The cardiovascular (CV) safety of glucagon-like peptide 1 (GLP-1) receptor agonists has been established in robust cardiovascular outcomes trials (CVOTs) in patients with type 2 diabetes at high CV risk. The GLP-1 receptor agonists liraglutide, dulaglutide, and injectable semaglutide demonstrated a significant CV benefit in these trials and now have indications to reduce the risk of major adverse CV events, including CV death, myocardial infarction, and stroke in adult patients with type 2 diabetes and established cardiovascular disease or high CV risk (dulaglutide). The dipeptidyl peptidase 4 inhibitors have also demonstrated CV safety in dedicated CVOTs but have not been associated with any CV benefit. Guidelines for the treatment of type 2 diabetes have evolved from a glucocentric focus to one that now focuses on reducing overall CV risk by personalizing therapy and using drugs such as GLP-1 receptor agonists with proven CV benefits.

The risk for cardiovascular (CV) morbidity and mortality is two to four times higher in patients with type 2 diabetes compared with those without (13). Intensive glucose lowering has been shown to reduce microvascular disease, but has minimal if any effect on CV events or mortality (47). In 2008, because of concerns about CV safety, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency issued guidance for the pharmaceutical industry with a regulatory framework for evaluating the CV safety of new agents for the management of diabetes (8,9). Consequently, all drugs in development for the treatment of diabetes were required to perform robust cardiovascular outcomes trials (CVOTs) as a post-marketing requirement for approval.

These trials varied in design, but all assessed major adverse cardiovascular events (MACE), which include CV death, nonfatal myocardial infarction (MI), and nonfatal stroke. Some trials also included hospitalization for unstable angina or heart failure (HF) in their primary end point or as a secondary end point (10,11). Some of the trials were designed primarily to test for noninferiority of the drug compared with placebo, indicative of the drug’s CV safety, whereas other trials also had prespecified end points to test for the superiority of the drug compared with placebo to demonstrate a CV benefit. Since implementation of this guidance, more than 28 CVOTs involving >200,000 patients with diabetes have been reported or are in progress. In addition to providing a more comprehensive view of the CV safety of drugs in widespread use for the treatment of diabetes, these trials have provided insight into the long-term safety of these drugs, including rare adverse events not apparent in typical phase 3 clinical trials. In this review, we focus on the CVOTs for incretin-based therapies.

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are small peptide hormones released by enteroendocrine cells in the gut after ingestion of nutrients. These hormones contribute to glucose homeostasis by enhancing insulin secretion from the β-cells of the pancreas in a glucose-dependent manner (12). GLP-1 also delays gastric emptying, increases satiety, and inhibits glucagon secretion. Patients with type 2 diabetes have a blunted insulin response to GLP-1 and GIP (13).

Two drug classes leverage the incretin system: GLP-1 receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors. GLP-1 receptor agonists are peptide molecules derived from either exendin-4 (exenatide and lixisenatide) or human GLP-1 (liraglutide, dulaglutide, semaglutide, and albiglutide) that have been structurally modified to prolong their half-life. They exert their action by directly interacting with the GLP-1 receptor. DPP-4 inhibitors, in contrast, are small, orally available molecules that prolong the half-life of endogenously secreted active GLP-1 and GIP by inhibiting DPP-4, the enzyme that inactivates both incretin hormones (14).

Seven randomized, placebo-controlled, parallel-arm studies of GLP-1 receptor agonists have reported results to date (Table 1). All trials compared the addition of active drug to usual care. The main results for the composite MACE end point, as well as CV death, hospitalization for HF, and renal outcomes are shown in Figure 1.

FIGURE 1

Results from CVOTs of GLP-1 receptor agonists. A) Primary composite MACE (for superiority). B) Cardiovascular death. C) Hospitalization for HF. D) Renal outcomes, including macroalbuminuria. GLP-1 RA, GLP-1 receptor agonist.

FIGURE 1

Results from CVOTs of GLP-1 receptor agonists. A) Primary composite MACE (for superiority). B) Cardiovascular death. C) Hospitalization for HF. D) Renal outcomes, including macroalbuminuria. GLP-1 RA, GLP-1 receptor agonist.

