Treatment with GLP-1 Receptor Agonists
The GLP-1 RAs have become popular because of their efficacy and durability in relation to glycemic control and their low risk of hypoglycemia in combination with weight loss in most patients. GLP-1 RAs mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases satiety, and slows gastric emptying. Notably, the insulinotropic and glucagonostatic effects are glucose dependent, and therefore the risk of hypoglycemia is very low during treatment with a GLP-1 RA. The effect on gastric emptying is primarily observed with the short-acting GLP-1 RAs, since significant tachyphylaxis for this effect develops after few days’ treatment with the long-acting GLP-1 RAs. The postprandial glucose control mediated by the short-acting GLP-1 RA seems to be primarily explained through the delaying effect on gastric emptying rather than the effect on insulin and glucagon secretion. In addition, GLP-1 RAs reduce blood pressure during chronic treatment, increase pulse rate, and reduce postprandial triglyceride concentrations. Studies have suggested that GLP-1 receptor agonists might have neuroprotective effects.
The most common adverse events are nausea and other gastrointestinal discomfort. The drawbacks of the GLP-1 RAs include the subcutaneous administration, the gastrointestinal side effects, and the cost.
Several GLP-1 RAs are now licensed for the treatment of type 2 diabetes. However, the intra-class difference raises challenges in relation to individual treatment. In the present chapter, the individual GLP-1 RAs will be presented followed by a head-to-head comparison of GLP-1 RAs. Thereafter, the adverse events and the cardiovascular effects of GLP-1 RAs including the cardiovascular endpoint trials with GLP-1 RAs will be discussed. The efficacy and safety of fixed combination of basal insulin and a GLP-1 RA will be reviewed. The use of GLP-1 RAs in the treatment of patients with type 1 diabetes or in treatment of obesity will also be examined.
KeywordsGLP-1RA Type 2 diabetes Type 1 diabetes Obesity, fixed combination Head-to-head comparison Adverse events Cardiovascular effects
The use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) has expanded the treatment options for type 2 diabetes (T2DM) over the last decade (Garber et al. 2016; Inzucchi et al. 2015). The GLP-1 RAs have become popular because of their efficacy and durability in relation to glycemic control and their low risk of hypoglycemia in combination with weight loss in most patients (Ostergaard et al. 2016; Meier 2012). GLP-1 RAs mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases satiety, and slows gastric emptying (Ostergaard et al. 2016; Meier 2012). Notably, the insulinotropic and glucagonostatic effects are glucose dependent, and therefore the risk of hypoglycemia is very low during treatment with a GLP-1 RA, unless it is combined with sulfonylurea or insulin (Ostergaard et al. 2016; Meier 2012; Nauck et al. 1993). The effect on gastric emptying is primarily observed with the short-acting GLP-1 RAs, since significant tachyphylaxis for this effect develops after few days’ treatment with the long-acting GLP-1 RAs (Jelsing et al. 2012; Meier et al. 2003). The postprandial glucose control mediated by the short-acting GLP-1 RA seems to be primarily explained through the delaying effect on gastric emptying rather than the effect on insulin and glucagon secretion (Meier et al. 2003). In addition, GLP-1 RAs reduce blood pressure during chronic treatment, increase pulse rate, and reduce postprandial triglyceride concentrations (Drucker 2016; Hermansen et al. 2013; Kumarathurai et al. 2017a). The potential effect of GLP-1 on cardiovascular function is an area of major interest and will be discussed in detail later in this chapter. Whether treatment with a GLP-1 RA may protect the beta-cell mass through beta-cell regeneration and inhibition of apoptosis and thereby reduce or halt the progression of type 2 diabetes has been debated (Kielgast et al. 2009). In one study, beta-cell function was evaluated after 3 years of treatment with a short-acting GLP-1 RA (exenatide), and during this period there was no deterioration, but the same was true in the control group subjected to intensive insulin therapy (Bunck et al. 2011). In the LEADER study of the cardiovascular safety of liraglutide, hemoglobin A1c levels remained almost unchanged over a period of 5 years, perhaps reflecting some protective action on the beta cells (Marso et al. 2016a). Studies in rodent models of Parkinson’s and Alzheimer’s diseases and mouse models of ischemic stroke have suggested that GLP-1 receptor agonist might have neuroprotective effects and prevent memory impairment (McClean et al. 2011; Harkavyi et al. 2008; Teramoto et al. 2011). However, studies in humans have not supported the use of GLP-1 RA in cerebral diseases (Calsolaro and Edison 2015), except for one clinical trial of 48 weeks, which suggested that exenatide once weekly had positive effects in Parkinson’s disease, which was sustained beyond the period of exposure (Athauda et al. 2017). Whether exenatide affects the underlying disease pathophysiology or the result simply is secondary to long-lasting metabolic improvement effects is uncertain.
The most common adverse events are nausea and other gastrointestinal discomfort (Ostergaard et al. 2016; Meier 2012). The drawbacks of the GLP-1 RAs include the subcutaneous administration, the gastrointestinal side effects, and the cost (Ostergaard et al. 2016).
As a drug class, the GLP-1 RAs have proven efficacy for lowering HbA1c and decreasing weight in T2D, with a reduced risk of hypoglycemia compared with insulin or sulfonylureas (Garber et al. 2016; Inzucchi et al. 2015; Ostergaard et al. 2016). These characteristics underlie the inclusion of GLP-1 RAs in various clinical practice guidelines. Their use as dual therapy with metformin after first-line metformin and as triple therapy (in combination with metformin and a sulfonylurea/thiazolidinedione/insulin) is part of the European Association for the Study of Diabetes/American Diabetes Association recommendations (Inzucchi et al. 2015). Glucagon-like peptide-1 receptor agonists are recommended as monotherapy, dual therapy, and triple therapy by the American Association of Clinical Endocrinologists/American College of Endocrinology guidelines (Garber et al. 2016).
