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Abstract

GLP-1 receptor agonists (GLP-1 RAs), introduced for clinical use in 2005, have excellent potency in reducing HbA_1c and mean glucose, improving fasting plasma glucose, inducing weight loss or protecting against the weight gain associated with insulin therapy, reducing appetite, and delaying gastric emptying. Two of these medications, liraglutide and semaglutide, appear to have cardioprotective effects as reflected in cardiovascular outcomes studies. The GLP-1 RAs are associated with gastrointestinal side effects that tend to diminish over time. They have very low risk of hypoglycemia unless used in conjunction with insulin or insulin secretagogues. Two coformulations of GLP-1 RAs together with long-acting basal insulin are available for daily use. The original GLP-1 RA, exenatide, requires twice-daily injections; two short-acting analogs are given once daily. Three currently available long-acting GLP-1 RAs are injected once weekly, providing greater convenience and potentially improving patient adherence. Semaglutide appears to be the most effective in terms of HbA_1c reduction and weight loss. GLP-1 RAs can be combined with all classes of antihyperglycemic agents except DPP-4 inhibitors. Current studies are exploring the use of an implantable osmotic pump for long-term administration of a rapid acting analog (exenatide), an oral preparation of semaglutide, benefits for management of obesity and nonalcoholic steatohepatitis, and mechanisms of cardioprotective effects.

Introduction

GLP-1 Receptor Agonists (GLP-1 RAs) are an important, well-established therapeutic option for management of patients with type 2 diabetes,^1,2 and may be used alone, with oral antihyperglycemic agents, with insulin, or as coformulations with long-acting insulins. These agents are highly effective in terms of reduction of HbA_1c, weight reduction (or to minimize weight gain when coadministered with insulin or sulfonylureas), appetite suppression, reduced glycemic variability, and have low risk of hypoglycemia. GLP-1 RAs can be classified as rapid or long acting and in terms of homology to GLP-1 or to exendin-4. Table 1 summarizes their pharmacokinetic properties.

Table 1.

GLP-1 Receptor Agonists: Pharmacokinetic Profiles

Agent	Half-life (T_½)	T_max
Short Acting
Exenatide bid	2.4 h	2 h
Lixisenatide qd	3 h	1–3.5 h
Liraglutide qd	13 h	8–12 h
Long Acting
Dulaglutide qw	∼4 days	24–48 h
Exenatide qw	7–14 days	6–7 weeks
Semaglutide qw	∼7 days	1–3 days

Of particular interest when treating people with diabetes is cardiovascular safety. The risk of death from any cause in people with diabetes is up to twice that of the general population³ and the risk of death from cardiovascular causes is up to fourfold that of people without diabetes.⁴ Liraglutide and semaglutide have beneficial effects in cardiovascular outcome trials.

Exenatide

Exenatide was the first GLP-1 RA approved for clinical use in the United States in 2005. The original formulation of exenatide is a short-acting medication and requires injections twice per day (Table 1). Subsequently, liraglutide was introduced; it has longer duration of action so that it can be used once daily (Table 1). Another short acting GLP-1 RA, lixisenatide, was approved for once-daily therapy (Table 1). Three longer lasting preparations that can be given once weekly are currently available in the United States: exenatide extended release (ER), dulaglutide, and semaglutide (Table 1). Another long-acting preparation, albiglutide, was withdrawn from the market in the United States, possibly due to limited efficacy. A once-daily oral preparation of semaglutide is currently undergoing clinical trials⁵ in a development program known as PIONEER. An alternative approach, now being explored in clinical trials, is to administer a short-acting agonist, exenatide, using an implantable osmotic pump.⁶

The structure of exenatide is based on exendin-4, a peptide from Gila monster saliva with limited homology with human GLP-1. Accordingly, it may have a higher incidence of allergic reactions and neutralizing antibodies than medications with a higher degree of homology with GLP-1. Subsequently, several GLP-1 RA analogs were developed with increased potency and increased duration of action.⁷ Tables 2 –4 summarize the effectiveness of exenatide ER and the other GLP-1 RAs used for management of people with diabetes. There is a small increased risk of mildly elevated pancreatic lipase and amylase and a small increased risk of pancreatitis that is weakly associated with all of the GLP-1 RA preparations. However, there is no credible evidence of increased risk of pancreatic or other malignancies in people receiving either short- or long-acting GLP-1 RAs.

Table 2.

Effectiveness Of Long-Acting Glp-1 Receptor Agonists: Exenatide Extended Release

Study	Duration	Comparators	HbA1c Change (%)	Weight Change (kg)
DURATION-1^a	30 weeks (N = 295)	Exenatide ER	−1.9%	−4.0
Background meds.:	30 weeks (N = 295)	Exenatide bid	−1.5%
1 or 2 of the following: Metformin, Sulfonylurea, or Thiazolidinedione	6-year extension(N = 136)	Exenatide ER	−1.6%	−4.2
DURATION-2^b	26 weeks	Exenatide ER	−1.6%	−2.7
Background meds.:		Sitagliptin	−1.0%	−1.0
Metformin		Pioglitazone	−1.4%	+3.3
N = 491
DURATION-3	3-year extension	Exenatide ER Insulin glargine	−1.0%	−2.6
Background meds.: Metformin ± sulfonylurea			−0.8%	+1.4
N = 456
DURATION-4^b	26 weeks	Exenatide ER	−1.5%	−2.0
Background meds.:		Metformin	−1.5%	−2.0
Drug Naïve		Pioglitazone	−1.6%	+1.5
N = 820		Sitagliptin	−1.2%	−0.8
DURATION-5	24 weeks	Exenatide ER	−1.6%	− 2.3
Background meds.:		Exenatide bid	−0.9%	− 1.4
Drug naïve, or oral agents
N = 252
DURATION-6	26 weeks	Exenatide ER	−1.3%	− 2.7
Background meds.:		Liraglutide	−1.5%	− 3.6
Metformin		1.8 mg/day
N = 911

Duration: Diabetes therapy Utilization: Researching changes in A1c, weight, and other factors Through Intervention with exenatide ONce weekly ^{27

-36}

Duration-2 and Duration-4 were double blind; other studies were open label.

