Current treatments and strategies for type 2 diabetes: Can we do better with GLP-1 receptor agonists?

Abstract

Diet, lifestyle modification, and pharmacotherapy with metformin are appropriate initial treatments for many patients with type 2 diabetes (T2DM). However, most individuals do not maintain glycemic control with metformin alone. Addition of other oral antidiabetes drugs (OADs), including sulfonylurea, meglitinide, or thiazolidinedione, is often the next step. Newer options, including incretin-based glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, offer important benefits as monotherapies or in combination with OADs, with low risk for hypoglycemia. Reductions in glycated hemoglobin (A1C) have been reported among patients treated with GLP-1 RAs (exenatide, −0.8 to −1.1%; liraglutide, −0.8 to −1.6%), as has weight loss (exenatide, −1.6 to −3.1 kg; liraglutide, −1.6 to −3.2 kg). GLP-1 RAs also stimulate β-cell responses and have positive effects on cardiovascular risk factors often present in patients with T2DM. The most common adverse events associated with GLP-1 RAs are nausea, which diminishes over time, and hypoglycemia (when used in combination with a sulfonylurea). A large number of trials demonstrated benefits of GLP-1 RAs, suggesting they could provide suitable treatment options for patients with T2DM.

Key words::

• Exenatide
• glucagon-like peptide-1 receptor agonists
• incretin-based therapy
• incretin mimetics
• liraglutide
• type 2 diabetes mellitus

Abbreviations
A1C	=	hemoglobin A1C (glycated hemoglobin)
AACE	=	American Association of Clinical Endocrinologists
ACE	=	American College of Endocrinology
ADA	=	American Diabetes Association
ADOPT	=	A Diabetes Outcome Progression Trial
BNP	=	B-type natriuretic peptide
BP	=	blood pressure
CHF	=	congestive heart failure
CV	=	cardiovascular
CVD	=	cardiovascular disease
DURATION	=	Diabetes therapy Utilization Researching changes in A1C, weight and other factors Through Intervention with exenatide Once Weekly
DPP-4	=	dipeptidyl peptidase-4
EASD	=	European Association for the Study of Diabetes
EMA	=	European Medicines Agency
EXSCEL	=	Exenatide Study of Cardiovascular Event Lowering Trial
FPG	=	fasting plasma glucose
GIP	=	glucose-dependent insulinotropic polypeptide
GLP-1 RAs	=	glucagon-like peptide-1 receptor agonists
HDL-C	=	high-density lipoprotein-cholesterol
HOMA-B	=	homeostasis model assessment of β-cell function
HTN	=	hypertension
LAR	=	long-acting release
LDL-C	=	low-density lipoprotein-cholesterol
LEAD	=	Liraglutide Effect and Action in Diabetes
LEADER	=	Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results
MI	=	myocardial infarction
NEP	=	neutral endopeptidase
OADs	=	oral antidiabetes drugs
PAI-1	=	plasminogen activator inhibitor-1
PPG	=	postprandial glucose
RECORD	=	Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes
SBP	=	systolic blood pressure
SUs	=	sulfonylureas
T2DM	=	type 2 diabetes
TNF-α	=	tumor necrosis factor-alpha
TZDs	=	thiazolidinedione
UKPDS	=	United Kingdom Prospective Diabetes study

Key messages

• Patients with T2DM often are not able to maintain treatment goals over time, and therefore require changes in therapy.

• During the last decade, glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have become available for treating patients with T2DM, and they can provide several advantages, including weight loss.

• Several recent trials have measured the efficacy and safety of GLP-1 RAs, thereby revealing their potential benefits and risks for treatment of patients with T2DM.

Introduction

The prevalence of type 2 diabetes (T2DM) has reached epidemic proportions, and this disease is well recognized as a major cause of mortality and morbidity worldwide (1). In the United States, T2DM was the seventh leading cause of death in 2006, and the mortality risk doubles in patients with diabetes versus those without the disease (2). Safe and effective treatments for diabetes are clearly needed, particularly interventions that may delay its progression and address common co-morbidities. The high mortality and morbidity rates among patients with diabetes are the result of the disease being associated with other risk factors for cardiovascular disease (CVD), including obesity, hypertension (HTN), and dyslipidemia (3). In addition, the pathophysiology of the disease leads to the development and progression of macrovascular and microvascular complications (4). In the Framingham Heart Study, the lifetime risk of developing CVD was 78% among men with diabetes, compared with 54.8% among those without diabetes. The respective values for women with diabetes were 67.1% and 38.0% (5).