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TABLE 1

Summary of Trials, Baseline Characteristics, and Changes in Weight and Glycemic Outcome

TrialN (% female)Follow-Up, yearsTreatment Arm*Age, years, mean (SD)BMI, kg/m2, mean (SD)A1C, %, mean (SD)Diabetes duration, years, mean (SD)Prior CVD, n (%)HF, n (%)eGFR ≤60 mL/min/ 1.73 m2, n (%)End-of-Trial Difference
Weight, kgA1C, %
CVOTs With Receptor Agonists 
ELIXA, 2015 (15,16) 6,068 (30.7) 2.1 Lixisenatide 10–20 µg
SC/OD 
60.2 (9.7) 30.2 (5.7) 7.7 (1.3) 9.3 (8.3) 6,068 (100) 1,358 (22.4) 1,407 (23.2) −0.7 −0.27 
LEADER, 2016 (17,18) 9,340 (35.7) 3.8 Liraglutide 1.8 mg SC/OD 64.3 (7.2) 32.5 (6.3) 8.7 (1.6) 12.7 (8) 7,592 (81.3) 1,599 (17.1) 2,158 (23.1) −2.3 −0.4 
SUSTAIN-6, 2016 (20) 3,297 (39.3) 2.1 Semaglutide 0.5 or 1 mg SC/QW 64.6 (7.4) 32.8 (6.2) 8.7 (1.5) 13.9 (8.1) 2,735 (83) 777 (23.6) 939 (28.5) −3.61 −0.85 
EXSCEL, 2017 (24,25) 14,752 (38.0) 3.2 Exenatide 2 mg SC/QW 62 (NR) 31.8 (NR) 8.1 (1.0) 12 (NR) 10,782 (73.1) 2,389 (16.2) 3,191 (21.6) −1.27 −0.53 
Harmony Outcomes, 2018 (27,28) 9,463 (30.6) 1.6 Albiglutide 30–50 mg
SC/QW 
64.2 (8.7) 32.3 (5.9) 8.7 (1.5) 14.1 (8.8) 9,463 (100) 1,922 (20.3) 2,222 (23.5) −0.83 −0.52 
REWIND, 2019 (29,30) 9,901 (46.3) 5.4 Dulaglutide 1.5 mg SC/QW 66.2 (6.5) 32.3 (5.8) 7.3 (1.1) 9.5 (NR) 3,114 (31.5) 853 (8.6) 2,199 (22.2) −1.46 −0.61 
PIONEER 6, 2019 (32) 3,183 (31.6) 1.3 Semaglutide 14 mg PO/OD 66 (7) 32.3 (6.5) 8.2 (1.6) 14.9 (8.5) 2,695 (84.7) NR 856 (26.9) −3.4 −0.7 
CVOTs With DPP-4 Inhibitors 
EXAMINE, 2013 (33) 5,380 (32.1) 1.5 Alogliptin 25 mg PO/OD§ 61.0 (10) 28.3 (NR) 8.0 (1.1) 7.2 (NR) 5,380 (100) 1,501 (27.9) 1,565 (29.1) 0.06 −0.36 
SAVOR-TIMI 53, 2013 (34) 16,490 (27.2) 2.1 Saxagliptin 5 mg PO/OD§ 65.1 (8.5) 31.2 (5.6) 8.0 (1.4) 10.3 (NR) 12,959 (78.6) 2,105 (12.8) 2,576 (15.6) −0.10 −0.20 
TECOS, 2015 (35) 14,671 (29.3) 3.0 Sitagliptin 100 mg PO/OD§ 65.5 (8.0) 30.2 (5.6) 7.2 (0.5) 11.6 (8.1) 10,863 (74) 2,643 (18) 3,324 (22.7) −0.05 −0.29 
CARMELINA, 2019 (36) 6,979 (37.1) 2.2 Linagliptin 5 mg PO/OD 65.9 (9.1) 31.4 (5.4) 8 (1.0) 14.7 (9.5) 4,081 (58.5) 1,873 (26.8) 4,348 (62.3) −0.15 −0.36 
CAROLINA, 2019 (41,42) 6,033 (40) 6.3 Linagliptin 5 mg vs. glimepirideǁ 64 (9.5) 30.1 (5.1) 7.2 (0.6) 6.3 (NR) 2,522 (42) 271 (4.6) 1,130 (18.8) −1.54 0.0 