Table 3.

Effectiveness of Long-Acting GLP-1 Receptor Agonists: Dulaglutide ^{37

–44}

Study	Treatment arms	Study duration (weeks)	A_1c change (%)	Weight change (kg)
AWARD-1: background metformin and pioglitazone	Dulaglutide 1.5 mg qw	52	−1.51	−1.3
AWARD-1: background metformin and pioglitazone	Exenatide twice daily (10-μg)	52	0.99	−1.3
AWARD-2: metformin	Dulaglutide 0.75 mg qw	78	−0.59	−1.33
	Dulaglutide 1.5 mg qw		−0.90	−1.87
	Insulin glargine qd		−0.62	+1.28
AWARD-6: background liraglutide 26 weeks	Dulaglutide 1.5-mg qw	26	−1.42	−2.9
AWARD-6: background liraglutide 26 weeks	Liraglutide 1.8-mg qd	26	−1.36	−3.6
AWARD 10: 24 weeks	Dulaglutide 0.75 mg qw + empagliflozin	24	−1.21	−2.6
	Dulaglutide 1.5 mg qw + empagliflozin		−1.34	−3.1
	Placebo qw + empagliflozin		−0.54	−2.1

Table 4.

Effectiveness of Long-Acting GLP-1 Receptor Agonists: Semaglutide ^{45

–53}

Study	Dose (mg)	Study duration (weeks)	HbA_1c (%) change	Weight change (pounds)
SUSTAIN-1: semaglutide (monotherapy)	0.5	30	−1.4	−8.4
	1.0		−1.6	−10.4
	Placebo		−0.1	−2.6
SUSTAIN-2: semaglutide (vs. sitagliptin)	0.5	56	−1.3	−9.3
	1.0		−1.5	−12.1
	Sitagliptin 100 mg		−0.7	−3.7
SUSTAIN-3 (vs. exenatide ER qw)	1.0	56	−1.4	10.6
SUSTAIN-3 (vs. exenatide ER qw)	Exenatide ER 2 mg qw	56	−0.9	−4.4
SUSTAIN-4: semaglutide+insulin (vs. glargine U100)	0.5	30	−1.2	−7.1
	1.0		−1.5	−10.4
	Insulin glargine U100		−0.9	+2.0
SUSTAIN-5: semaglutide added to basal insulin (vs. placebo)	0.5	30	−1.3	−7.7
	1.0		−1.7	−13.2
	Placebo		−0.2	−2.6

SUSTAIN, Semaglutide Unabated Sustainability in Treatment of type 2 diabetes.

Exenatide can be continuously infused using a small implantable osmotic minipump that continuously delivers exenatide for 3–6 months.^8,9 In a randomized, open-label, phase 2 study, patients with poorly controlled type 2 diabetes receiving metformin were treated using ITCA 650 delivering 20 μg of exenatide/day for 12 weeks followed by 60 μg/day for 12 weeks. These patients experienced significant reductions in HbA_1c of −1.4% and reductions in body weight of −3.1 kg during the initial 24-week treatment period, and these effects were maintained during a 24-week extension.¹⁰ In another recent study, 60 patients with longstanding, uncontrolled type 2 diabetes (HbA_1c 10%–12%) were enrolled in a 39-week, open-label, phase 3 trial. The initial exenatide dose was 20 μg/day for 13 weeks, then 60 μg/day for 26 weeks. At the end of the trial there was a mean reduction of HbA_1c of −2.8% and body weight was reduced by −1.2 kg, and 25% of patients achieved HbA_1c <7%. The most common side effects, typical of the entire GLP-1 RA class, were nausea, vomiting, and diarrhea. Discontinuation of treatment related to side effects was low (7%).

Liraglutide

Liraglutide was the second GLP-1 RA to become available in the United States. Its major advantage was longer half-life and hence greater effectiveness when administered as a once-daily injection. It was generally more effective than exenatide and has much higher homology (97%) with human GLP-1, and therefore, a lower risk of immunogenicity and allergic reactions.

Liraglutide was evaluated in a phase 3 clinical program known as LEAD (Liraglutide Effect and Action in Diabetes), using monotherapy and combination therapy, with multiple comparators.^11

–16 Liraglutide administered once daily demonstrated significant HbA_1c reductions ranging from −0.8% to −1.1% with the lower dose (1.2 mg/day), and from −1.0% to −1.5% with the higher dose (1.8 mg/day). Significant weight reductions were demonstrated with weight loss in these studies ranging from −2.2 to −5.9 lbs with the lower dose (1.2 mg/day) and from −4.0 to −7.3 lbs with the higher dose (1.8 mg/day).

Insulin Degludec/Liraglutide Coformulation

Because of the attractiveness of simultaneous initiation of therapy with a GLP-1 RA and a long-acting basal insulin, a coformulation of liraglutide and insulin degludec was developed and found to be both effective and well tolerated. It is administered as one injection per day, thereby providing convenience and hopefully resulting in better compliance. Its use markedly reduces the weight gain associated with insulin therapy and the gastrointestinal side effects of a GLP-1 RA. For patients who require more than 50 U of insulin per day, one can use the separate preparations of the two medications so that they can be titrated independently.