This paper reviews treatment for T2DM with a focus on incretin-based treatment with glucagon-like peptide (GLP)-1 receptor agonists (RAs). This growing class of antidiabetic agents has several advantages over some older therapies, including reduction in body weight, low risk for hypoglycemia, improvement of β-cell function, and favorable effects on other CVD risk factors.

Disease progression in T2DM and effects on glycemic control

Lifestyle modifications and metformin monotherapy are recommended as the first step in the treatment of patients with T2DM (6). These interventions may be effective for achievement of glycated hemoglobin (A1C) goals in many patients; however, because T2DM is a progressive condition, most patients will eventually need treatment with more than one oral antidiabetes drug (OAD) to attain or maintain glycemic goals (7).

The traditional stepwise approach to the treatment of T2DM may contribute to less-than-desired A1C levels in many patients with diabetes and increase the risk for long-term complications of this disease. Clinical evidence from the A Diabetes Outcome Progression Trial (ADOPT) and the United Kingdom Prospective Diabetes Study (UKPDS) shows that many patients with T2DM on monotherapy with a single OAD will fail to maintain glycemic control after just a few years, or even sooner, depending on duration of disease prior to diagnosis and treatment adherence (7). More and/or different drugs are then added, but, as seen in the UKPDS, even combination treatment may eventually fail to maintain glycemic control (8). After treatment failure, A1C levels progressively increase, and treatment with insulin is often required once β-cell function has been completely lost (7,8).

There is also evidence that some diabetes treatments may have adverse effects on CVD risk. Some studies have shown an association between treatment with rosiglitazone and an increased risk for adverse cardiovascular (CV) events, including myocardial infarction (MI), heart failure, stroke, and death. Aside from the purported risk of increased ischemic CV morbidity and mortality, thiazolidinediones (TZDs) increase the rate of congestive heart failure (CHF) as well as fractures (6). In September 2010, the US Food and Drug Administration (FDA) placed significant restrictions on the use of rosiglitazone in response to data that suggest an elevated risk of CV events, stating ‘it will significantly restrict the use of the diabetes drug Avandia and other drugs containing rosiglitazone to patients with Type 2 diabetes who cannot control their diabetes on other medications’ (9) following completion of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial (10).

The negative effects of a number of standard therapies for T2DM on weight and CV outcomes, the risk of hypoglycemia associated with some agents (particularly with sulfonylureas (SU) and insulin), along with the failure of current treatments to provide long-term glycemic control in a substantial proportion of patients, provide strong evidence for the need for new, more optimized treatment options.

Perhaps the most important reason for failure of current OADs to maintain glycemic control in many patients is the fact that no single agent fully addresses all of the pathophysiologic defects underlying T2DM: insulin resistance, β-cell dysfunction, increased hepatic glucose production, inappropriate glucagon secretion, and impaired incretin effect. Treatment for T2DM must focus not only on elevated blood glucose, but also simultaneously on the underlying metabolic abnormalities of the disease.

GLP-1 RAs: recently developed options for the treatment of T2DM

The incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), are naturally occurring peptides secreted by enteroendocrine L-cells and K-cells, respectively, in response to nutrient intake (11,12). GLP-1 also produces a glucose-dependent decrease in glucagon release (13).

In patients with T2DM, incretin-mediated insulin secretion is significantly reduced, primarily due to the compromised action of GIP, while GLP-1 remains effective (14). Since both hormones contribute to the overall insulinotropic response, the levels of endogenous GLP-1 alone are insufficient for a full response in patients with T2DM. Thus, current treatment strategies are aimed at restoring the insulinotropic response in patients with T2DM, either by supplementing endogenous GLP-1 levels with GLP-1 RAs or by administering dipeptidyl peptidase-4 (DPP-4) inhibitors that inhibit the enzymatic degradation of endogenous GLP-1 (and GIP).

Incretin-based therapies, including the GLP-1 RAs, exenatide and liraglutide, and the DPP-4 inhibitors, sitagliptin, linagliptin, and saxagliptin, have distinct mechanisms of action that translate into differential efficacy and safety profiles observed in clinical trials (11,15–17). DPP-4 inhibitors act indirectly by inhibiting the degradation of endogenous GLP-1 and GIP and produce physiological levels of receptor activity (11); therefore, the efficacy of DPP-4 inhibitors depends primarily on endogenous secretion of GLP-1. DPP-4 inhibitors have been shown to safely reduce A1C levels, with a low risk of hypoglycemia, but are generally not associated with improvements in weight and cardiovascular risk factors (16–20).

GLP-1 RAs can supplement endogenous secretion of the hormone and produce pharmacologic levels of receptor activity (21). Studies in patients with T2DM show that GLP-1-based therapies effectively reduce A1C levels with low rates of hypoglycemia, promote weight loss, and may have β-cell-protective and cardioprotective effects (11). The remainder of this review focuses on the efficacy and safety of GLP-1 RAs for the treatment of T2DM.

