflozin and canagliflozin occurred rapidly and markedly reduced hospitalization for heart failure, suggesting that a hemodynamic effect may have been an important mechanism.[64 65] In the LEADER, SUSTAIN 6, EMPA-REG, and CANVAS trials, most patients had established CVD. Whether people without established CVD would derive similar benefits is unknown and would likely require study of a larger number of patients over a longer duration. Q: Did any other antihyperglycemic agents demonstrate notable results from cardiovascular outcomes trials? Fonseca: Aside from the GLP-1 receptor agonists liraglutide and semaglutide, and the

18 SGLT2 inhibitors canagliflozin and empagliflozin, no other antihyperglycemic drugs have demonstrated CV benefit in high-risk patients with T2D. In the PROactive study, pioglitazone reduced the relative risk for a CV event by 10% compared with placebo, but the reduction was not statistically significant.[67] In the IRIS study, patients treated with pioglitazone had a reduced risk for recurrent stroke or myocardial infarction versus placebo.[68] But IRIS studied patients with insulin resistance not patients with T2D. In the Cycloset Safety Trial, patients with T2D who were treated with quick-release bromocriptine experienced fewer CV events compared with those receiving placebo; however, the short duration of the trial (52 weeks) challenges application of these data to long-term treatment.[69] Blonde: To date, all completed DPP-4 CV outcomes trials (SAVOR-TIMI 53, saxagliptin; EXAMINE, alogliptin; TECOS, sitagliptin) show that these agents neither increase nor reduce the risk of major CV events.[70-72] However, in the SAVOR-TIMI 53 trial, more patients in the saxagliptin group than in the placebo group were hospitalized for heart failure (3.5% versus 2.8%; HR, 1.27; 95% CI, 1.07 to 1.51; P=.007).[70] In the EXAMINE trial, 106 (3.9%) of patients treated with alogliptin and 89 (3.3%) of patients treated with placebo were hospitalized for congestive heart failure, although this difference was not statistically significant.[73] There was no increase in hospitalization for heart failure in the TECOS trial with sitagliptin.[72] Other CV outcomes trials of DPP- 4 inhibitors are underway (CARMELINA, linagliptin vs placebo; and CAROLINA, linagliptin vs glimepiride).[74 75]

19 Q: What study features do you consider when interpreting the results of GLP-1 receptor agonist CV outcomes trials? Fonseca: The CV outcomes trials of GLP-1 receptor agonists feature important differences. First, as Dr. Blonde just mentioned, the results apply only to the patient population enrolled; they are not generalizable. Second, the duration of the trial is important. For example, the LEADER trial (liraglutide) duration was 5 years, and the ELIXA trial (lixisenatide) was 2 years. The SUSTAIN 6 trial (semaglutide) was 2 years. These differences in study duration are significant. You cannot show a reduction in mortality if the study is so short that nobody died; but if you run a trial too long, everybody dies. The duration of diabetes and declining event rates are also important considerations in trial design, as are unanticipated side effects. Consider also that patients in the placebo group might behave differently from your patients, and that the patients in placebo groups of some of the trials were receiving other medications (eg, insulin, sulfonylureas) that could increase hypoglycemia risk. INDIVIDUALIZING SELECTION OF GLP-1 RECEPTOR AGONIST THERAPY Q: Once you ve decided that a GLP-1 receptor agonist is a good choice, how do you choose among the available agents? Fonseca: The head-to-head trials of GLP-1 receptor agonists showed small differences in glycemic efficacy and tolerability, but not safety.[20] These differences in A1C, although statistically significant, are not enough to have a major impact on clinical practice. In my opinion, the differences that impact practice relate to duration of action and the frequency of injections (see Table 2).[ ]

20 Blonde: The shorter-acting agents (exenatide twice daily and lixisenatide) tend to have a greater effect on reducing post-meal glycemic excursions than the longer-acting agents (liraglutide, exenatide ER, dulaglutide, and semaglutide), but they have a lesser effect on improving fasting hyperglycemia (see Figure 4).[20 80] Other differences may include contraindications, warnings, and precautions, all of which should be reviewed with patients. The patient s medical history, glycemic profile (primarily fasting, or postprandial hyperglycemia, or both), and clinician and patient preference (eg, would they rather take medication once weekly, once daily, or twice daily), as well as insurance coverage, are all likely to affect the choice of specific GLP-1 receptor agonists for individual patients. Consider which GLP-1 receptor agonist s properties would most closely match the characteristics of a particular patient. For example, a patient with established ASCVD may be a good candidate for liraglutide, which recently received an indication to reduce the risk of MACE in adults with T2D and established CV disease. Q: What adverse events should we be vigilant for when using a GLP-1 receptor agonist? Blonde: Adverse events and/or their rates differ among specific agents, but GI adverse events (nausea, vomiting, and diarrhea) and injection-site reactions are most common.[81] In GLP-1 receptor agonist trials, GI adverse events were typically mild and led to discontinuation in fewer than 5% of patients studied.[ ] GI adverse events are usually self-limiting and can typically be mitigated by avoiding overeating,