In a development program known as DUAL, the efficacy and safety of the coformulation of insulin degludec and liraglutide were evaluated.^17

–22 In a 52-week comparison of IDegLira with insulin degludec or liraglutide alone,²² the mean HbA_1c at 52 weeks was reduced by 1.84% in the IDegLira group, 1.40% in the insulin degludec group, and 1.21% in the liraglutide group. Seventy-eight percent of the patients on IDegLira achieved an HbA_1c of <7% compared with 63% of patients receiving insulin degludec and 57% of those receiving liraglutide. The mean fasting plasma glucose at the end of the trial was similar for patients receiving IDegLira or insulin degludec but higher in the liraglutide group. At 52 weeks, the daily insulin dose was 37% lower with IDegLira than with insulin degludec. IDegLira was associated with a greater decrease in body weight of 2.8 kg, and a 37% lower rate of hypoglycemia compared with insulin degludec.²²

Lixisenatide

Lixisenatide is another GLP-1 RA available for once-daily use. Its half-life is shorter than that of liraglutide (Table 1). Lixisenatide is less effective than liraglutide in reducing HbA_1c, fasting plasma glucose, and body weight, after 24 weeks of therapy,²³ but it has greater efficacy in reducing the postprandial glucose levels both at 28 days and 24 weeks of therapy.^23
–25 HbA_1c was reduced by 0.5% with morning injection and 0.4% with evening injection (placebo corrected). The 2-h postprandial glucose was reduced by 4.5 mmol/L (placebo corrected), and body weight was reduced by 0.9 kg (morning) or 0.6 kg (evening injection, placebo corrected).²³ When lixisenatide was administered to people inadequately controlled with basal insulin alone, there was an average reduction in HbA_1c of 0.4%, the percentage of subjects achieving an HbA_1c <7% increased from 12% for placebo to 28%, the postprandial glucose was reduced by 3.8 mmol/L, average body weight decreased by 1.3 kg, and total insulin dose per day decreased by an average of 3.7 U/day from a baseline of 55 U/day.²⁵

Lixisenatide/Insulin Glargine Coformulation

Lixisenatide was introduced as a coformulation with insulin glargine, for the same reasons as for liraglutide combined with insulin degludec: convenience (one injection per day), reducing the extent of weight gain associated with insulin therapy, and a reduced risk of gastrointestinal side effects, as the doses of GLP-1 RA and insulin glargine are gradually escalated. This can be an effective manner to intensify therapy after failing to achieve goal with a mono- or combination oral therapy.

The LixiLan-L study evaluated 736 patients inadequately controlled on basal insulin alone or in combination with 1 or 2 oral agents.²⁶ Patients treated with iGlarLixi showed reductions in HbA_1c of −1.1% and with iGlar of −0.6%. A higher percentage of patients achieved the HbA_1c target level of <7% (P < 0.0001): 55% of iGlarLixi patients reached HbA_1c <7% compared with 30% of iGlar patients. iGlarLixi also demonstrated significant reductions in 2-h postprandial glucose (PPG) following a standardized liquid breakfast meal compared with iGlar. Mean body weight decreased by 0.7 kg with iGlarLixi and increased by 0.7 kg with iGlar (P < 0.0001). These improvements were accompanied by no increased risk of hypoglycemia.

Long-Acting GLP-1 RAs for Weekly Administration

Short-acting GLP-1 RAs require either twice-daily or daily administration. Currently, three long-acting agents are available, permitting administration on a weekly basis: exenatide ER, dulaglutide, and semaglutide. These offer greater convenience and therefore are expected to improve adherence.

There appears to be increased potency both in terms of HbA_1c reduction and weight loss in the longer acting preparations, semaglutide, dulaglutide, and exenatide ER, compared with the short-acting preparations.

Exenatide ER

Exenatide ER was the first weekly agent to become available. It consists of the same exenatide molecule that is absorbed slowly because it is encapsulated into a polymeric matrix of microspheres. This preparation is associated with a greater incidence of local reactions at the injection site that resolve spontaneously with time. The gastrointestinal side effects are less frequent and mild than for the other GLP-1 RAs, presumably because the final therapeutic blood level is achieved relatively slowly due to the gradual accumulation of the peptide over a period of up to 6–7 weeks. The phase 3 clinical trials of exenatide ER, consisting of six studies, were designated as the DURATION studies,^{27

–36} (Table 2). These included two randomized placebo-controlled trials^27,31 and four open-label studies. The studies used several comparators and several different types of background medications and included subjects with HbA_1c ranging from 6% to 12%. Most studies were 24–30 weeks in duration, but DURATION-1 was extended (open label) to 6 years and DURATION-3 was extended to 3 years. In all six studies, HbA_1c levels were reduced by 1.3%–1.6%. The extent of HbA_1c reduction was linearly related to the baseline HbA_1c level, which is characteristic of nearly all medications for type 2 diabetes. Benefits in terms of HbA_1c and weight loss persisted through 6 years of follow-up in the open-label study although the number of subjects showed major attrition. The major side effects were gastrointestinal, as is characteristic for this entire class of therapeutic agents, both short and long acting. Minor reactions at the injection site were common for this agent, in contrast to all of the other GLP-1 RAs, presumably due to the polymeric microspheres. In the DURATION development program, exenatide ER was found to be superior in terms of its ability to lower HbA_1c to all agents studied, metformin, pioglitazone, sitagliptin, exenatide bid, and insulin glargine, with the exception of liraglutide. In DURATION-6, liraglutide 1.8 mg/day was found to be more efficacious that exenatide ER.³⁶

Dulaglutide

Dulaglutide is a long-acting GLP-1 analog suitable for once-weekly use. Dulaglutide shows considerably greater potency than the short-acting analogs discussed above and greater potency than exenatide ER. It has been evaluated in a series of 10 phase 3 clinical trials. The Assessment of Weekly AdministRation or AWARD clinical trials included ten phase 3 trials with multiple comparators.^{37

–44} (Tables 2 –4) The comparators included placebo, a sulfonylurea, exenatide, insulin glargine, and liraglutide in a variety of settings and patient populations.

When dulaglutide was added to prior therapy with the SGLT₂ inhibitor empagliflozin, it resulted in additional improvement in HbA_1c and greater weight loss.⁴⁴

The AWARD-1 trial compared dulaglutide 1.5 mg versus exenatide (10 μg) twice daily with background therapy of metformin and pioglitazone. Participants receiving dulaglutide (1.5 mg/week) experienced dose-dependent reduction in HbA_1c level of 1.51%, while those receiving exenatide showed a 0.99% reduction. Both groups experienced similar weight loss, 1.3 kg, and similar incidence of gastrointestinal side effects.³⁸ Thus, in subjects with metformin and pioglitazone background therapy, once-weekly dulaglutide therapy shows superior efficacy compared with exenatide, with similar tolerability.