Efficacy

Exenatide

Exenatide, the first GLP-1 RA approved for the treatment of T2DM, is a derivative of the reptilian protein exendin-4 with a 53% homology to native GLP-1 and a 2.4-hour half-life (22). It is indicated as adjunctive therapy to improve glycemic control in patients with T2DM who are taking metformin, an SU, a TZD, a combination of metformin and an SU, or a combination of metformin and a TZD, but who have not achieved adequate glycemic control. Recently, the FDA amended the exenatide prescribing information to include an indication for first-line monotherapy in conjunction with diet and exercise (23). The efficacy of exenatide has been demonstrated in multiple clinical trials, and an overview of study designs and results is provided in Table I (12,24–36).

Table I. Summary of exenatide and liraglutide clinical trials.

Reference		n	Compound	Dose	Weeks duration	A1C (%)	Weight (kg)	FPG (mmol/L)	PPG (mmol/L)
DURATION	Bergenstal et al., 2010 (24) DURATION-2	170	exenatide	2 mg once weekly	26	−1.5	−2.3	−1.8	—
	Buse et al., 2010 (25) DURATION-1	258	exenatide	2 mg once weekly	52	−2.0	−4.5	−2.6	—
	Buse et al., 2011 (26) DURATION-6	911	exenatide	2 mg once weekly	26	−1.28	−2.68	—	—
LEAD	Buse et al., 2009 (42) LEAD-6	233	liraglutide	1.8 mg/day	26	−1.12	−3.24	−1.61	—
		231	exenatide	10 μg BID	26	−0.79	−2.87	−0.60
	Garber et al., 2009 (43) LEAD-3	746	liraglutide	1.2, 1.8 mg/day	52	−0.84, –1.14	−1.85, –2.26	−0.84, –1.42	−1.71, –2.08
	Nauck et al., 2009 (44) LEAD-2	1,091	liraglutide	0.6, 1.2, 1.8 mg/day	26	−0.7, −1.0, −1.0	−1.8, −2.6, −2.8	−1.1, −1.6, −1.7	−1.7, −2.3, −2.6
	Russell-Jones et al., 2009 (45) LEAD-5	581	liraglutide	1.8 mg/day	26	−1.33	−1.8	−1.55	−1.81
	Zinman et al., 2009 (46) LEAD-4	533	liraglutide	1.2, 1.8 mg/day	26	−1.5, −1.5	−1.5, −1.5	−1.0, −2.0	90 min: −2.6, −2.7
Additional trials	Blonde et al., 2006 (27)	314	exenatide	10 μg BID	82	−1.1	−4.4	−0.9	—
	Bunck et al., 2009 (28)	69	exenatide	10 μg BID	156	−1.0	−5.7	−0.2	—
	Buse et al., 2004 (29)	377	exenatide	5 μg, 10 μg BID	30	−0.46, −0.86	−0.9, −1.6	−0.3, −0.6	—
	Buse et al., 2011 (30)	261	exenatide + basal insulin	10 μg BID	30	−1.74	−1.8	−1.6	a.m. 2-h: −2.0 mid 2-h: −0.5 p.m. 2-h: −1.6
	DeFronzo et al., 2005 (31)	336	exenatide	5 μg, 10 μg BID	30	−0.4, −0.78	−1.6, −2.8	−0.4, −0.6	34% reduction for both doses
	DeFronzo et al., 2008 (32)	61	exenatide	5 μg then 10 μg BID cross-over with sitagliptin	4	—	−0.8	−0.8	−6.2
	Drucker et al., 2008 (12)	295	exenatide	5 μg then 10 μg BID 2 mg once weekly	30	−1.5 −1.9	−3.6 −3.7	−2.3 −1.4	−6.9 −5.3
	Kendall et al., 2005 (33)	733	exenatide	5 μg, 10 μg BID	30	−0.6, −0.8	−1.6, −1.6	−0.5, −0.6	−2.9, −1.9
	Klonoff et al., 2008 (36)	217	exenatide	5 μg then 10 μg BID	≥ 156	−1.0	−5.3	−1.3	—
	Pratley et al., 2010 (47)	665	liraglutide	1.2, 1.8 mg/day	26	−1.24, −1.5,	−2.86, −3.38	−1.87, −2.14	NS
	Pratley et al., 2011 (48)	665	liraglutide	1.2, 1.8 mg/day	52	−1.29, −1.51	−2.78, −3.68	−1.71, −2.04	—
	Seino et al., 2008 (49)	226	liraglutide	0.1, 0.3, 0.6, 0.9 mg/day	14	−0.79, −1.22, −1.64, −1.85	0.87, 1.08, 0.84, 0.46	−0.76, −1.26, −2.27, −2.48	2−h: −1.43, −2.83, −4.22, −5.23
	Zinman et al., 2007 (35)	233	exenatide	10 μg BID	16	−0.98	−1.51	−1.69	−1.27