In the present chapter, the individual GLP-1 RAs will be presented followed by a head-to-head comparison of GLP-1 RAs. Thereafter, the adverse events and the cardiovascular effects of GLP-1 RAs including the cardiovascular endpoint trials with GLP-1 RAs will be discussed. The efficacy and safety of fixed combination of basal insulin and a GLP-1 RA will be reviewed. The use of GLP-1 RAs in the treatment of patients with type 1 diabetes or in treatment of obesity will also be examined. Lastly, some future aspects of GLP-1-based therapy will be presented. A thorough review of all trials with GLP-1 RAs in type 2 and type 1 diabetes up to 2016 can be found in Ostergaard et al. (2016), Dejgaard et al. (2016a), and Frandsen et al. (2016).
Characteristics of GLP-1 Receptor Agonists
For therapeutic purposes, continuous subcutaneous administration of native GLP-1 is necessitated because of its extremely short plasma half-life (1–2 min) but has limited therapeutic value (Zander et al. 2002). Therefore, several GLP-1 RAs have been developed with an extended duration of action achieved by various changes of the molecular structure compared with the native peptide (Ostergaard et al. 2016; Madsbad et al. 2011; Madsbad 2016).
Comparative characteristics of the GLP-1 RAs
Percentage amino acid sequence similarity to native GLP-1
Properties of the drug
Resistant to DPP-4 cleavage, largely due to the substitution of alanine in position 2 by glycine
Encapsulated in biodegradable polymer microspheres
C-16 fatty acid confers albumin binding and heptamer formation
Based on exenatide but is modified by the deletion of one proline residue and addition of six lysine residues at the C-terminal
GLP-1 dimer fused to albumin
The GLP-1 portion of the molecule is fused to an IgG4 molecule, limiting renal clearance and prolonging activity
Modifications designed to hinder cleavage by DPP-4 and by serine proteases and also allows greater receptor binding
Half-life is unpublished but steady-state concentrations at 6–7 weeks
2.1–5.1 h during the first 48 h
4, 6, and 8 h at 1, 8, and 30 mg doses, respectively
0.75 mg and 1.5 mg at steady state was 0.073 and 0.107 l/h, respectively
In head-to-head studies, antibodies were more common, and titers were higher with exenatide OW compared with exenatide BID
Antibodies did not correlate with rates of reported AEs
From six phase 3 studies, 8.7 and 8.3% of participants had low-titer antibodies to liraglutide 1.2 and 1.8 mg, respectively, after 26 weeks
Antibodies developed in:
56–60% of participants treated with 20 μg OD
43% of participants treated with 10 μg OD and 71% treated with 20 μg BID
Antibodies developed in 3.7% of participants treated with albiglutide
Dulaglutide anti-drug antibodies in 1% of participants and dulaglutide neutralizing anti-drug antibodies in 1% of patients
Detected in 49% of participants
One method to extend the half-life of GLP-1 has been to make it resistant to degradation by DPP-4 by changing the penultimate N-terminal amino acid (Gallwitz et al. 2000). However, the intact hormone is still subject to renal elimination, which alone results in a half-life of 4–5 min (Deacon et al. 1998; Meier et al. 2004). Therefore, other approaches to prolong half-life have been based on reversible or irreversible binding to albumin (liraglutide, semaglutide, and albiglutide), whereby renal filtration is prevented (Meier 2012). Dulaglutide is conjugated with the Fc fragment of IgG to extend the duration of action (Meier 2012). The GLP-1 RA can also be coupled to biodegradable polymer microspheres resulting in a protracted release of the peptide from a subcutaneous depot as in exenatide-LAR (Bydureon) (Meier 2012).
Taspoglutide once weekly was halted in development due to serious hypersensitivity reactions and GI adverse events (AEs) during clinical trials (due to an inexpedient prolongation technique, resulting in an unsuitable plasma profile). Semaglutide once weekly is not yet approved for the treatment of people with type 2 diabetes but is expected in 2017. Therefore, the available data for these two compounds are included here to give a full picture of the GLP-1 RA family.
The chemical and pharmacokinetic differences between GLP-1 RAs are also reflected in their varying efficacy with regard to HbA1c reduction and weight loss, their differing tolerability profiles, and potential for immunogenicity (Ostergaard et al. 2016; Meier 2012; Madsbad et al. 2011; Madsbad 2016; Kapitza et al. 2013; Meier et al. 2015). It is important to understand these specific characteristics to make the appropriate choice of GLP-1 RA for the individual patient. Head-to-head clinical trials are the best way to evaluate the differences in efficacy and tolerability, and a number of such studies have been conducted with GLP-1 RAs in T2D, but first the eight GLP-1 RAs will be discussed. The GLP-1 RA family is presented in Fig. 1, and the differences in molecular structure, chemical and physiological properties, and durations of action are summarized in Table 1.