The AWARD-2 trial³⁹ compared dulaglutide (0.75 and 1.5 mg/week) with insulin glargine titrated using a fasting blood glucose target of 100 mg/dL, with both groups also receiving metformin treatment. The dulaglutide-treated participants exhibited an average 0.59% reduction in HbA_1c with the 0.75 mg dose or a 0.9% reduction with the 1.5-mg dulaglutide dose, compared with a 0.62% reduction in the group receiving insulin glargine. Dulaglutide demonstrated a dose-dependent weight loss while the insulin glargine-treated group showed a +1.28 kg weight gain. Thus, dulaglutide (1.5 mg/week) was superior to insulin glargine and a 0.75 mg dose was noninferior.

The AWARD-6 trial⁴³ compared dulaglutide (1.5 mg/week) versus liraglutide (1.8 mg daily), both with concomitant metformin, for 26 weeks. The dulaglutide and liraglutide groups showed nearly identical decreases in HbA_1c levels of 1.42% and 1.36%, respectively. The liraglutide group demonstrated significantly greater weight loss (3.6 kg) compared with the dulaglutide group (2.9 kg). Adverse events were similar in the two groups.

Additional AWARD studies compared dulaglutide with several other comparators.^40

–44

Semaglutide

Semaglutide is a GLP-1 RA that has recently become available for treatment of type 2 diabetes using once-weekly injection at dosages of 0.5 or 1.0 mg/week. The molecule has 94% amino acid sequence homology to native GLP-1. Structural modifications render semaglutide more resistant to degradation by dipeptidyl peptidase-4, confer strong binding to albumin, and extend its half-life to ∼1 week (Table 1). To minimize gastrointestinal side effects, therapy should be initiated at 0.25 mg/week for 4 weeks and subsequently at 0.5 mg/week.

Semaglutide is the latest addition to the once-weekly GLP-1 RA class of therapies. It has been extensively studied in the SUSTAIN clinical trials—Semaglutide Unabated Sustainability in Treatment of type 2 diabetes (Table 4)^45

–51 and found to be more effective in terms of HbA_1c reduction and weight loss than placebo, sulfonylureas, exenatide, DPP-4 inhibitors, or basal insulin (glargine), either in the presence or absence of oral agents such as metformin. Semaglutide results in HbA_1c reduction and weight loss that are statistically and clinically significant. The combination of HbA_1c reduction and weight loss was seen in more than 75% of subjects in a series of five clinical trials (SUSTAIN-1 through SUSTAIN-5).^45

–51 There is a modest increase in potency of the higher 1.0 mg/week dose compared with 0.5 mg/week. Gastrointestinal side effects are comparable to those of the other GLP-1 RAs and tend to become milder after continued use.

The phase 3a development program for semaglutide included subjects across the entire spectrum of diabetes progression (Table 4). There were five trials in the SUSTAIN 3a program. SUSTAIN-1 enrolled drug-naive patients with shorter duration of diabetes; SUSTAIN-2 enrolled patients receiving metformin and/or thiazolidinediones and the comparator was sitagliptin; in SUSTAIN-3, subjects had been receiving one or two oral antidiabetic agents and the comparator was once-weekly exenatide ER; in SUSTAIN-4, patients were receiving metformin with or without sulfonylureas and insulin, and in SUSTAIN-5, the patients had longer duration of diabetes and were being treated with basal insulin in both the semaglutide treatment and the placebo groups.

HbA_1c reduction

Reduction in HbA_1c was dose dependent with modest improvement as dose was increased from 0.5 to 1.0 mg/week. The reduction in HbA_1c was nearly maximal by 16 weeks and highly statistically significant. The odds ratio for achieving an HbA_1c of 7.0% with semaglutide compared with placebo was ∼15 for the 0.5 mg/week dosage and ∼30 for the 1.0 mg/week dosage. Similar odds ratios were observed when using a target HbA_1c of 6.5%. Weight loss was also dose dependent: −3.7 kg at the 0.5 mg/week dosage and −5.4 kg at 1.0 mg/week after 30 weeks.⁴⁵

Composite endpoint

HbA_1c reduction and weight loss

In an analysis of subjects achieving any degree of HbA_1c reduction ≥1% and any degree of weight loss ≥5% using data from all five SUSTAIN 3a clinical trials, significantly more subjects receiving semaglutide achieved this dual composite endpoint than any of the comparators. The proportion of subjects achieving this endpoint was generally greater with semaglutide 1.0 versus 0.5 mg, suggesting a dose-dependent effect. Semaglutide was well tolerated with a safety profile similar to that of the other GLP-1 RAs.⁴⁵ SUSTAIN-6 was a cardiovascular outcome trial.⁵²

SUSTAIN-7 was a phase 3b clinical trial that compared the effectiveness of semaglutide (0.5 or 1.0 mg/week dose levels) and dulaglutide (0.75 mg or 1.5 mg/week) when added to previous therapy with empagliflozin. The lower dose of semaglutide was more effective than the higher dose of dulaglutide in reducing HbA_1c and achieving weight loss. The higher dose of semaglutide (1.0 mg/week) reduced mean A_1c by 1.8% and average weight by 6.5 pounds, in comparison with an average 1.4% reduction in HbA_1c and 3.0 pounds weight loss for the group receiving the higher dose of dulaglutide 1.5 mg/week.⁵³