Twice daily. In a 30-week study in which exenatide was added to SU and metformin in 486 patients with T2DM, A1C declined by –0.8% in patients who received exenatide versus an increase of + 0.2% for placebo (P < 0.0001) (33). Exenatide has also been compared with placebo in 223 patients with T2DM not controlled with TZD (with or without metformin) (35). After 16 weeks of treatment, A1C declined by –0.89% for patients who received exenatide versus an increase of + 0.09% for placebo (P < 0.001). Body weight decreased by –1.75 kg with exenatide versus –0.24 kg for placebo (P < 0.001).

Once weekly. A once-weekly exenatide formulation was recently approved by the European Medicines Agency (EMA) and the FDA. That compound has been compared with twice-daily exenatide in the 52-week DURATION-1 (Diabetes therapy Utilization Researching changes in A1C, weight and other factors Through Intervention with exenatide Once Weekly 1) study (25). The first part of this 30-week trial compared exenatide once weekly (2 mg) with exenatide twice daily (10 μg) in 295 patients with T2DM and A1C > 7.0% despite disease management with either diet modification and exercise alone, or pharmacological treatment with metformin, an SU, a TZD, or any combination of these agents. After 30 weeks, results indicated that exenatide once weekly was more effective than twice-daily exenatide in lowering A1C (–1.9% versus –1.5%, P = 0.0023). In the second 22-week phase of the study, patients previously receiving exenatide twice daily switched to exenatide once weekly, while patients originally randomized to exenatide once weekly continued treatment. Patients continuing exenatide once weekly maintained A1C improvements at week 30 through week 52 (change from baseline to week 52, –2.0%) and those switching from exenatide twice daily to exenatide once weekly achieved further A1C improvements (change from baseline to week 52, –2.0%), with both groups achieving a mean A1C of 6.6% at week 52. After 52 weeks, patients in each treatment group had lost > 4 kg of body weight (12,25). Exenatide twice daily has also been shown to lower A1C and decrease body weight when added to an SU (A1C, –0.86 ± 0.11% for 10 μg, –0.46 ± 0.12% for 5 μg; weight, –1.6 ± 0.3 kg for 10 μg, –0.9 ± 0.3 kg for 5 μg) or metformin (A1C, –0.78 + 0.10 % for 10 μg, –0.40 ± 0.11% for 5 μg; weight, –2.8 ± 0.5 kg for 10 μg, –1.6 ± 0.4 kg for 5 μg) monotherapy (29,31,35). It has also been demonstrated that adding twice-daily exenatide injections to insulin glargine treatment in patients with uncontrolled T2DM improved glycemic control (A1C, –1.74% with exenatide versus –1.04% with placebo, P < 0.001) without increased hypoglycemia or weight gain (–1.8 kg with exenatide versus + 1.0 kg with placebo) (30).

When administered once weekly, exenatide produced a significantly greater reduction of A1C than either sitagliptin (–0.6% difference, P < 0.0001) or pioglitazone (–0.3% difference, P = 0.0165) (24). Another study reported that after 2 weeks of therapy, 2-hour postprandial glucose (PPG) was lower among patients who received exenatide long-acting release (LAR) than among those treated with sitagliptin (7.8 ± 0.3versus 11.5 ± 0.3 mmol/L (133 ± 6 versus 208 ± 6 mg/dL), P < 0.0001) (24,32). When patients were switched from exenatide to sitagliptin, 2-hour PPG increased by 4.1 ± 0.6 mmol/L (73 ± 11mg/dL), but when they changed from sitagliptin to exenatide, 2-hour PPG was reduced by –4.2 ± 0.5 mmol/L (–76 ± 10 mg/dL). PPG parameters, including AUC, C_ave, and C_max, were also lower after treatment with exenatide than with sitagliptin (P < 0.0001). The delay of gastric emptying induced by exenatide contributes to the lowering of PPG levels by slowing transfer of glucose from the intestines to the blood supply (37). Exenatide is being evaluated as add-on therapy in patients using insulin pumps, but it is currently not approved for use in conjunction with insulin (38).