21 and by slowing titration (when using an agent that requires titration). GLP-1 receptor agonists have warnings, precautions, and contraindications that can differ between longer- versus shorter-acting agents, and even among agents in each of those categories. Longer-acting GLP-1 receptor agonists (semaglutide, liraglutide, exenatide ER, and dulaglutide) are contraindicated in patients with a personal or family history of medullary thyroid cancer or MEN2 because of increased c- cell tumors observed in rodents receiving these agents. The human relevance of this is not known. Despite postmarketing reports of pancreatitis in patients taking GLP-1 receptor agonists, a causal relationship has not been demonstrated.[82] The prescribing information for all GLP-1 receptor agonists recommends closely monitoring patients for signs and symptoms of pancreatitis, discontinuing GLP-1 receptor agonist therapy if pancreatitis is suspected, and not reinitiating GLP-1 receptor agonist therapy if pancreatitis is confirmed.[ ] It is unknown whether patients with a history of pancreatitis who are treated with a GLP-1 receptor agonist are at a higher risk for pancreatitis. Prescribing information for all GLP-1 receptor agonists except liraglutide recommend considering or using antihyperglycemic agents other than GLP-1 receptor agonists in patients with a history of pancreatitis.[ ] This statement was removed from the liraglutide PI because of the absence of an increase in pancreatitis in the LEADER trial. Fonseca: That is correct. Liraglutide was not associated with an increase in pancreatitis in the LEADER study, and that includes nearly 4 years of data and a large study population (N=9340 patients with T2D).[57] Only 1.5 episodes of pancreatitis per 1000

22 patient-years were observed in the liraglutide and placebo groups combined. The liraglutide group experienced fewer acute or chronic pancreatitis events than the placebo group (18 vs 23, respectively). There were more episodes of gallstone disease with liraglutide compared with placebo (145 vs 90, respectively; P<.001). There were also higher rates of pancreatic cancer (13 vs 5, respectively), but the difference was nonsignificant.[57] In the LEAD trials, the rate of pancreatitis (<0.2%, 5 acute cases with liraglutide treatment) was consistent with the expected rate for patients with T2D.[ ] Similar findings were reported in SUSTAIN 6. Acute pancreatitis occurred in fewer semaglutide-treated patients compared with placebo-treated patients (9 vs 12, respectively), and all events were mild. The rate of pancreatic cancer was also lower in the semaglutide group versus the placebo group.[52] Blonde: In the EXSCEL exenatide ER CV outcomes trial, the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the exenatide and placebo groups.[59] Q: Is renal function a consideration in your use or choice of a GLP-1 receptor agonist? Fonseca: GLP-1 receptor agonists are not directly nephrotoxic, but they do have renal warnings and precautions to consider, as postmarketing reports of acute renal failure and worsening of chronic renal failure have been noted with many agents in this class.[ ] Caution is recommended when using lixisenatide in patients with

23 glomerular filtration rate (GFR) <30 ml/min/1.73m 2 and exenatide is not recommended for such patients.[ ] There are no significant restrictions for liraglutide, semaglutide, or dulaglutide.[ ] Blonde: Because GI adverse events may worsen renal impairment, care should be taken when initiating and uptitrating GLP-1 receptor agonists in adults with renal disease, and renal function should be monitored in such patients if severe GI adverse events are reported. No dose adjustments are needed when using GLP-1 receptor agonists that are degraded in the body (semaglutide, dulaglutide, or liraglutide) in patients with renal and/or hepatic impairment.[ ] Several clinical trials offer support for the safe use of certain GLP-1 receptor agonists in patients with renal impairment. A study of a composite of renal outcomes in 9340 patients from the LEADER trial for a median of 3.84 years showed similar rates of renal adverse events in the liraglutide group and the placebo group, except that macroalbuminuria occurred in fewer liraglutide-treated patients (161 versus 215 patients; HR, 0.74; 95% CI, 0.60 to 0.91; P=.004).[87] Other renal outcomes (eg, dialysis) were no different, which is what matters most. The 26-week, double-blind LIRA-RENAL trial randomized patients with T2D and moderate renal impairment to receive either liraglutide 1.8 mg/d (n=140) or placebo (n=139).[88] Liraglutide-treated patients experienced greater A1C reductions (-1.05%) versus placebo-treatment patients (-0.38%) and greater weight loss (-2.41 kg vs kg, respectively), with no significant estimated (egfr) change from baseline through 26 weeks.