Potential Mechanisms for Cardiovascular Protection

GLP-1 exerts direct and indirect actions on the cardiovascular system, including effects on cardiomyocytes, blood vessels, and adipocytes.⁵⁴ The GLP-1 RAs have beneficial effects on blood pressure⁵⁵ and reduce postprandial lipoprotein levels.⁵⁶ GLP-1 RAs have cardioprotective actions in preclinical models of cardiovascular ischemia, and short-term studies in humans have shown beneficial effects on cardiac function in people with ischemic heart disease. GLP-1 receptor activation in the hypothalamus reduces appetite and contributes to weight loss.⁵⁷ Obesity is a significant risk factor for atherosclerotic cardiovascular disease and increased risk of heart failure. Therefore, weight loss associated with the use of GLP-1 RA may contribute to potential cardioprotective effects. Furthermore, weight loss is associated with increased plasma adiponectin levels, which have been shown to protect against acute myocardial infarctions and cardiac hypertrophy.⁵⁸

Cardiovascular Outcome Trials for GLP-1 RAs

Large randomized placebo-controlled trials have been conducted in patients with type 2 diabetes with high cardiovascular risk to evaluate the cardiovascular safety of four GLP-1 RAs: liraglutide and lixisenatide for daily administration, and semaglutide and exenatide ER for weekly administration (Table 5).

Table 5.

Cardiovascular Outcome Trials for Four GLP-1 Receptor Agonists ^52,59

–62

Trial	Patient population	Median follow-up	HR
Lixisenatide ELIXA⁵⁹	T2D with acute cardiovascular event ≤180 days; N = 6058	25 Months	HR = 1.02. No significant difference versus placebo for 4-point MACE (3-point MACE; or unstable angina requiring hospitalization), nor all-cause mortality.
Liraglutide LEADER⁶⁰	T2D, age ≥50 years; CVD or CKD; or age ≥60 years with one risk factor; N = 9340	3.8 Years	HR = 0.85 for all-cause death. HR = 0.87 for 3-point MACE. HR = 0.78 for CVD death.
Exenatide qw EXSCEL⁶¹	T2D, 70% with prior cardiovascular event; N = 14752	3.2 Years	HR = 0.91 for 3-point MACE
Semaglutide qw SUSTAIN-6⁵²	T2D, age ≥50 years with CVD, HF, or CKD, or ≥60 years with one risk factor; N = 3297	2.1 Years	HR = 0.74 for 3-point MACE

CKD, chronic kidney disease; CVD, cardiovascular disease; EXSCEL, Exenatide Study of Cardiovascular Event Lowering; HF, heart failure; HR, hazard ratio; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; MACE, major adverse cardiovascular event; SUSTAIN, Trial to Evaluate Cardiovascular and Other Long-Term Outcomes with Semaglutide in Subjects with type 2 Diabetes; T2D, type 2 diabetes.

ELIXA: The Evaluation of Lixisenatide in Accute Coronary Syndrome

The ELIXA trial compared lixisenatide with placebo in 6068 patients with type 2 diabetes who had an acute coronary event within 180 days and had a mean HbA_1c of 7.7%, followed up for a median of 2.1 years. The primary outcome was a 4-point major adverse cardiovascular event (MACE) that added hospitalization for unstable angina. The hazard ratio (HR) for the primary outcome was 1.02 (noninferior) with P < 0.001 for noninferiority and P = 0.81 for superiority.⁵⁹

LEADER: Liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results

This study compared liraglutide 1.8 mg once daily with placebo in 9340 patients with type 2 diabetes and established cardiovascular disease (81%) or cardiovascular risk factors and a mean HbA_1c of 8.7%, followed up for a median of 3.8 years. The HR for the primary outcome was 0.87 with P < 0.001 for noninferiority and P = 0.01 for superiority.⁶⁰

SUSTAIN-6: Trial to Evaluate Cardiovascular and Other Long-Term Outcomes with Semaglutide in Subjects with type 2 Diabetes

SUSTAIN-6 compared semaglutide (0.5 and 1.0 mg once per week) with placebo in 3297 patients with type 2 diabetes and established cardiovascular disease (83%) or cardiovascular risk factors and a mean HbA_1c of 8.7%, followed up for a median of 2.1 years. The HR was 0.74 with P < 0.001 for noninferiority and P = 0.02 for superiority.⁵²

EXSCEL: Exenatide study of cardiovascular event lowering

EXSCEL was the cardiovascular trial with once-weekly exenatide ER. This study compared exenatide extended-release (2 mg once per week) with placebo in 14,752 patients with type 2 diabetes and established cardiovascular disease (73%) or without previous cardiovascular events and a median HbA_1c of 8.0% followed up for a median of 3.2 years. The HR was 0.91 with P < 0.001 for noninferiority and P = 0.06 for superiority.⁶¹

A meta-analysis of the four cardiovascular trials reported to date evaluating cardiovascular safety of the GLP-1 RA included ELIXA, LEADER, SUSTAIN-6, and EXSCEL.⁶² These trials demonstrated cardiovascular safety, with findings from two trials (LEADER and SUSTAIN-6) showing significant reductions in the primary endpoint, a 3-point MACE outcome, including cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke. Only liraglutide was associated with significant reductions in all-cause mortality and cardiovascular mortality, and only semaglutide was associated with a significant reduction in nonfatal stroke. The authors concluded that drugs in the class of GLP-1 RA can reduce the 3-point MACE, cardiovascular mortality, and all-cause mortality risk, although to varying degrees for individual drugs and without safety concerns. If one assumes that all of the GLP-1 RAs were to show a class effect for cardioprotection and average the results of the LEADER, ELIXA, SUSTAIN-6, and EXSCEL studies, then the HR would be 0.90.⁶²

Discussion

The following considerations apply to commercially available GLP-1 RA class of therapies (Tables 2 –4).

Use of GLP-1 RAs alone or as part of combination therapy with oral agents or insulin greatly improves the ability to achieve an HbA_1c target of either 6.5% or 7.0%. GLP-1 RAs are synergistic with metformin, SGLT₂ inhibitors, insulins, and have been used in conjunction with pioglitazone.

GLP-1 RAs have been shown to be safe, effective, and well tolerated. The gastrointestinal side effects—nausea, vomiting, and diarrhea—generally decline in frequency and severity within a matter of weeks. Slower titration of dose of the GLP-1 RA can reduce the risk of these side effects.