TrialN (% female)Follow-Up, yearsTreatment Arm*Age, years, mean (SD)BMI, kg/m2, mean (SD)A1C, %, mean (SD)Diabetes duration, years, mean (SD)Prior CVD, n (%)HF, n (%)eGFR ≤60 mL/min/ 1.73 m2, n (%)End-of-Trial Difference
Weight, kgA1C, %
CVOTs With Receptor Agonists 
ELIXA, 2015 (15,16) 6,068 (30.7) 2.1 Lixisenatide 10–20 µg
SC/OD 
60.2 (9.7) 30.2 (5.7) 7.7 (1.3) 9.3 (8.3) 6,068 (100) 1,358 (22.4) 1,407 (23.2) −0.7 −0.27 
LEADER, 2016 (17,18) 9,340 (35.7) 3.8 Liraglutide 1.8 mg SC/OD 64.3 (7.2) 32.5 (6.3) 8.7 (1.6) 12.7 (8) 7,592 (81.3) 1,599 (17.1) 2,158 (23.1) −2.3 −0.4 
SUSTAIN-6, 2016 (20) 3,297 (39.3) 2.1 Semaglutide 0.5 or 1 mg SC/QW 64.6 (7.4) 32.8 (6.2) 8.7 (1.5) 13.9 (8.1) 2,735 (83) 777 (23.6) 939 (28.5) −3.61 −0.85 
EXSCEL, 2017 (24,25) 14,752 (38.0) 3.2 Exenatide 2 mg SC/QW 62 (NR) 31.8 (NR) 8.1 (1.0) 12 (NR) 10,782 (73.1) 2,389 (16.2) 3,191 (21.6) −1.27 −0.53 
Harmony Outcomes, 2018 (27,28) 9,463 (30.6) 1.6 Albiglutide 30–50 mg
SC/QW 
64.2 (8.7) 32.3 (5.9) 8.7 (1.5) 14.1 (8.8) 9,463 (100) 1,922 (20.3) 2,222 (23.5) −0.83 −0.52 
REWIND, 2019 (29,30) 9,901 (46.3) 5.4 Dulaglutide 1.5 mg SC/QW 66.2 (6.5) 32.3 (5.8) 7.3 (1.1) 9.5 (NR) 3,114 (31.5) 853 (8.6) 2,199 (22.2) −1.46 −0.61 
PIONEER 6, 2019 (32) 3,183 (31.6) 1.3 Semaglutide 14 mg PO/OD 66 (7) 32.3 (6.5) 8.2 (1.6) 14.9 (8.5) 2,695 (84.7) NR 856 (26.9) −3.4 −0.7 
CVOTs With DPP-4 Inhibitors 
EXAMINE, 2013 (33) 5,380 (32.1) 1.5 Alogliptin 25 mg PO/OD§ 61.0 (10) 28.3 (NR) 8.0 (1.1) 7.2 (NR) 5,380 (100) 1,501 (27.9) 1,565 (29.1) 0.06 −0.36 
SAVOR-TIMI 53, 2013 (34) 16,490 (27.2) 2.1 Saxagliptin 5 mg PO/OD§ 65.1 (8.5) 31.2 (5.6) 8.0 (1.4) 10.3 (NR) 12,959 (78.6) 2,105 (12.8) 2,576 (15.6) −0.10 −0.20 
TECOS, 2015 (35) 14,671 (29.3) 3.0 Sitagliptin 100 mg PO/OD§ 65.5 (8.0) 30.2 (5.6) 7.2 (0.5) 11.6 (8.1) 10,863 (74) 2,643 (18) 3,324 (22.7) −0.05 −0.29 
CARMELINA, 2019 (36) 6,979 (37.1) 2.2 Linagliptin 5 mg PO/OD 65.9 (9.1) 31.4 (5.4) 8 (1.0) 14.7 (9.5) 4,081 (58.5) 1,873 (26.8) 4,348 (62.3) −0.15 −0.36 
CAROLINA, 2019 (41,42) 6,033 (40) 6.3 Linagliptin 5 mg vs. glimepirideǁ 64 (9.5) 30.1 (5.1) 7.2 (0.6) 6.3 (NR) 2,522 (42) 271 (4.6) 1,130 (18.8) −1.54 0.0 
*

Treatment was versus placebo except in the CAROLINA trial, which compared a DPP-4 inhibitor to a sulfonylurea.