Liraglutide

Liraglutide, a once-daily human GLP-1 analog, has 97% homology to human GLP-1 (39,40), and its 13-hour half-life makes it suitable for once-daily administration (41). Liraglutide has been studied extensively in several studies, including the Liraglutide Effect and Action in Diabetes (LEAD) trials either as monotherapy or as an add-on therapy to one or two OADs, and results demonstrated that treatment with liraglutide can provide significantly larger reductions in A1C, fasting plasma glucose (FPG), and PPG than placebo or several active comparators (Table I) (42–49). Liraglutide monotherapy has been evaluated in the LEAD-3 trial in 746 patients with early T2DM who received once-daily liraglutide (1.2 or 1.8 mg) or glimepiride (8 mg/day) for 52 weeks. At 52 weeks, A1C had decreased by –0.51% with glimepiride versus –0.84% and –1.14% with 1.2 and 1.8 mg liraglutide (P = 0.0014 and P < 0.0001 versus glimepiride, respectively). Patients treated with liraglutide lost > 2 kg, while those who received glimepiride gained > 1 kg (43).

LEAD-2 assessed three doses of liraglutide (0.6, 1.2, or 1.8 mg/day) versus placebo or glimepiride (4 mg/day) as add-on therapy to metformin in 1091 patients with T2DM for 26 weeks. Liraglutide produced significant decreases in A1C compared with placebo: –1.0% for liraglutide 1.2 mg, 1.8 mg, and glimepiride, and –0.7% for liraglutide 0.6 mg; there was an increase of + 0.1% for placebo (P < 0.0001 versus all liraglutide groups). Body weight decreased in all liraglutide groups (–1.8 to –2.8 kg) versus a + 1.0 kg increase with the glimepiride group (P < 0.0001 glimepiride versus all liraglutide groups) (44). Two-year extensions of LEAD-2 and LEAD-3 have shown that liraglutide provides sustained reductions in A1C, FPG, and body weight (50,51).

Liraglutide (1.2 or 1.8 mg/day) has also been compared with placebo as add-on therapy to a combination of metformin and rosiglitazone in the 26-week LEAD-4 trial in 533 patients with T2DM. A1C values decreased significantly more with liraglutide than with placebo (–1.5% for both liraglutide doses versus –0.5% for placebo, P < 0.0001). Weight loss was –1.0 and –2.0 kg for 1.2 and 1.8 mg liraglutide versus + 0.6 kg for placebo (P < 0.0001 versus placebo for both groups) (46). The 26-week LEAD-5 trial compared liraglutide (1.8 mg/day) with insulin glargine or placebo as add-on treatment to a combination of metformin and glimepiride in 533 patients with T2DM. Liraglutide reduced A1C by –1.33% versus –1.09% for insulin glargine (P = 0.0015) and –0.24% for placebo (P < 0.0001). Weight changes were –1.8 kg with liraglutide versus –0.42 kg with placebo (P = 0.0001) and + 1.6 kg for insulin glargine (P < 0.0001 versus liraglutide) (45).

The first 26 weeks of the open-label LEAD-6 trial directly compared exenatide (10 μg twice daily) and liraglutide (1.8 mg/day) as add-on therapy to metformin, an SU, or both, in 464 adult patients with T2DM. Liraglutide reduced A1C significantly more than exenatide (–1.12% versus –0.79%, P < 0.0001) (42). The authors of that paper noted that similar results were found in five other studies that included liraglutide, and in three that assessed the efficacy of exenatide. The two agents produced similar weight reductions (liraglutide, –3.24 kg versus exenatide, –2.87 kg) (42). A 14-week extension of LEAD-6 demonstrated that switching from twice-daily exenatide to once-daily liraglutide further significantly reduced A1C by –0.32% (P < 0.0001) and lowered body weight by an additional 0.9 kg (P < 0.0001) from week 26 (52).

Two trials compared the efficacy and safety of liraglutide and sitagliptin among patients with T2DM who continued receiving metformin. The first of those studies found a greater reduction of mean A1C among patients treated with 1.8 mg of liraglutide (–1.5% (95% CI –1.63 to –1.37, n = 218)) and 1.2 mg of liraglutide (–1.24% (95% CI –1.37 to –1.11, n = 221)) than among those who received 100 mg of sitagliptin (–0.90% (95% CI –1.03 to –0.77, n = 219)) (47). A 52-week study that included the same three treatment groups found that both liraglutide groups had superior reduction of A1C from baseline compared with the sitagliptin group (–1.29%, –1.51%, and –0.88% for 1.2 mg, 1.8 mg, and sitagliptin groups, respectively) (48). There was also greater weight loss among the liraglutide 1.2 mg (–2.78 kg) and 1.8 mg (–3.68 kg) groups than among those who received sitagliptin (–1.16 kg) (both P < 0.0001). Although they improved in all three groups, Diabetes Treatment Satisfaction Questionnaire scores increased significantly more among the subjects taking liraglutide 1.8 mg than in the sitagliptin group (P = 0.03).