HbA_1c reduction and weight loss are largely accomplished within 15 weeks and can be expected to have reached maximal effectiveness by 30 weeks. The reduction in HbA_1c and weight loss is dose dependent.

In addition to the reduction of HbA_1c and weight loss, the GLP-1 RAs reduce glycemic variability measured by several standard metrics (% coefficient of variation, standard deviation, mean amplitude of glycemic excursions) and accompanied by an increase in the percentage of time in the target range.^63

–66

If the HbA_1c is <8%, or if the patient is at high risk for hypoglycemia for any reason (e.g., hypoglycemia unawareness, or history of severe or frequent hypoglycemia), it is advisable to reduce the dosage of insulin and/or other antihyperglycemic agents by a moderate amount to reduce the risk of hypoglycemia when adding another highly effective agent.

GLP-1 RAs are highly effective and even better tolerated when coformulated with insulin (liraglutide with insulin degludec, lixisenatide with insulin glargine U-100)). This ensures that dosage is escalated slowly and gradually.

Cardiovascular protection has been observed for liraglutide in the LEADER study. A smaller effect with borderline statistical significance was observed for exenatide ER in the EXSCEL trial but not for lixisenatide in the ELIXA. A cardiovascular outcome trial for dulaglutide is ongoing. It is worth noting that the curves for both liraglutide and semaglutide in the cardiovascular outcome trials (CVOTs) separate from placebo after more than 1 year. This is in contrast to the results reported in the EMPA-REG CVOT for empagliflozin, in which separation of the curves occurs within 3 months of initiation of the medication. This suggests that the mechanisms of cardiovascular benefit are distinctive for these two classes of medications.

For people with type 2 diabetes experiencing unacceptable levels of hypoglycemia while receiving insulin therapy, it may be possible to reduce or even eliminate the use of insulin by addition of highly effective therapies such as GLP-1 RAs.

Ongoing research and development can be expected to clarify the effectiveness and safety of the implantable osmotic pump for administration of exenatide or other relatively rapidly cleared analogs, the potential clinical utility of an oral preparation of semaglutide,⁶⁷ and the effectiveness of GLP-1 RAs for management of obesity^57,68 and of nonalcoholic hepatosteatosis.⁶⁹

Conclusions

GLP-1 RAs are one of the most effective and well-tolerated class of therapies for type 2 diabetes. These medications are usually more effective in terms of HbA_1c reduction and weight loss than metformin, sulfonylureas, and DPP-4 inhibitors. The GLP-1 RA class of medications has a low risk of hypoglycemia, but adjustments of the doses of other medications are advisable, especially if the initial baseline HbA_1c is <8%, or if the patient is receiving insulin or sulfonylureas.

The effects of GLP-1 RAs appear to be additive with basal insulin. Lixisenatide is available as a fixed dose-ratio coformulation with insulin glargine U-100 and liraglutide is available as a fixed dose-ratio coformulation with insulin degludec. These coformulations facilitate slow and systematic titration of dose, which has the benefit of reduced gastrointestinal side effects related to the GLP-1 RA, reduced risk of hypoglycemia related primarily to the insulin, and often permit use of smaller doses for both medications than when they are used alone. Liraglutide has been demonstrated to be cardioprotective with respect to the prespecified 3-component MACE.

Footnotes

Acknowledgments

The author thanks her colleagues, coworkers, and patients involved in several clinical trials.

Author Disclosure Statement

The author has served as a principal investigator, as a consultant, speaker, and advisor to companies that manufacture GLP-1 RAs, including AstraZeneca, Novo Nordisk, Sanofi, Boehringer Ingelheim, and Eli Lilly.

References

Garber

, Abrahamson

, Barzilay

, et al.: Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2016 executive summary. Endocr Pract, 2016; 22:84–113.

American Diabetes Association: 8. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2018. Diabetes Care, 2018; 41(Suppl 1):S73–S85.

Tancredi

, Rosengren

, Svensson

, et al.: Excess mortality among persons with type 2 diabetes. N Engl J Med, 2015; 373:1720–1732.

Centers for Disease Control and Prevention: National diabetes statistics report.. 2017. www.cdc.gov.

Davies

, Pieber

, Hartoft-Nielsen

M-L

, et al.: Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA, 2017; 318:1460–1470.

Henry

, Rosenstock

, Logan

, et al.: Continuous subcutaneous delivery of exenatide by ITCA 650 leads to sustained glycemic control and weight loss for 48 weeks in metformin-treated subjects with type 2 diabetes. J Diabetes Complications, 2014; 28:393–398.

Nauck

, Meier

: Incretin hormones: their role in health and disease. Diabetes Obes Metab, 2018; 20(Suppl 1):5–21.

Rosenstock

, Buse

, Azeem

, et al.: Efficacy and safety of ITCA 650, a novel drug-device GLP-1 receptor agonist, in type 2 diabetes uncontrolled with oral antidiabetes drugs: the FREEDOM-1 Trial. Diabetes Care, 2018; 41:333–340.

Rosenstock

, Buse

, Azeem

, et al.: Efficacy and safety of ITCA 650, a novel drug-device GLP-1 receptor agonist, in type 2 diabetes uncontrolled with oral antidiabetes drugs: the FREEDOM-1 trial. Diabetes Care, 2018; 41:333–340.

10.

Henry

, Rosenstock

, Denham

, et al.: Clinical impact of ITCA 650, a novel drug-device GLP-1 receptor agonist, in uncontrolled type 2 diabetes and very high baseline HbA1c: the FREEDOM-1 HBL (high baseline) study. Diabetes Care, 2018; 41:613–619.

11.

Marre

, Shaw

, Brandle

, et al.: Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabetic Med, 2009; 26:268–278.

12.

Nauck

, Frid

, Hermansen

, et al.: Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutideeffect and action in diabetes)-2 study. Diabetes Care, 2009; 32:84–90.

13.