Mean group difference between the study arms.

For 0.5 mg: –0.7%, 1 mg: –1.0%.

§

Renally adjusted dose.

ǁ

Versus glimepiride 1–4 mg PO/OD. NR, not reported; OD, once daily; PO, by mouth; SC, subcutaneous; QW, once weekly.

Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA)

The ELIXA trial assessed the safety and efficacy of lixisenatide in patients with type 2 diabetes and a recent acute coronary syndrome event. The primary composite outcome of CV death, MI, stroke, or hospitalization for unstable angina (four-point MACE) occurred in 13.4% of patients treated with lixisenatide and 13.2% of those in the placebo arm (P <0.001 for noninferiority). Thus, lixisenatide demonstrated safety in a high-risk population but was not shown to have a CV benefit (P = 0.81 for superiority compared with placebo) (15). In exploratory analyses, lixisenatide reduced the urinary albumin to creatinine ratio relative to placebo in patients with macroalbuminuria (P = 0.007). There was also a significant reduction in risk of new-onset macroalbuminuria compared with placebo when adjusted for A1C (P = 0.04) (16) but no significant difference in decline in estimated glomerular filtration rate (eGFR) between the two arms.

Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER)

The LEADER trial assessed the CV safety and efficacy of liraglutide compared with placebo (17). Liraglutide significantly reduced the first occurrence of a composite of CV death, nonfatal MI, or nonfatal stroke (three-point MACE; 13.0 vs. 14.9%, P = 0.01). Liraglutide was also associated with significant reductions in all-cause mortality (P = 0.02) and CV death (P = 0.007) (18). In secondary analyses, liraglutide resulted in lower rates of development and progression of diabetic nephropathy, primarily by reduction of new-onset persistent macroalbuminuria (1.5 vs. 1.9 events of macroalbuminuria per 100 patient-years, P = 0.003) (19).

Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6)

SUSTAIN-6 was a phase 3 pre-registration study of once-weekly subcutaneous semaglutide in patients with type 2 diabetes and with established cardiovascular disease (CVD) or with significant CV risk factors. The primary composite outcome (three-point MACE) occurred in fewer patients in the semaglutide group compared with those in the placebo group (6.6 vs. 8.9%, P = 0.02). A significant decrease in the rate of nonfatal stroke (P = 0.04) was also seen. New or worsening nephropathy was observed in fewer participants in the semaglutide group (P = 0.005), which was primarily driven by a reduction in incident macroalbuminuria (20). Diabetic retinopathy adverse events were significantly higher in the semaglutide group than in the placebo group (3.0 vs. 1.8%, P = 0.02). Post-hoc analysis of these data showed that the higher rate of retinopathy was predominantly seen in participants with preexisting diabetic retinopathy and was also associated with the rapidity and magnitude of A1C reduction (21), similar to what was observed in the Diabetes Control and Complications Trial and what has been reported in pregnancy (22,23).

Exenatide Study of Cardiovascular Event Lowering (EXSCEL)

EXSCEL was a pragmatic trial that evaluated the safety and efficacy of exenatide once weekly, enrolling a larger number of participants and with broader eligibility criteria than other trials. The primary composite outcome (three-point MACE) occurred in 11.4% of patients in the exenatide group compared with 12.2% of patients in the placebo group (P = 0.06 for superiority) (24,25). A nonsignificant reduction in new-onset macroalbuminuria was reported in patients treated with exenatide compared with placebo (2.2 vs. 2.5%, P = 0.19) (26).