Co-administration of liraglutide 1.8 mg and insulin detemir has been shown to produce an additive glucose-lowering effect without affecting the pharmacokinetics profile of either agent (53). This finding indicates that adding insulin detemir to the treatment paradigm of patients receiving liraglutide could be achieved by using titration algorithms comparable to those used when insulin is added to OADs. The co-administration of insulin detemir and liraglutide was well tolerated. Liraglutide is currently being evaluated in combination therapy with insulin detemir and metformin in a 26-week study of 821 patients with T2DM (54).

Effects beyond glucose lowering and weight reduction

Cardiovascular risk factors

Incretin-based therapies have a number of beneficial effects beyond lowering A1C and body weight in patients with T2DM. GLP-1 RA treatment is associated with significant improvements in blood pressure (BP) as well as in some measures of hyperlipidemia. Reductions of up to 7.9 mmHg in systolic BP (SBP) were seen with liraglutide in a 14-week phase 2 trial (55). In phase 3 trials, reductions in SBP averaged –3.7 mmHg with exenatide and ranged from –0.6 to –6.7 mmHg with liraglutide (56,57). Such reductions in SBP among patients who receive liraglutide have been reported as early as two weeks after initiation of treatment (45,58,59), which is prior to any significant weight loss. It has also been shown that liraglutide lowers BP independently of antihypertensive drug treatment in patients with hypertension (HTN) and diabetes (60). Significant reductions in total cholesterol (–0.06 mmol/L (–2.4 mg/dL)), low-density lipoprotein-cholesterol (LDL-C) (–0.04 mmol/L (–1.6 mg/dL)), and triglyceride (–0.9 mmol/L (–38.6 mg/dL)) levels have been demonstrated with exenatide (27). Similar decreases have also been reported among patients treated with liraglutide. In fact, after 26 weeks of open-label treatment with liraglutide for patients (n = 217) who had completed previous placebo-controlled trials, there were significant reductions of total cholesterol from baseline (P < 0.01), but there was a significant increase in total cholesterol among those who received rosiglitazone (P < 0.01) (61). There were also significant reductions from baseline in LDL-C, free fatty acids, and triglyceride levels among those treated with liraglutide (all P < 0.01). Patients treated with exenatide for at least 3 years demonstrated significant and sustained reductions in total A1C (–1.0 ± 0.1%, P < 0.0001), triglycerides (–12%, P = 0.0003), total cholesterol (–5%, P = 0.0007), and LDL-C (–6%, P < 0.0001), along with increased high-density lipoprotein-cholesterol (HDL-C) (+ 24%, P < 0.0001) (36).

Improvements in several indicators of CV risk have also been reported. Post-hoc analysis of cardiovascular biomarkers has found decreased risk for CV events among patients treated with exenatide (62). Another such analysis reported that those who receive liraglutide have benefited from decreases of both plasminogen activator inhibitor-1 (PAI-1) and B-type natriuretic peptide (BNP) levels (63). Liraglutide has also been shown to inhibit tumor necrosis factor-alpha (TNF-α) in vitro (64).

A retrospective analysis of medical and pharmaceutical insurance claims for June 2005 through March 2009 that included information for 39,275 patients with T2DM treated with exenatide twice daily and 381,218 patients who received other glucose-lowering therapies indicated that patients who initiated exenatide were more likely to have prior ischemic heart disease, obesity, hyperlipidemia, HTN, and/or other co-morbidities at baseline, but lower on-treatment risk for CV events than those who received other agents (hazard ratio 0.81, P = 0.01). Patients receiving exenatide also had lower rates of CVD-related hospitalization (hazard ratio 0.88, P = 0.02) (62). The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial is an international randomized, placebo-controlled phase 3b trial that will assess and confirm the CVD safety of liraglutide in the treatment of T2DM. It aims to enroll approximately 9000 patients who will be treated for up to 5 years (65). A phase 3 trial titled Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL), designed to assess cardiovascular outcomes among patients treated with long-acting exenatide once weekly, is currently recruiting patients with T2DM (66). However, no studies designed to assess the impact of GLP-1 RAs on diabetic complications have yet been published.