Exenatide Twice Daily
Exenatide (Byetta®), which is a 39-amino-acid peptide, was the first GLP-1 RA introduced to the market (2005). Exenatide BID is derived from the saliva of the Gila monster and is 53% homologous to native GLP-1 with respect to the first 30 amino acids (the sequence of the remaining 9 has no human homologies) (Kolterman et al. 2005). Exenatide BID is indicated as adjunct to diet and exercise in patients with type 2 diabetes. It can be used in monotherapy or in combination with oral antidiabetic agents including basal insulin. After injection, the duration of action is about 8–10 h, and peak levels are achieved 2–3 h after injection (Kolterman et al. 2005). Injection should be administered 20–60 min prior to two main meals at least 6 h apart. The delayed gastric emptying after breakfast and dinner is the main mechanism by which exenatide improves postprandial glucose excursions. Exenatide has only minor effect on lunch glucose excursions. The increase in insulin secretion and reduction in glucagon secretion, which result in a decreased hepatic glucose production, also contributes to the improved glucose metabolism (Cervera et al. 2008), but the effect on fasting plasma glucose is less than that of the long-acting GLP-1 RAs (Buse et al. 2009). Initial dose is 5 μg, increasing to 10 μg BID. Exenatide is not recommended in patients with severe renal impairment (eGFR<30 ml/min). The phase 3 studies are discussed in details in Inzucchi et al. (2015). Exenatide BID has demonstrated similar efficacy as glimepiride or pioglitazone with a reduction of 0.8–1.5% in HbA1c and induces a weight loss ranging from 1 to 4 kg (Ostergaard et al. 2016). Compared with basal insulin, the reduction in HbA1c is similar or greater with exenatide BID (Ostergaard et al. 2016). Nausea occurs initially in 30–60% of patients with vomiting in about 15–20% (Ostergaard et al. 2016). The gastrointestinal side effects are often transient. Antibodies against exenatide have been detected in 40–60% of the patients, but in the majority of the patients, their presence does not seem to impair efficacy of exenatide (Buse et al. 2011; Drucker et al. 2008). In patients with very high titers of antibodies, the reduction in HbA1c was smaller compared with patients without antibodies (Buse et al. 2011; Drucker et al. 2008). Apparently, the antigenicity of exenatide has not lead to major clinical complications so far.
Lixisenatide Once Daily
Lixisenatide is identical to exendin-4 but has a proline deletion in position 38 and is extended with six lysine residues at the C-terminus (Ratner et al. 2010). The half-life is 2–3 h, and peak plasma concentrations are achieved 1.5–2.5 h after injection, similar to exenatide, but lixisenatide is nevertheless approved for s.c. administration once daily (Ratner et al. 2010). The dose is 10 μg increasing to 20 μg after 2 weeks. The efficacy of lixisenatide has been tested in monotherapy and in combination therapy and has been compared with placebo and exenatide BID (Bolli et al. 2014; Fonseca et al. 2012; Rosenstock et al. 2013a, 2014a; Pinget et al. 2013). Compared with exenatide, the mean change in HbA1c was −0.79% for lixisenatide versus −0.96% for exenatide BID (Rosenstock et al. 2013a). Both agents induced weight loss (from 94.5 to 91.7 kg and from 96.7 to 92.9 kg with lixisenatide and exenatide, respectively) (Rosenstock et al. 2013a). Incidence of adverse events (AEs) was similar for lixisenatide and exenatide. Lixisenatide has been added on to insulin in Asian people, and after 24 weeks, the HbA1c changes were −0.77% and +0.11% in the lixisenatide and placebo groups (Seino et al. 2012). A weight loss of 0.4 kg was observed in the lixisenatide group, while a weight gain of 0.1 kg was found in the placebo group. In another 24 weeks study, the reductions in HbA1c were −0.6% and −0.3% and in body weight −1.8 versus −0.5 kg in the lixisenatide and placebo groups, respectively (Riddle et al. 2013). Because of the short action, the effect on fasting plasma glucose is less than with the long-acting GLP-1 RAs (Nauck et al. 2016b). In most of the trials, body weight decreased significantly with lixisenatide compared with placebo. The cardiovascular endpoint trial ELIXA with lixisenatide will be discussed later.
Liraglutide Once Daily
The amino acid sequence of liraglutide shows 97% identity with that of native human GLP-1, and liraglutide has a half-life of approximately 13 h; therefore, it is suitable for subcutaneous administration once daily (Agerso et al. 2002). The peptide differs from GLP-1 owing to a Lys34Arg amino acid substitution and addition of glutamate residue and a 16-carbon free fatty acid to Lys26, modifications that promote non-covalent binding to plasma albumin (Knudsen et al. 2000). Consequently about 99% of the liraglutide molecules are bound to albumin, ensuring a rather constant, high plasma level after once-daily administration (Knudsen et al. 2000).
Dose-finding studies resulted in the doses of 0.6 mg, 1.2 mg, and 1.8 mg being moved forward to the clinical phase 3 development program “Liraglutide Effect and Action in Diabetes” (LEAD™), completed in 2007 (Ostergaard et al. 2016; Madsbad 2009). Treatment is initiated with 0.6 mg for 1 week and then titrated to the standard dose of 1.2 mg, which can be escalated to 1.8 mg once daily (Ostergaard et al. 2016; Madsbad 2009).
In the phase 3 program, the HbA1c reduction was 1.1–1.8% with only minor differences between 1.2 and 1.8 mg, but there was little effect on postprandial glucose excursions during chronic therapy, probably because of the tachyphylaxis with respect to gastric emptying (Ostergaard et al. 2016; Madsbad 2009). The reduction in mean body weight was in the range of 2–3 kg in the LEAD studies (Ostergaard et al. 2016; Madsbad 2009). The effect on body weight seems to be dose dependent, but the greatest mean weight loss of 4.5 kg was observed in subjects with a BMI > 35 kg/m2 and when liraglutide was combined with metformin (Ostergaard et al. 2016; Madsbad 2009). Liraglutide reduced systolic blood pressures by about 2–7 mm HG, and increases in pulse rate of 2–4 beat per minutes were reported (Ostergaard et al. 2016; Madsbad 2009). As discussed later, liraglutide therapy has been associated with reduced risk of cardiovascular events and mortality (Marso et al. 2016a). Nausea was reported by 20–40% of the patients and vomiting in 5–10%, but both were generally transient and could be reduced by slow up-titration (Ostergaard et al. 2016; Madsbad 2009). The number of patients developing antibodies against liraglutide is about 3–10% (Ostergaard et al. 2016; Madsbad 2009).