Garber

, Henry

, Ratner

, et al.: Liraglutide, a once-daily human glucagon-like peptide 1 analogue, provides sustained improvements in glycaemic control and weight for 2 years as monotherapy compared with glimepiride in patients with type 2 diabetes. Diabetes Obes Metab, 2011; 13:348–356.

14.

Zinman

, Gerich

, Buse

, et al.: Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met TZD). Diabetes Care, 2009; 32:1224–1230.

15.

Russell-Jones

, Vaag

, Schmitz

, et al.: Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met SU): a randomised controlled trial. Diabetologia, 2009; 52:2046–2055.

16.

Buse

, Rosenstock

, Sesti

, et al.: Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomized, parallel-group, multinational, open-label trial (LEAD-6). Lancet, 2009; 374:39–47.

17.

Gough

, Bode

, Woo

, et al.: Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes. Lancet Diabetes Endocrinol, 2014; 2:885–893.

18.

Rodbard

, Bode

, Harris

, et al.: Safety and efficacy of insulin degludec/liraglutide (IDegLira) added to sulphonylurea alone or to sulphonylurea and metformin in insulin-naïve people with type 2 diabetes: the DUAL IV trial. Diabet Med, 2017; 34:189–196.

19.

Rodbard

, Buse

, Woo

, et al.: Benefits of combination of insulin degludec and liraglutide are independent of baseline glycated haemoglobin level and duration of type 2 diabetes. Diabetes Obes Metab, 2016; 18:40–48.

20.

Holst

, Buse

, Rodbard

, et al.: IDegLira improves both fasting and postprandial glucose control as demonstrated using continuous glucose monitoring and a standardized meal test. J Diabetes Sci Technol, 2015; 10:389–397.

21.

Billings

, Doshi

, Gouet

, et al.: Efficacy and safety of IDegLira versus basal-bolus insulin therapy in patients with type 2 diabetes uncontrolled on metformin and basal insulin; DUAL VII randomized clinical trial. Diabetes Care, 2018; 41:1009–1016.

22.

Gough

, Bode

, Woo

, et al.: One-year efficacy and safety of a fixed combination of insulin degludecand liraglutide in patients with type 2 diabetes: results of a 26-week extension to a 26-week main trial. Diabetes Obes Metab, 2015; 17:965–973.

23.

Ahrén

, Leguizamo Dimas

, Miossec

, et al.: Efficacy and safety of lixisenatide once-daily morning or evening injections in type 2 diabetes inadequately controlled on metformin (GetGoal-M). Diabetes Care, 2013; 36:2543–2550.

24.

Kapitza

, Forst

, Coester

, et al.: Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin. Diabetes Obes Metab, 2013; 15:642–649.

25.

Riddle

, Aronson

, Home

, et al.: Adding once-daily lixisenatide for type 2 diabetes inadequately controlled by established basal insulin: a 24-week, randomized, placebo-controlled comparison (GetGoal-L). Diabetes Care, 2013; 36:2489–2496.

26.

Wysham

, Bonadonna

, Aroda

, et al.: Consistent findings in glycaemic control, body weight and hypoglycaemia with iGlarLixi (insulin glargine/lixisenatide titratable fixed-ratio combination) vs insulin glargine across baseline HbA1c, BMI and diabetes duration categories in the LixiLan-L trial. Diabetes Obes Metab, 2017; 19:1408–1415.

27.

Henry

, Klein

, Han

, Iqbal

: Efficacy and tolerability of exenatide once weekly over 6 years in patients with type 2 diabetes: an uncontrolled open-label extension of the DURATION-1 study. Diabetes Technol Ther, 2016; 18:677–686.

28.

Drucker

, Buse

, Taylor

, et al.: Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet, 2008; 372:1240–1250.

29.

Wysham

, Bergenstal

, Malloy

, et al.: DURATION-2: efficacy and safety of switching from maximum daily sitagliptin or pioglitazone to once-weekly exenatide. Diabet Med, 2011; 28:705–714.

30.

Blonde

, Pencek

, MacConell

: Association among weight change, glycemic control, and markers of cardiovascular risk with exenatide once weekly: a pooled analysis of patients with type 2 diabetes. Cardiovasc Diabetol, 2015; 14:12.

31.

Diamant

, Van Gaal

, Stranks

, et al.: Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet, 2010; 375:2234–2243.

32.

Diamant

, Van Gaal

, Guerci

, et al.: Exenatide once weekly versus insulin glargine for type 2 diabetes (DURATION-3): 3-year results of an open-label randomised trial. Lancet Diabetes Endocrinol, 2014; 2:464–473.

33.

Russell-Jones

, Cuddihy

, Hanefeld

, et al.: Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes Care, 2012; 35:252–258.

34.

Blevins

, Ruggles

, Hardy

: Onset of glycemic and weight outcomes in patients initiating exenatide once weekly: the relationship of exenatide exposure with efficacy over the first 24 weeks of treatment. Diabetes Ther, 2016; 7:361–368.

35.

Blevins

, Pullman

, Malloy

, et al.: DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab, 2011; 96:1301–1310.

36.

Buse

, Nauck

, Forst

, et al.: Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet, 2013; 381:117–124.

37.

Gurung

, Shyangdan

, O'Hare

, et al.: A novel, long-acting glucagon-like peptide receptor agonist: dulaglutide. Diabetes Metab Syndr Obes, 2015; 8:363–386.

38.

Wysham

, Blevins

, Arakaki , et al.: Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care, 2014; 37:2159–2167.

39.

Giorgino

, Benroubi

, Sun

, et al.: Efficacy and safety of once weekly dulaglutide versus insulin glargine in combination with metformin and glimepiride in type 2 diabetes patients (AWARD-2). Diabetes, 2014; 63(Suppl 1):A87.

40.

Umpierrez

, Povedano

, Manghi

, et al.: Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care, 2014; 37:2168–2176.

41.