Preservation of β-cell function

Native GLP-1 has been shown to stimulate β-cell proliferation and neogenesis in animal models, while also inhibiting β-cell apoptosis (11,67,68). Results from placebo-controlled studies have shown significant improvements in measures of β-cell function (e.g. homeostasis model assessment of β-cell function (HOMA-B)) in patients treated with either exenatide or liraglutide (49,69). In fact, a head-to-head comparison of liraglutide and exenatide revealed a significantly greater improvement in HOMA-B with liraglutide (+ 32.12%) than exenatide (+ 2.74%, P < 0.0001) despite no significant differences in fasting C-peptide or proinsulin:insulin ratio (42). However, the time of administration of the drugs may have affected those results, since liraglutide was administered once at the same time every day without relation to time of food intake, while exenatide was administered 0–60 minutes before breakfast and dinner (42). In addition, although no studies to date have demonstrated long-term effects on β-cell function after cessation of treatment with exenatide or liraglutide, it has been shown that, after 52 weeks, stopping exenatide results in reversal of any improvements in β-cell function to baseline levels, including A1C and plasma glucose levels (28).

Safety

Adverse events

The most common adverse effects of GLP-1 RAs involve the gastrointestinal system. Nausea is the most common adverse event, with an incidence in phase 3 clinical trials ranging from 4.5% to 48.5% with exenatide twice daily (33), 19% to 27% with exenatide once weekly (22), and from 8% to 29% with liraglutide (43), but nausea was less persistent with liraglutide than with exenatide (42). Dose titration limits the duration of nausea to several weeks in most affected patients.

Proportions of patients reporting hypoglycemia (combined major and minor) are related to combination therapy, usually with a sulfonylurea, and ranged from 4.5% to 36% with exenatide and from 3% to 27% with liraglutide (40). GLP-1 RAs stimulate insulin secretion in a glucose-dependent manner, resulting in a low risk of hypoglycemia when these agents are used as monotherapy or in combination with metformin (55,70). Reductions in the SU dosage can help minimize the risk of hypoglycemia (56).

Antibody formation. Antibody formation is more common with exenatide (27%–49%) compared with liraglutide (9%–13%), because liraglutide shares a 97% homology with the native human GLP-1 (56). Antibody formation to exenatide affects its efficacy (71), and it is more frequent when patients receive exenatide once weekly than twice a week. However, among patients switched from exenatide (10 μg twice daily) after 26 weeks to liraglutide (1.2 mg (n = 368) or 1.8 mg (n = 587) once daily) for 52 weeks during the LEAD-6 extension study, anti-exenatide antibodies did not significantly influence the glycemic response to liraglutide (< 8% of patients in both 1.2 and 1.8 mg liraglutide groups were anti-liraglutide antibody positive) (71,72). However, when considering this result, it should be noted that the effects of antibody development on the A1C-lowering effects of either exenatide or liraglutide are minor (73).

Renal impairment. Exenatide and liraglutide have different clearance routes. Because exenatide undergoes renal elimination, it is not recommended in patients with end-stage renal disease and severe renal impairment (creatinine clearance < 0.5 mL/s (< 30mL/min)) (74,75). In contrast, liraglutide is metabolized within the body in a similar manner as large proteins, mainly by the DPP-4 and neutral endopeptidase (NEP) enzymes, without a specific organ (i.e. kidney or liver) as a major route of elimination. As a result, no dosage adjustment of liraglutide is required for patients with renal impairment, but cautious use is recommended (76). A recent meta-analysis of the LEAD studies demonstrated that mild renal impairment (creatinine clearance 1.0–1.5 mL/s (60–89 mL/min)) had no effect on the efficacy and safety of liraglutide (77).

Pancreatitis and pancreatic cancer. Concerns have been raised regarding a possible link between pancreatitis and treatment with incretin-based therapy (56). Results from a 1-year follow-up of 27,996 patients who initiated treatment with exenatide indicated that acute pancreatitis occurred in 0.13% (78). An analysis of the FDA database published in 2011 reported that both sitagliptin and exenatide increase the odds ratio for pancreatitis 6-fold (P < 2 × 10²¹⁶) (79). In addition, pancreatic cancer was present among significantly more patients treated with sitagliptin or exenatide than other therapies (P < 0.008, P < 9 × 10²⁵), but all other types of cancer occurred at similar rates regardless of which therapeutic agents patients had received (79). During liraglutide clinical trials, three patients developed acute pancreatitis and one developed chronic pancreatitis (80). The incidence of acute pancreatitis in liraglutide trials was not higher than would be expected in patients with T2DM, and no causal relationship could be established (80). When assessing the risk of incretin-based agents for acute pancreatitis, it should be noted that regardless of therapy, patients with T2DM are at a nearly 3-fold greater risk for pancreatitis than is the general population (81).