Liraglutide has been compared with all oral antidiabetic agents and with basal insulin glargine and showed better efficacy with respect to both reduction in HbA1c and weight loss (Ostergaard et al. 2016; Madsbad 2009). As discussed later, liraglutide has also been compared with lixisenatide, exenatide BID, exenatide QW, and dulaglutide QW (Ostergaard et al. 2016; Madsbad 2016, 2009; Nauck et al. 2016b).
Exenatide Once Weekly
Exenatide administered once weekly (QW) (2 mg/dose) was marketed in Europe in 2011 and in the USA in 2012. The drug, in a fixed dose of 2 mg, is encapsulated in biodegradable microspheres (0.06 mm in diameter), allowing the drug to be slowly released through diffusion and microsphere breakdown gradually over 10 weeks (Drucker et al. 2008; Mann and Raskin 2014). The microspheres are reconstituted in a premeasured aqueous solution before injection. The plasma concentration continues to rise for weeks after treatment initiation, and steady-state levels are obtained after 6–7 weeks (Drucker et al. 2008; Mann and Raskin 2014). The gradual release from the formulation eliminates the need for slow up-titration. The main results of the phase 3 DURATION 1–6 trials are discussed in Ostergaard et al. (2016) and Brunton and Davidson (2016). Exenatide QW has been compared with exenatide BID, liraglutide, insulin glargine, and oral antidiabetic agents, and the HbA1c reduction ranges between 1.3% and 1.9% (Ostergaard et al. 2016; Brunton and Davidson 2016). In a head-to-head comparison, the HbA1c reduction was significantly greater (1.9% vs. 1.5%) with exenatide QW compared with exenatide BID, primarily explained by a greater reduction in plasma glucose during nighttime, while postprandial glucose excursions were more reduced with exenatide BID (Drucker et al. 2008). The increase in morning pulse rate was also greater with exenatide QW compared with exenatide BID (Drucker et al. 2008). The reduction in weight did not differ between the short- and long-acting exenatide. More patients developed antibodies against exenatide QW than against exenatide BID (74% vs. 43%), but only in few patients did the antibodies seem to affect efficacy in relation to HbA1c reduction (Drucker et al. 2008). Compared with liraglutide 1.8 mg once daily, the reduction was less (1.48% vs. 1.28%), and patients treated with liraglutide lost more weight than exenatide QW-treated patients (Buse et al. 2013). More patients experienced nausea with liraglutide, while serious adverse events were more often reported with exenatide QW (Buse et al. 2013). Compared with insulin glargine, the reduction in HbA1c was greater with exenatide QW (1.5% vs. 1.3%), and most patients experienced weight loss in contrast to weight gain during treatment with insulin glargine (Diamant et al. 2014). Hypoglycemia occurred more often with insulin glargine. In a recent trial exenatide once weekly was compared with dapagliflozin (DURATION-8) as add-on to metformin, and after 28 weeks the reduction in HbA1c was 1.6% and 1.4%, respectively, while the reduction was 2.0% in the combined exenatide plus dapagliflozin group (Frias et al. 2016). Weight loss was greater with dapagliflozin compared with exenatide once weekly (2.2 kg vs. 1.5 kg) compared with 3.4 kg in the combined group (Frias et al. 2016).
Because of the consistency of the injection suspension, injections of exenatide previously required a rather large-bore needle (23 gauge, 0.64 mm), and a convenient device was not available. Today, exenatide QW is available in a new, prefilled single-dose pen device, which simplifies reconstitution of the drug. Injection site reactions including erythema, pruritus, and nodules are being reported by about 10–15% of patients (Brunton and Davidson 2016). The most frequent gastrointestinal side effects are the expected: nausea, vomiting, and diarrhea, which, however, occur less frequently than with exenatide BID (Drucker et al. 2008). No cases of pancreatic cancer were reported in the DURATION trials, and exenatide QW was not associated with an increased risk of pancreatitis (Brunton and Davidson 2016). The cardiovascular safety of exenatide QW will be discussed later in relation to the EXSCEL trial .
Albiglutide Once Weekly
Albiglutide is composed of two DPP-4-resistant GLP-1 molecules arranged in tandem and fused to human albumin, which consequently leads to a plasma half-life of 5–8 days, allowing QW dosing. Maximal concentration is observed 3–5 days after s.c. injection (Young et al. 2014). An amino acid substitution (alanine to glycine at residue no 2 from the N-terminus) in the GLP-1 dimer makes it resistant to DPP-4 degradation (Young et al. 2014). Otherwise the two GLP-1 moieties are 97% homologous to native GLP-1 (Young et al. 2014). Albiglutide is a large molecule and is thus relatively inaccessible to the central nervous system; this quality may have implications for gastrointestinal tolerability of the drug and for weight loss. The European Medicines Agency (EMA) and US Food and Drug Administration (FDA) approved albiglutide in 2014. Studies comparing different dosing regimens have suggested that a dose of 30 mg once weekly might be optimal. For patients unable to reach glycemic goal, escalating to 50 mg weekly is appropriate and results in further improvement in glycemic control. The efficacy and safety of albiglutide were tested in the phase 3 HARMONY 1–8 program, and the main results are presented in Ostergaard et al. (2016), Madsbad et al. (2011), Madsbad (2016), and Blair and Keating (2015). The reduction in HbA1c and weight has been less, and rates of gastrointestinal side effects are also reduced compared to other GLP-1 RAs (Ostergaard et al. 2016; Madsbad et al. 2011; Madsbad 2016; Blair and Keating 2015). In the HARMONY 4 study, albiglutide was compared with insulin glargine and gave a reduction of HbA1c of 0.66 versus 0.81 for albiglutide and insulin glargine, respectively, with an additional small weight loss in the albiglutide group (Ostergaard et al. 2016; Weissman et al. 2014). Compared with liraglutide in the HARMONY 7 trial, the reduction in HbA1c was 0.78% for albiglutide and 0.99% for liraglutide, and liraglutide was also associated with a greater weight loss (Pratley et al. 2014). More gastrointestinal side effects were reported with liraglutide (Pratley et al. 2014). In the HARMONY 6 trial, including patients taking basal insulin, albiglutide add-on was tested versus thrice-daily prandial insulin lispro (Rosenstock et al. 2014b). After 26 weeks, the reduction in HbA1c was 0.82% with albiglutide and 0.66% with lispro, and the weight changes were −0.73 kg and +0.81 kg, respectively (Rosenstock et al. 2014b).