Albiglutide and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Cardiovascular Disease (Harmony Outcomes)

The Harmony Outcomes trial tested the safety and efficacy of once-weekly albiglutide in participants with type 2 diabetes and established CVD. The primary composite outcome (three-point MACE) occurred in 7% of patients in the albiglutide group compared with 9% of patients in the placebo group (P = 0.0006 for superiority) (27,28). The 22% reduction in MACE in the albiglutide treated arm was mostly driven by a reduction in fatal or nonfatal MI (P = 0.003). Reductions in the other components of the composite and all-cause mortality were not statistically significant between the two arms (28). This trial did not assess renal dysfunction or retinopathy. Of note, albiglutide has been discontinued by the manufacturer since 2017 because of limited prescribing of the drug.

Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND)

The REWIND trial distinguished itself from the other trials in being designed to test for CV benefit instead of CV safety, having a larger female population (46%), and having the lowest number of participants with established CVD (31.5%). The trial also had a longer duration of follow-up (5.4 years) (29). The primary composite outcome (three-point MACE) occurred in 12% of participants in the dulaglutide group compared with 13.4% in the placebo group (P = 0.026 for superiority). Among the secondary outcomes, nonfatal stroke was significantly lower in the dulaglutide group compared with placebo (2.7 vs. 3.5%, P = 0.017) (30).

A composite renal outcome of new macroalbuminuria, ≥30% decline in eGFR from baseline, or chronic renal replacement therapy occurred at a lower rate in the dulaglutide group compared with placebo (17.1 vs. 19.6%, P = 0.0004), with the largest effect on the development of macroalbuminuria (30,31). Because only about one-third of the participants in REWIND had prior CVD and no significant differences between those with and without prior CVD were observed for the primary outcome, the REWIND study supports the use of dulaglutide for both primary and secondary prevention.

Peptide Innovation for Early Diabetes Treatment (PIONEER 6)

PIONEER 6 was a pre-approval, phase 3 trial that assessed the CV safety of oral semaglutide—the first and only FDA-approved oral GLP-1 receptor agonist. The primary composite outcome (three-point MACE) occurred in 3.8% of patients in the semaglutide group compared with 4.8% of those in the placebo group, but this difference was not significant when tested for superiority (P = 0.17) (32). Renal outcomes have not been reported for this trial.

Four randomized, placebo-controlled CVOTs have been reported with DPP-4 inhibitors. The primary composite outcome for most of these trials was the three-point MACE including CV death, nonfatal MI, or nonfatal stroke. The baseline characteristics of the trials’ participants are shown in Table 1.

Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care (EXAMINE)

EXAMINE (33) was a dedicated trial to determine the CV safety of alogliptin versus placebo. Although the trial succeeded in determining the CV safety of alogliptin (P <0.001 for noninferiority), the primary composite outcome (three-point MACE) occurred in a similar number of participants in both groups (11.3% in alogliptin vs. 11.8% in placebo).

Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus—Thrombolysis in Myocardial Infarction (SAVOR-TIMI) 53

The SAVOR-TIMI 53 study (34) demonstrated the CV safety of saxagliptin compared with placebo for a composite three-point MACE end point (P <0.001 for noninferiority). The number of events in the primary outcome was not significantly different between the two groups (7.3% in saxagliptin and 7.2% in placebo).

Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS)

TECOS (35) was a large trial with a primary composite outcome of four-point MACE (CV death, nonfatal MI infarction, nonfatal stroke, or hospitalization for unstable angina). Like the other CVOTs of DPP-4 inhibitors, there was no significant between-group difference in the primary composite outcome. The trial did demonstrate CV safety for sitagliptin (P <0.001 for noninferiority).

Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus (CARMELINA)

The CARMELINA trial (36) was conducted to determine the CV safety of linagliptin. The primary outcome (three-point MACE) occurred in a similar proportion of patients in both groups (12.4% in linagliptin and 12.1% in placebo), but linagliptin was shown to have CV safety (P <0.001 for noninferiority).

Other Outcomes in Trials Testing a DPP-4 Inhibitor Against Placebo

In the CVOTs comparing a DPP-4 to placebo, there was a mixed response with regard to hospitalization for HF. Interestingly, in the SAVOR-TIMI 53 trial, more patients assigned to saxagliptin than placebo were hospitalized for HF (3.5 vs. 2.8%, P = 0.007); whereas, in the EXAMINE trial, there was a nonsignificant trend for higher rates of hospitalization for HF with alogliptin compared with placebo. Analyses of TECOS and CARMELINA did not show any significant difference in this outcome (37,38). Finally, none of the trials with DPP-4 inhibitors showed significant effects on decline in eGFR, need for kidney replacement therapy, or kidney-related death, but some showed a modest benefit on albuminuria (33,36,39,40).