24 In the phase 3 AWARD trials, dulaglutide treatment did not affect egfr, was associated with a slight decrease in albuminuria, and was not associated with an increase in adverse events reflecting potential acute renal failure. Further, exposure was no different in patients with reduced renal function.[89] Q: Can you explain the higher rate of diabetic retinopathy complications reported in the SUSTAIN 6 trial? Fonseca: Semaglutide was associated with a higher rate of diabetic retinopathy complications (DRC) versus placebo in its CV outcomes trial (HR, 1.76; 95% CI, ; P=.02).[52] However, a recent analysis of SUSTAIN 6 suggests that these results may be attributable to rapid glucose-lowering in already high-risk patients, rather than a drug-specific effect. According to the subanalysis, DRC occurred in 84% of semaglutide-treated patients who had pre-existing DR at baseline.[90] Those without pre-existing DR at baseline had a low risk of DRC (10%), comparable to placebo (13.8%). Most patients with DRC events were treated with insulin prior to, or at the time of, the event. In addition, they were older, had a higher baseline A1C, a longer duration of diabetes, and a higher proportion had pre-existing DR compared with those included in the other SUSTAIN trials. In addition, patients with A1C reduction >1.5% were significantly more likely to experience DRC, whether they were treated with semaglutide or placebo. Rapid and pronounced glucose-lowering has been associated with early worsening of DR.[91 92] Based on the SUSTAIN 6 trial results and subsequent analyses, patients with a history

25 of diabetic retinopathy should be monitored when using semaglutide.[21] Q: Are you concerned about hypoglycemia when combining a GLP-1 receptor agonist with other antihyperglycemic agents that may increase the risk? Fonseca: The risk of hypoglycemia is low with GLP-1 receptor agonists. Rates were similar across most GLP-1 receptor agonist treatment groups in head-to-head clinical studies, although the rate for non-severe hypoglycemia was lower with liraglutide versus exenatide twice daily.[50] The risk of hypoglycemia increases with concomitant insulin or sulfonylurea therapy.[81] When combining insulin and/or a sulfonylurea or other insulin secretagogue with a GLP-1 receptor agonist, one should reduce the dose of insulin to reduce the risk of hypoglycemia. Q: Can GLP-1 receptor agonists be safely combined with SGLT2 inhibitors? Fonseca: Combination therapy with a GLP-1 receptor agonist and an SGLT2 inhibitor has not been widely studied. Each drug class has positive CV outcomes trials that are different. Theoretically, if you have positive results with each, you d have even better results with both. But that is not necessarily true and needs to be tested in clinical trials. Blonde: The DURATION 8 trial assessed outcomes among different subsets of patients with type 2 diabetes who were given (along with background metformin) subcutaneous exenatide 2 mg once weekly plus oral dapagliflozin 10 mg once daily (n=231), exenatide once weekly plus oral placebo once daily (n=230), or dapagliflozin (n=233) for 28 weeks.[93] Those enrolled had inadequate glycemic control (A1c 8% 12%) despite