Albiglutide has been associated with up to a 20% incidence of injection site reaction, and antibodies against albiglutide developed in up to 5.5% of patients but had no obvious effect on the efficacy of albiglutide (Blair and Keating 2015). On July 26, 2017, GlaxoSmithKline (GSK) in a press release announced that they plan to discontinue the manufacturing and sale of albiglutide by July 2018.
Dulaglutide Once Weekly
Dulaglutide is a GLP-1 RA constructed by two GLP-1 analogues linked to a human IgG4-Fc heavy chain (Barrington et al. 2011). The association with the IgG4-Fc heavy chain prevents renal clearance (Barrington et al. 2011; Glaesner et al. 2010), and the molecule is resistant to DPP-4 degradation because of amino acid substitutions at position 2 of the GLP-1 parts; additional substitutions are present at positions 8 and 22 (Barrington et al. 2011; Glaesner et al. 2010). The half-life is approximately 5 days, making it suitable for QW administration (Barrington et al. 2011; Glaesner et al. 2010). Dulaglutide was approved in the USA and in Europe in 2014. Dulaglutide is administered as 0.75 mg once weekly, which can be escalated to 1.5 mg once weekly (Barrington et al. 2011). Steady-state concentration is obtained after 2–4 weeks (Barrington et al. 2011; Jendle et al. 2016). Dulaglutide is available as a prefilled pen syringe ready for injection. Across the clinical studies, about 1.6% of dulaglutide-treated patients developed antibodies, which did not reduce the glucose-lowering effect (Jendle et al. 2016). Injection site reactions (rash and erythema) were reported in 0.5% of the patients (Jendle et al. 2016). Dulaglutide’s efficacy and safety has been tested in a variety of phase 3 trials known as the AWARD-studies, and the findings are reviewed in Jendle et al. (2016). Dulaglutide has been found to reduce HbA1c more than sitagliptin, metformin, and exenatide BID, while weight reduction and gastrointestinal side effects did not differ between dulaglutide and exenatide (Jendle et al. 2016). Dulaglutide 1.5 mg reduced HbA1c (−0.9% vs. −0.62%) more than insulin glargine (Jendle et al. 2016). In the AWARD-6 trial comparing dulaglutide with liraglutide, the HbA1c reduction was 1.42% with dulaglutide and 1.36 for liraglutide, while patients treated with liraglutide experienced a significantly greater weight loss (3.61 vs. 2.90 kg). The incidence of adverse events did not differ between the two groups (Jendle et al. 2016; Dungan et al. 2014). In AWARD-10 dulaglutide 1.5 mg and 0.75 mg or placebo were add-on to SGLT-2 inhibitor with or without metformin for 24 weeks. The reduction in HbA1c was for 1.5 mg −1.34 % (−14.7 mmol/mol) and for 0.75 mg −1.21% (−13.2 mmol/mol) compared with −0.54% (−5.9 mmol/mol) for placebo (Ludvig B et al. Lancet Diabetes Endocrinol 2018, Febr 23 epub ahead of print). Head- to head comparison between dulaglutide and semaglutide is discussed below under semaglutide.
Taspoglutide Once Weekly
The GLP-1 receptor agonist, taspoglutide, has 93% homology with the native hormone and contains two α-aminoisobutyric acid substitutions replacing Ala8 and Gly35 of hGLP-1 (7–36)NH2 (Dong et al. 2011). Taspoglutide is fully resistant to DPP-4 degradation, while protraction is provided by a sustained release formulation (Dong et al. 2011). Its biological actions have been shown to be similar to those of native GLP-1, but after a single dose, a glucose-lowering effect was found for up to 2 weeks.
Taspoglutide was evaluated in seven clinical trials in the T-emerge program using 10 and 20 mg once weekly (Madsbad et al. 2011). Both doses of taspoglutide reduced HbA1c more than exenatide BID (difference 0.33% for 20 mg) with comparable weight loss but with unacceptable levels of nausea/vomiting, injection site reactions, and systemic allergic reactions (Madsbad et al. 2011). Vomiting occurred in most cases on the day of injection in the taspoglutide groups and in the majority already after the first injection. In other trials, taspoglutide reduced HbA1c more than sitagliptin but had similar effects as pioglitazone and insulin glargine (Madsbad et al. 2011). In September 2010 the T-emerge program was halted because a potential association between hypersensitivity reactions and anti-drug antibodies was suggested, and taspoglutide is not expected to come to the market (Madsbad et al. 2011).