C-cell hyperplasia. C-cell hyperplasia, adenoma, and carcinoma have been reported in rodents treated with high doses of liraglutide in preclinical toxicity studies (82,83). The relevance of these rodent findings to humans was explored via calcitonin monitoring in clinical studies, and it was found that up to 2 years of exposure to liraglutide did not result in increased calcitonin levels. In fact, calcitonin levels remained within the lower end of the normal range and did not differ between liraglutide and active comparators. Further, monkeys receiving liraglutide for 20 months at levels more than 60 times that of human exposure did not demonstrate increased calcitonin release or C-cell hyperplasia (84). Thus, the relevance of the earlier findings in rodents to humans is not clear. However, the prescribing information for liraglutide states that it is contraindicated in patients with medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2 (84). Elevated levels of calcitonin, a biomarker for C-cell activation, and increases in C-cell mass preceded lesion development in rodents. This effect was not observed in non-human primates exposed to a liraglutide dose 60-fold greater than the highest human dose (1.8 mg) (21). Mild C-cell hyperplasia has been observed in patients with T2DM treated with liraglutide (6). In addition, a pooled analysis of more than 5000 patients from six phase 3 trials demonstrated that serum calcitonin levels remained at the low end of the normal range over 2 years of treatment with liraglutide (85). Monitoring of calcitonin levels is not recommended.

Place in therapy

Patients who cannot maintain glycemic control with OADs can be effectively managed by addition of insulin to these agents. However, insulin use is associated with undesirable side-effects such as weight gain and hypoglycemia. Treatment-associated complications may also contribute to failure to maintain glycemic control in T2DM. SUs, insulin, and TZDs are associated with weight gain, and insulin and SUs also increase risk of hypoglycemia (6). It has been suggested that hypoglycemia may be the greatest barrier to achieving euglycemia, followed by patient and physician concerns about weight gain. Treatments associated with weight gain may lose effectiveness, since increased adiposity is associated with insulin resistance and hyperglycemia (86). Hypoglycemia, and fear of hypoglycemia, may discourage treatment adherence, thereby limiting effectiveness, and may also prevent physicians from prescribing insulin to patients who cannot achieve control over blood glucose levels with oral therapy (87).

GLP-1 RAs have been studied across the continuum of T2DM care and provide effective glycemic control when used as monotherapy in drug-naive patients or in combination with one or two additional agents later in the course of the disease (65,66). In light of their additional positive effects demonstrated thus far on β-cell function, CV risk factors, and weight, along with a relatively low risk of hypoglycemia, GLP-1 RAs may overcome the limitations of traditional OADs. Future randomized controlled trials will hopefully determine whether or not such benefits are maintained for long periods of time.

The two major diabetes guidelines in the United States provide somewhat different recommendations for the use of GLP-1 RAs. The American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus algorithm for the management of hyperglycemia in patients with T2DM includes GLP-1 RAs as a tier 2 intervention, along with pioglitazone (88,89). Basal insulin and SU are considered tier 1 interventions subsequent to failure of lifestyle change plus metformin. However, GLP-1 RAs are specifically recommended as add-on therapy to metformin and lifestyle changes in cases where hypoglycemia and weight loss are major concerns, such as for elderly or critically ill patients with co-morbid conditions or in obese patients with T2DM. In contrast, the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) consensus panel recommends more aggressive, individualized combination therapy with a wider range of agents (e.g. metformin, TZD, DPP-4 inhibitor, GLP-1 RA) as initial pharmacotherapy for patients with T2DM to achieve A1C < 6.5% (88,89).

Conclusion

GLP-1 RAs are an important addition to the armamentarium of clinicians who treat patients with T2DM. These agents improve glycemic control with good safety and tolerability and have also demonstrated positive effects on common co-morbidities of diabetes, including obesity, HTN, and hyperlipidemia. In addition, the potential of exenatide and liraglutide for reducing CV events in patients with T2DM is currently being investigated in long-term (> 5years) clinical trials (88). The utility of GLP-1 RAs in combination therapy with OADs, especially after metformin failure, and their positive effects on β-cell function support their use as part of initial and continuing treatment for patients with T2DM.

Acknowledgements

The author would like to thank Robert McCarthy, PhD, of AdelphiEden Health Communications and Robert W. Rhoades, of MedVal Scientific Information Services, LLC, for providing medical writing and editorial services. This manuscript was prepared according to the International Society for Medical Publication Professionals’ Good Publication Practice for Communicating Company-Sponsored Medical Research: the GPP2 Guidelines. Funding for the preparation of this review was provided by Novo Nordisk Inc.

Declaration of interest: The author is a principal investigator for clinical trials sponsored by Lilly, Merck, and Novo Nordisk. He serves on the speaker's bureau for Novo Nordisk. He owns stock in Merck and Novo Nordisk.