26 receiving metformin monotherapy ( 1500 mg/d) for at least 2 months prior to screening. Patient subsets were grouped by baseline A1c (<8.0%, 8.0% to <9.0%, or 9.0%), age (<65 or 65 years), gender, body mass index (<25, 25 to <30, or 30 kg/m 2 ), type 2 diabetes duration (<3 years, 3 to 10 years, or >10 years), race (white, black, Asian, American Indian/Alaskan native, or all other races), ethnicity (Hispanic/Latino or not Hispanic/Latino), and egfr (<60 ml/min/1.73 m 2, 60 to <90 ml/min/1.73 m 2, or 90 ml/min/1.73 m 2 ). Clinically relevant A1c reductions were seen across all subgroups and treatments. However, once-weekly, subcutaneous exenatide injections plus once-daily oral dapagliflozin reduced A1C by 2 percentage points more than either medication alone and without hypoglycemic events or any unexpected safety findings.[94] Only 45% of patients in the combination-therapy group achieved an A1C <7.0%, probably because of the high mean baseline A1C of 9.3%. In addition to the A1C reduction demonstrated in DURATION 8, patients receiving the combination of dapagliflozin and exenatide lost 3.6 kg, on average, compared with 2.2 kg and 1.6 kg, respectively, for those receiving dapagliflozin or exenatide alone.[94] These results show that the combination of exenatide once weekly plus dapagliflozin is effective in reducing blood glucose and body weight regardless of sex, age, body weight, race, ethnicity, or disease characteristics. SURMOUNTING BARRIERS TO ADHERENCE AND ENSURING TREATMENT SUCCESS Q: What are barriers to adherence to GLP-1 receptor agonist therapy?

27 Fonseca: Patients may have misperceptions that GLP-1 receptor agonists carry the same risks as insulin namely, hypoglycemia and weight gain.[95-98] Patient education is needed to set expectations about efficacy and safety. Once a GLP-1 receptor agonist is prescribed, patient adherence is driven mainly by tolerability (ie, GI adverse events) and convenience (the complexity of the overall regimen) rather than by resistance to injections.[95 99] We need to educate patients about the type and severity of side effects they might experience and how to manage them.[95] And we need to select an agent with a dosing regimen that works best for the patient. Persistence and adherence may also be influenced by the cost of therapy and the gauge of the needle (needles with a larger gauge may be associated with lower adherence or persistence).[98] For patients who require therapy with both basal insulin and a GLP-1 receptor agonist, the new fixed-ratio basal insulin/glp-1 receptor agonist coformulations allow both agents to be administered with a single injection and purchased with a single copay. If oral semaglutide is approved by the FDA, it would obviate injection concerns. However, the cost of newer agents can be considerable and poses a challenge in getting patients access to therapies that may be optimal for them. Q: How do you manage patient expectations? Blonde: With all prescribed medications, patients should be told: the name of the medication; the reason that it is being prescribed; the expected primary benefits; other potential benefits of treatment; how it should be administered; the planned duration of treatment; and potential adverse events. Patients should be informed that, while

28 improvement in glycemia is the primary effect of therapy with GLP-1 receptor agonists, it is also likely that treatment will be associated with some weight loss. They should be told how much weight loss they might expect from GLP-1 receptor agonist treatment, but that reduction in glucose is beneficial even without weight loss. Support for these recommendations was demonstrated in a pooled analysis of eight studies of exenatide once weekly, clinically important reductions in A1C were seen across all body weight change quartiles, even in those patients with small reductions in body weight or small weight gain, demonstrating that exenatide improved glycemic control independent of weight loss.[47] Nevertheless, most patients achieved reductions in body weight and the greatest antihyperglycemic efficacy of exenatide once weekly was seen in the patient quartiles with the greatest reductions in body weight. Q: How do you gauge treatment success? Is it mainly about glycemic control, or does it extend beyond that? Blonde: Successful antihyperglycemic therapy will result in achievement of a patient s glycemic target without hypoglycemia (or with minimal hypoglycemia), and without any significant weight gain (or with weight loss). Significant glycemic improvement is likely to be of substantial benefit even if the glycemic goal is not achieved. Among GLP-1 receptor agonists, liraglutide has the additional indication to reduce the risk of MACE in adults with T2D and established CVD, but assessing success of this treatment is problematic. Fonseca: If prescribed for the reduction of mortality in patients with both T2D and CVD,

29 it is difficult to know whether the medication is working. It is impossible to predict who will get an event and when; we can only go by statistical probabilities. However, as we manage groups of patients within large systems, it is possible for a system to report on rates of CV events to determine if those are falling as more people take cardioprotective agents. SUMMARY As a class, GLP-1 receptor agonists have demonstrated superiority to oral antihyperglycemics in reducing blood glucose, weight, blood pressure, and lipids, without hypoglycemia risk; therefore, they are indicated and recommended (as an option by ADA, and as the first-choice treatment by AACE), for the treatment of T2D in patients who have not reached glycemic targets with metformin and lifestyle modifications. Liraglutide and semaglutide have shown CV benefit in patients with established CVD or high risk for CVD (in the absence of CVD); based on these compelling data, liraglutide recently received an expanded indication to reduce the risk of MACE in adults with T2D and established CVD. Data on CV outcomes of GLP-1 receptor agonists continue to emerge. For most T2D patients who are not at goal on basal insulin, consideration of adding a GLP-1 receptor agonist therapy is recommended before initiating prandial or premixed insulin. This can also be accomplished by switching to a fixed-ratio formulation that combines a GLP-1 receptor agonist and basal insulin. When combined with basal insulin in a fixed-ratio coformulation, the GLP-1