Semaglutide Once Weekly
Semaglutide was developed from liraglutide by increasing the albumin affinity and securing full stability against metabolic degradation. The fatty acid moiety and its linking to GLP-1 were the key features securing high albumin affinity and GLP-1 receptor (GLP-1R) potency and also resulted in a prolonged exposure and action of the GLP-1 analogue (Lau et al. 2015). Like liraglutide, semaglutide has an amino acid substitution at position 34 (Lys-Arg) and is derivatized at lysine 26 (Lau et al. 2015). An additional substitution at position 8 (Ala- > Aib) secures DPP-4 resistance. The GLP-1R affinity of semaglutide is similar to that of liraglutide, while the albumin affinity is improved (Lau et al. 2015). The plasma half-life is reported to be 165 h in human (Kapitza et al. 2015). Semaglutide is currently in late phase 3 clinical testing, and the first six trials have been presented in public. In a 12 weeks phase 2 study, semaglutide reduced HbA1c by impressive 1.7% from a baseline of 8.1% and body weight up to 4.8 kg, which was greater than with liraglutide 1.8 mg QD (Nauck et al. 2016a). Semaglutide doses of 0.5 mg and 1.0 mg with a 4-week dose escalation were selected for the SUSTAIN phase 3 program (Nauck et al. 2016a). In SUSTAIN-1, semaglutide 0.5 mg and 1.0 mg in patients with type 2 diabetes reduced HbA1c from a baseline of 8.1% by 1.4% and 1.5% compared with placebo after 30 weeks, and about 73% reached a HbA1c below 7.0% and 60% below 6.5% (Sorli et al. 2017). Weight loss was 2.8 and 3.6 kg greater than with placebo, respectively (Sorli et al. 2017). In the 56 weeks SUSTAIN-2 trial, semaglutide 0.5 mg and 1.0 mg reduced HbA1c by 1.3% and 1.6% versus 0.5% with sitagliptin (baseline, 8.1%). Weight losses were 4.3 kg, 6.1 kg, and 1.9 kg, respectively (Ahren et al. 2017). In the SUSTAIN-3, trial semaglutide was compared with exenatide QW (Ahmann Aj et al. Diabetes Care 2018; 41: 258–66). After 56 weeks, semaglutide 1.0 mg reduced HbA1c by 1.5% from a baseline HbA1c of 8.3%, compared with 0.9% with exenatide QW, and 67% versus 40% reached a HbA1c < 7.0%, respectively. Weight losses were 5.6 kg and 1.9 kg, respectively. Gastrointestinal adverse events occurred in 42% and 33%, and injection site reactions were reported by 1.2% and 22%, respectively. In SUSTAIN-4, semaglutide was compared with insulin glargine in insulin-naïve patients. After 30 weeks, the reduction in HbA1c was 1.2%, 1.6%, and 0.8% from a baseline of 8.2% with 0.5 mg and 1.0 mg of semaglutide and insulin glargine, respectively (Aroda et al. 2017). Weight loss was 3.5 kg and 5.2 kg versus a weight gain of 1.2 kg with insulin glargine (Aroda et al. 2017). Risk of hypoglycemia was also reduced with semaglutide. Efficacy and safety of semaglutide versus placebo as add-on to basal insulin was investigated in SUSTAIN-5. After 30 weeks (baseline HbA1c 8.4%) 61% and 79% versus 11% with 0.5 mg, 1.0 mg, or placebo had achieved a HbA1c below 7.0%. Weight losses were 3.7 kg, 6.4 kg, and 1.4 kg, respectively. The cardiovascular endpoint study SUSTAIN-6 will be discussed later in this chapter (Marso et al. 2016b). The SUSTAIN-7 trial is a head-to-head comparison between semaglutide and dulaglutide as add-on to metformin during 40 weeks (Pratley RE et al. Lancet Diabetes Endocrinol 2018 Jan 31, Epub ahead of print). Patients in the 0.5 mg semaglutide group had a reduction in HbA1c of 1.5% against a 1.1% reduction in the 0.75 mg dulaglutide group. Additionally, 1.0 mg of semaglutide reduced HbA1c by 1.8% compared with a decrease by 1.4% among patients treated with 1.5 mg dulaglutide. Those on 0.5 mg semaglutide lost on average 4.6 kg of body weight compared to 2.3 kg with 0.75 mg dulaglutide. The higher doses led to losses of 6.5 kg and 3.0 kg, respectively. The side effects including changes in retinopathy did not differ between the two GLP-1 RAs.
Semaglutide has not yet been approved for treatment of type 2 diabetes. Overall, semaglutide seems at least as effective and possibly more potent than the other GLP-1 RAs. Safety profile of semaglutide did not differ from those reported with other GLP-1 RAs (Marso et al. 2016b; Sorli et al. 2017). In the SUSTAIN 6 trial semaglutide was associated with a significant increase in the risk of diabetic retinopathy (Marso et al. 2016b). In a post-hoc analyses of the SUSTAIN 6 data the increase in diabetic retinopathy was attributed to the magnitude and rapidly of HbA1c reduction during the first 16 weeks of treatment in patients who had pre-existing diabetic retinopathy and poor glycemic control at baseline, and who were treated with insulin (Vilsbøll T et al. Diabet Obes Metab 2018, 20: 889–97). In the SUSTAIN 1-5 trials there were no imbalance in diabetic retinopathy with semaglutide versus placebo (Vilsbøll T et al. Diabet Obes Metab 2018; 20: 889–97). Semaglutide is also in development as an obesity drug .
Intarcia (ITCA) 650
Safety and Adverse Events of GLP-1 RAs
As discussed above the most frequently observed AEs with GLP-1 RAs are nausea, vomiting, and diarrhea (Ostergaard et al. 2016; Frandsen et al. 2016; Madsbad et al. 2011; Madsbad 2016, 2009; Bettge et al. 2017). They are usually described as gastrointestinal, although they are more likely to be due to interaction with receptors in the central nervous system. Importantly, they can be reduced by slow up-titration of the dose. In most patients these adverse events are transient, and less than 5% of the patients discontinued treatment in clinical trials (except for taspoglutide), although higher rates may be seen in clinical practice (Ostergaard et al. 2016; Madsbad et al. 2011; Madsbad 2016; Bettge et al. 2017; Cefalu et al. 2014).