Cardiovascular Outcome Trial of Linagliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA)

The CAROLINA trial was unique among the CVOTs in that it compared linagliptin to an active comparator, the sulfonylurea glimepiride. Although prior observational studies and limited clinical trials suggested that sulfonylureas might be associated with an increased risk for CVD, this was not evident in CAROLINA, as the primary outcome (three-point MACE) occurred in 11.8% of the linagliptin group compared with 12.0% in the glimepiride group (hazard ratio 0.98, P <0.001) (41,42).

Based on the results from these CVOTs, the FDA recently revised its prescribing information for certain antihyperglycemic agents. GLP-1 receptor agonists such as liraglutide, dulaglutide, and injectable semaglutide are now indicated to reduce the risk of MACE in adult patients with type 2 diabetes and established CVD or, for dulaglutide only, with high CV risk (4345). In contrast, the FDA has advised caution when using saxagliptin and alogliptin in patients at risk for HF (46,47).

With the exception of the increased risk for HF with saxagliptin (and possibly alogliptin), none of the robust CVOTs to date has identified an increased risk of CV events. As a consequence, the FDA recently revisited its CV safety guidelines. In 2020, the FDA withdrew its February 2008 guidance and replaced it with the new guidance entitled “Type 2 Diabetes Mellitus: Evaluating the Safety of New Drugs for Improving Glycemic Control: Draft Guidance for Industry” (48). Although this new guideline does not mandate separate CVOTs, evaluation of a drug’s CV safety profile continues to be required, for which trials must include data from a substantial number of high-risk patients over a considerable period of time.

In addition to satisfying the FDA mandate to establish the CV safety of new diabetes drugs, the CVOTs completed to date have provided invaluable evidence of the benefit and safety of drugs now in common use for the treatment of diabetes. This evidence has allowed treatment guidelines to evolve from a glucocentric perspective to one that takes into account CV risk and focuses on reducing clinically important outcomes such as CV events, hospitalization for HF, and progression of chronic kidney disease. Indeed, there has been a remarkable convergence of the recommendations for managing diabetes and CV risk from diverse groups including Diabetes Canada’s clinical practice guidelines (49,50); the American College of Cardiology’s consensus report on CV risk reduction in patients with type 2 diabetes and atherosclerotic CVD (51); the 2019 European Society of Cardiology guidelines on diabetes, prediabetes, and CVD (developed in collaboration with the European Association for the Study of Diabetes (EASD) (52); and the recent consensus report on the management of hyperglycemia in type 2 diabetes from the American Diabetes Association and EASD (53).

In most of these guidelines, lifestyle modification and metformin remain the foundation for type 2 diabetes management (8,5153). When making clinical decisions about the choice of agents for patients with type 2 diabetes, it is crucial to consider the other comorbidities these patients may have. For patients with established CVD or high CV risk, GLP-1 receptor agonists should be prescribed, whereas for patients in whom HF predominates, a sodium–glucose cotransporter 2 inhibitor should be used. Such individualized treatment stands to improve outcomes in patients with type 2 diabetes.

Duality of Interest

T.K.T. has received consulting fees from and serves on a speaker’s bureau for Novo Nordisk. R.E.P. has received consulting fees from AstraZeneca, Glytec, Janssen, Merck, Mundipharma, Novo Nordisk, Pfizer, Sanofi, Sanofi US Services, Scohia Pharma, and Sun Pharmaceutical Industries; grants from Hanmi Pharmaceutical, Janssen, Lexicon Pharmaceuticals, Novo Nordisk, Poxel SA, and Sanofi; and speaker fees from Novo Nordisk. Except for consulting fees in February 2018 and June 2018 from Sanofi US Services, fees for his services were paid to AdventHealth, a nonprofit organization. No other potential conflicts of interest relevant to this article were reported.

Author Contributions

T.K.T. and R.E.P. reviewed/edited the manuscript and contributed to discussion. A.B. researched data and wrote the manuscript. T.K.T. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data.

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