30 receptor agonists liraglutide and lixisenatide provide an effective (and more convenient) alternative to prandial insulin to improve glycemia in patients who have not achieved their glycemic targets on basal insulin with or without oral antihyperglycemic agents. Data informing the combination of GLP-1 receptor agonists with other noninsulin antihyperglycemic agents, especially SGLT2 inhibitors, continue to emerge.

31 Figure 1. Reductions in A1C with GLP-1 Receptor Agonists: Head-to-Head Studies[10-20] a Noninferiority criteria met b Noninferiority criteria not met In head-to-head trials, semaglutide reduced A1C significantly more than active comparators.[10-20]

32 Figure 2. Nonglycemic Effects of GLP-1 Receptor Agonists[54] Abbreviations: CNS, central nervous system; CV, cardiovascular; GI, gastrointestinal. The mechanisms for extraglycemic benefits observed with the use of GLP-1 receptor agonists are complex and not all are fully understood.[54]

33 Figure 3. Comparison of GLP-1 Receptor Agonist CV Outcomes Trials: Time to Primary Composite Endpoint[ ] Left: From The New England Journal of Medicine. Marc A. Pfeffer, Brian Claggett, Rafael Diaz, et al, Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome, Volume 373(23), Pages Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Center: From The New England Journal of Medicine. Steven P. Marso, Gilbert H. Daniels, Kirstine Brown-Frandsen, et al, Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes, Volume 375(4), Pages Copyright 2016 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Right: From The New England Journal of Medicine. Steven P. Marso, Stephen C. Bain, Agostino Consoli, et al, Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes, Volume 375(19), Pages Copyright 2016 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. All of the reported CV outcomes trials with GLP-1 receptor agonists demonstrated noninferiority to placebo for their primary CV composite end point, thus meeting the

34 primary endpoint of CV safety (Table 1).[ ] Liraglutide and semaglutide not only met the noninferiority safety endpoints, but also demonstrated improvement in CV outcomes compared with placebo.[ ]

35 Figure 4. Gastric-emptying effects of short- vs long-acting GLP-1 Receptor Agonists[ ] (A) Short-acting GLP-1 receptor agonists (GLP-1RA) suppress gastric emptying, which prolongs the presence of food in the stomach and upper small intestine; the reduced transpyloric flow causes delayed intestinal glucose absorption and diminished postprandial insulin secretion. (B) Longer-acting GLP-1 receptor agonists do not significantly affect gastric motility, because of tachyphylaxis. Instead, longer-acting GLP-1 receptor agonists exert more of their effect via the pancreas, increasing insulin secretion, and inhibiting glucagon secretion via paracrine release of somatostatin. By targeting the central nervous system, both shorter- (A) and longer- (B) acting GLP-1 receptor agonists increase satiety and may induce nausea.[80]

36 Table 1. Overview of CV Outcomes Trials of GLP-1 Receptor Agonists in T2D[ ](52,57-62) LEADER[5 2] (liraglutide) ELIXA[58] (lixisenatide) EXSCEL[ 59] (exenatide ER) REWIND [60] (dulaglutide) FREEDOM- CVO[61 62] (ITCA-650) * SUSTAIN 6[57] (semaglutide) N , > Age 50 y with clinical Main CV inclusion criteria Age 50 y with CVD/ PAD/CRF /CHF or age 60 y with >1 CV risk factor ACS <180 d; age 30 y Age 18 y vascular disease, or age 55 y and subclinical vascular disease or age 60 y History of CAD, cerebrovascul ar disease, or PAD, or multiple CV risk factors; age 40 y Age >50 y with CVD or CKD stage >3 or age >60 y with >1 CV risk factor and >1 CV risk factor A1C inclusion criteria, > , >6.5 >7.0 % Study duration 3.8 y 2.1 y 3.2 y 6.5 y 3 y 2.1 y Primary CV death, CV death, MI, CV death, CV death, CV death, CV death, endpoint nonfatal stroke, or nonfatal nonfatal MI, nonfatal MI, nonfatal MI, or