Concerns have been raised with respect to potential pancreatic side effects associated with GLP-1 RAs (Egan et al. 2014), but in the four cardiovascular endpoint studies so far available, there was no increased risk of pancreatitis or pancreas cancer (Marso et al. 2016a, b; Pfeffer et al. 2015; Holman et al. 2017). In 2014, FDA and European Medicines Agency (EMA) reviewed studies with over 28.000 patients and concluded that no evidence existed suggesting a causal association between use of GLP-1 RAs and pancreatitis or pancreas cancer (Egan et al. 2014). There are limited published data on the effects of GLP-1 RAs on pancreatic enzymes. In a 26-week study, serum amylase and lipase levels increased with lixisenatide and liraglutide, more so with liraglutide (Nauck et al. 2016b). Notably, the increased enzyme levels are not associated with or predict subsequent development of acute pancreatitis (which occurs with increased frequency in patients with T2DM).
In rodent models, GLP-1 RAs stimulate the release of calcitonin and during long-term exposure may lead to hyperplasia and adenoma formation and with high doses cancer (Bjerre et al. 2010). In humans the C-cells express a very low number of GLP-1 receptors compared to rodents, and the GLP-1 RAs do not stimulate release of calcitonin (Bjerre et al. 2010; Hegedus et al. 2011). In addition, there is no evidence of a causal relationship between GLP-1 RAs and thyroid tumors in humans (Hegedus et al. 2011). In the phase 3 trials and the cardiovascular endpoint trials, there were no cases of medullary thyroid carcinoma in the exposed patients (Hegedus et al. 2011). In a resent post-hoc anlayses of the LEADER trial There was no evidence of a difference in calcitonin concentrations between the liraglutide and placebo groups, and no C-cell malignancies occurred in the liraglutide group (Hegedus L et al. Diabetes Care 2018; 41: 620–22). Nevertheless, GLP-1 RAs should not be used in patients with a personal or familiar history of medullary thyroid carcinoma.
Injection Site Reactions
It is difficult to compare injection site reactions across all studies because of differences in methods of reporting outcomes. Overall, once-weekly GLP-1 RAs appear to be associated with higher incidences of injection site reaction than exenatide twice daily (Ostergaard et al. 2016; Madsbad et al. 2011; Madsbad 2016, 2009) or liraglutide once daily (Ostergaard et al. 2016; Madsbad et al. 2011; Madsbad 2016, 2009).
The exception appears to be dulaglutide once weekly, which in AWARD-6 was associated with low rates (<1%) of injection site reactions, comparable to those observed with liraglutide (Dungan et al. 2014). In SUSTAIN 7 injection site reaction did not differ between semaglutide and dulaglutide (Pratley RE et al. Lancet Diabetes Endocrinol 2018, Jan 31, Epub ahead of print).
As GLP-1 RAs are peptides, antibody formation could potentially occur, which might result in injection site reactions, loss of efficacy, and anaphylaxis. Antibody formation has been reported in several head-to-head trials, as discussed in relation to the individual GLP-1 RAs (Ostergaard et al. 2016; Madsbad et al. 2011; Madsbad 2016), but has not resulted in major immune reactions .
Cardiovascular Effects and Endpoint Studies with GLP-1 RAs
Multiple studies have demonstrated a role for GLP-1 to regulate endothelial function, but it remains unclear whether direct or indirect activation of GLP-1 receptors in blood vessels is involved in the regulation of blood flow (Drucker 2016; Pujadas and Drucker 2016). It also remains uncertain whether endothelial cells within blood vessels express the GLP-1 receptor.
Blood Pressure and Heart Rate
Improvements in both systolic blood pressure (SBP) and diastolic blood pressure (DBP) preceding weight loss have been reported in clinical trials of GLP-1 RAs (Gallwitz et al. 2010). Indeed, a meta-analysis of trials involving exenatide OW, exenatide BID, or liraglutide found that these treatments all significantly decreased SBP by −1.79 and −2.39 mmHg compared with placebo and active controls, respectively (Robinson et al. 2013). There was also a trend toward decreased DBP with GLP-1 RAs, but the reductions did not reach statistical significance. In the clinical studies, office blood pressure measurements have been used. However, in four studies using 24 h ambulatory blood glucose monitoring in subjects with type 2 diabetes and in one study in type 1 diabetic patients, treatment with liraglutide did not show any significant blood pressure-lowering effect (Dejgaard et al. 2017; Kumarathurai et al. 2017b). The mechanisms linking GLP-1 RA treatment to reduction in blood pressure are poorly understood, but potential mechanisms include vasodilation and natriuresis or unknown neurohormonal mechanisms.
Increases in resting heart rate and cardiac output have been reported with GLP-1 RAs (Drucker 2016; Pujadas and Drucker 2016). Although the underlying physiological mechanisms have not yet been defined, activation of the GLP-1 receptors in the sinoatrial node and changes in the activity of the autonomic nervous system by enhancing sympathetic and reducing parasympathetic nervous system activity have been proposed to be responsible for the changes (Pyke et al. 2014; Smits et al. 2016). Another potential explanation for the increased heart rate could include a reflex mechanism compensating for vasodilation and lowering of BP (Asmar et al. 2015). A meta-analysis of studies involving exenatide OW, exenatide BID, or liraglutide found that these treatments increased heart rate by 1.86 beats/min (bpm) versus placebo and by 1.90 bpm versus active comparators (Robinson et al. 2013). However, in studies involving 24-h heart rate registration much greater increases may be seen (Kumarathurai et al. 2017a). The acute effect of GLP-1 on BP is an increase, consistent with the increase in heart rate and a consequent increase in cardiac output (Asmar et al. 2015). Postmarketing reports have not demonstrated any prolongation of QT interval during treatment with a GLP-1 RA, but the GLP-1 RA liraglutide has been shown to reduce heart rate variability in conjunction with a decrease in parasympathetic activity suggesting that liraglutide may affect sympatho-vagal balance (Kumarathurai et al. 2017a).