Jendle

, Rosenstock

, Blonde

, et al.: Better glycemic control and less weight gain with once weekly dulaglutide versus once daily insulin glargine, both combined with premeal insulin lispro in type 2 diabetes patients (AWARD-4). Diabetes, 2014; 63:A246–A247.

42.

Nauck

, Weinstock

, Umpierrez

, et al.: Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5). Diabetes Care, 2014; 37:2149–2158.

43.

Dungan

, Povedano

, Frost

, et al.: Once weekly dulaglutide versus once daily liraglutide in metformin treated patients with type 2 diabetes (AWARD-6): a randomized, open-label, phase 3, non-inferiority trial. Lancet, 2014; 384:1349–1357.

44.

Ludvik

, Frías

, Tinahones

, et al.: Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol, 2018; 6:370–381.

45.

Rodbard

, Bellary

, Hramiak

, et al.: Responder analysis of subjects achieving HbA1c reduction >1% and body weight loss >5% across SUSTAIN 1–5 clinical trials. Diabetes, 2017; 7(Suppl):Abstract P-0525.

46.

Sorli

, Harashima

, Tsoukas

, et al.: Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol, 2017; 5:251–260.

47.

Ahrén

, Masmiquel

, Kumar

, et al.: Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial. Lancet Diabetes Endocrinol, 2017; 5:341–354.

48.

Ahmann

, Capehorn

, Charpentier

, et al.: Efficacy and safety of once-weekly semaglutide versus exenatide er in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial. Diabetes Care, 2018; 41:258–266.

49.

Aroda

, Bain

, Cariou

, et al.: Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. Lancet Diabetes Endocrinol, 2017; 5:355–366.

50.

Rodbard

, Lingway

, Reed

, et al.: Efficacy and safety of semaglutide once-weekly vs. placebo as add-on to basal insulin alone or in combination with metformin in subjects with type 2 diabetes (SUSTAIN-5). Diabetologia, 2016; 59:S364–S365, Abstract A-766.

51.

Rodbard

, Lingvay

, Reed

, et al.: Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): a randomised, controlled trial. J Clin Endocrinol Metab. 2018 Eprint ahead of print 23 April 2018 https:/doi.org/10.1210/jc.2018–00070.

52.

Marso

, Bain

, Consoli

, et al.: Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med, 2016; 375:1834–1844.

53.

Pratley

, Aroda

, Lingvay

, et al.: Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol, 2018; 6:275–286.

54.

Ussher

, Drucker

: Cardiovascular biology of the incretin system. Endocr Rev, 2012; 33:187–215.

55.

Schwartz

, Koska

, Mullin

, et al.: Exenatide suppresses postprandial elevations in lipids and lipoproteins in individuals with impaired glucose tolerance and recent onset type 2 diabetes mellitus. Atherosclerosis, 2010; 212:217–222.

56.

Meier

, Gethmann

, Gotze

, et al.: Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans. Diabetologia, 2006; 49:452–458.

57.

Flint

, Raben

, Astrup

, et al.: Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest, 1998; 101:515–520.

58.

Shibata

, Ouchi

, Ito

, et al.: Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med, 2004; 10:1384–1389.

59.

Pfeffer

, Claggett

, Diaz

, et al.: Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med, 2015; 373:2247–2257.

60.

Marso

, Daniels

, Brown-Frandsen

, et al.: Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med, 2016; 375:1834–1844.

61.

Holman

, Bethel

, Mentz

, et al.: Effects of once weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med, 2017; 377:1228–1239.

62.

Bethel

, Patel

, Merrill

, et al.: Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol, 2018; 6:105–113.

63.

Lane

, Weinrib

, Rappaport

, Hale

: The effect of addition of liraglutide to high-dose intensive insulin therapy: a randomized prospective trial. Diabetes Obes Metab, 2014; 16:827–832.

64.

Jendle

, Testa

, Martin

, et al.: Continuous glucose monitoring in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonist dulaglutide in combination with prandial insulin lispro: an AWARD-4 substudy. Diabetes Obes Metab, 2016; 18:999–1005.

65.

Bajaj

, Venn

, Ye

, et al.: Lowest glucose variability and hypoglycemia are observed with the combination of a GLP-1 receptor agonist and basal insulin (VARIATION study). Diabetes Care, 2017; 40:194–200.

66.

King

, Philis-Tsimikas

, Kilpatrick

, et al.: A fixed ratio combination of insulin degludec and liraglutide (IDegLira) reduces glycemic fluctuation and brings more patients with type 2 diabetes within blood glucose target ranges. Diabetes Technol Ther, 2017; 19:255–264.

67.

Davies

, Pieber

, Hartoft-Nielsen

, et al.: Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA, 2017; 318:1460–1470.

68.

Blundell

, Finlayson

, Axelsen

, et al.: Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes Obes Metab, 2017; 19:1242–1251.

69.

Mills

, Brown

KPD

, Smith

, et al.: Treating nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a review of efficacy and safety. Ther Adv Endocrinol Metab, 2018; 9:15–28.

The Clinical Impact of GLP-1 Receptor Agonists in Type 2 Diabetes: Focus on the Long-Acting Analogs

Abstract

Introduction

Exenatide

Liraglutide

Insulin Degludec/Liraglutide Coformulation

Lixisenatide

Lixisenatide/Insulin Glargine Coformulation

Long-Acting GLP-1 RAs for Weekly Administration

Exenatide ER

Dulaglutide

Semaglutide

HbA1c reduction

Composite endpoint

HbA1c reduction and weight loss

Potential Mechanisms for Cardiovascular Protection

Cardiovascular Outcome Trials for GLP-1 RAs

ELIXA: The Evaluation of Lixisenatide in Accute Coronary Syndrome

LEADER: Liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results

SUSTAIN-6: Trial to Evaluate Cardiovascular and Other Long-Term Outcomes with Semaglutide in Subjects with type 2 Diabetes

EXSCEL: Exenatide study of cardiovascular event lowering

Discussion

Conclusions

Footnotes

Acknowledgments

Author Disclosure Statement

References

HbA_1c reduction

HbA_1c reduction and weight loss