Lipids and Cardiovascular Risk Markers
Effects on lipids have in most trials, including the large outcome trial with liraglutide, been minimal (Marso et al. 2016a, b; Pfeffer et al. 2015; Holman et al. 2017; Pujadas and Drucker 2016), but an interesting study with liraglutide 1.8 mg suggested that liraglutide treatment in patients with T2DM significantly and markedly reduces postprandial excursions of triglyceride and apolipoprotein B48 after a fat-rich meal, independently of gastric emptying (Hermansen et al. 2013). Cardiovascular risk markers as PAI-1, B-type natriuretic peptide, ICAM-1, monocyte chemoattractant protein-1 (MCP-1), and CRP levels were reduced during treatment with GLP-1 RAs (Pujadas and Drucker 2016). Whether GLP-1 RAs exert clinically relevant effects on platelets and coagulation is not yet known (Drucker 2016; Pujadas and Drucker 2016).
Animal studies have demonstrated cardioprotection in experimental models of myocardial infarction, reviewed in Drucker (2016) and Pujadas and Drucker (2016). Administration of a GLP-1 RA reduced infarct size, improved survival, and preserved left ventricular function in mice (Drucker 2016; Pujadas and Drucker 2016). However, the precise mechanisms explaining the results remain unclear, especially since it has been a challenge to find GLP-1 receptors on the myocytes and endothelial cells in the heart (Drucker 2016; Pujadas and Drucker 2016). Studies in mice suggested that the primary metabolite of GLP-1 (9-36NH2) may mediate some of the effects via hypothetical non-GLP-1 receptor-mediated cardioprotective actions (Ban et al. 2008). Support for a similar mechanism to operate in humans is lacking. In a pilot study, 72 h infusion of native GLP-1 in human with acute myocardial infarction and impaired ejection fraction (< 40%) improved ventricular function (Nikolaidis et al. 2004). In an acute study, intravenous infusions of exenatide were demonstrated to be cardioprotective as an adjunct to primary percutaneous coronary intervention in patients with ST-segment-elevation myocardial infarction (STEMI) (Lonborg et al. 2012). The infusion was commenced 15 min before intervention and maintained for 6 h after the procedure. The exenatide treatment was associated with a 30% decrease in final infarct size, if treatment could be instituted within 130 min after the attack, whereas there was no cardioprotective effect in patients with longer system delay (Lonborg et al. 2012). In another study in patients with STEMI, liraglutide administered 30 min before PCI and continued for 7 days lowered level of troponin T and improved ventricular function (Chen et al. 2015).
However , 48 h of native GLP-1 infusion in patients with NYHA class II-III failed to show any benefit (Halbirk et al. 2010). Albiglutide versus placebo over 12 weeks did not improve ventricular function in patients with EF < 40% (Lepore et al. 2016). In a double-blind, placebo-controlled, randomized clinical trial, patients with established heart failure and reduced LVEF (median LVEF of 25%) were randomized to liraglutide 1.8 mg (n = 154) or placebo (n = 146) for 180 days (Margulies et al. 2016). Compared with placebo, liraglutide had no significant effect on the number of deaths or rehospitalizations for heart failure (Margulies et al. 2016). In two other studies, no effect of liraglutide treatment for 12–24 weeks on left ventricular function was reported in patients with or without type 2 diabetes and stable heart failure (Jorsal et al. 2017; Kumarathurai et al. 2016). On the contrary a tendency to an increased frequency of adverse cardiovascular events was reported in Jorsal et al. (2017). These findings do not support the use of liraglutide for the treatment of heart failure. Notably, in the ELIXA, LEADER, SUSTAIN-6, and EXSCEL studies, there was no increased risk of hospitalization because of heart failure in the treated groups (Marso et al. 2016a, b; Pfeffer et al. 2015; Holman et al. 2017).
Cardiovascular Endpoint Studies
In 2008 the FDA recommended that all drugs investigated for diabetes should be evaluated for cardiovascular effects in large and long-term trials. The short-acting GLP-1 RA, lixisenatide, was assessed with respect to cardiovascular outcome versus placebo (the ELIXA trial) in 6068 patients with type 2 diabetes, who had had a recent acute coronary event (Pfeffer et al. 2015). The primary endpoint of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina did not differ between the lixisenatide and placebo groups after a median of 25 months follow-up (Pfeffer et al. 2015). There was no difference in heart failure or death. Lixisenatide treatment was not associated with a higher risk of hypoglycemia, pancreatitis, or pancreatic neoplasm (Pfeffer et al. 2015).
The safety of liraglutide was evaluated in the LEADER trial, a double-blinded trial, including 9340 type 2 patients with a mean follow-up of 3.8 years (Marso et al. 2016a). Patients included had cardiovascular or kidney disease or were at high risk for developing cardiovascular disease. The primary endpoint: death, nonfatal myocardial infarction, and nonfatal stroke, was reduced by 13% (p < 0.001), and mortality from cardiovascular disease was reduced by 22% (p = 0.007) and death of any course by 15%, (p = 0.002) (Marso et al. 2016a). The incidence of pancreatitis was nonsignificantly lower in the liraglutide group. There was a significant reduction in severe hypoglycemic episodes in the liraglutide group. Subgroup analysis showed benefit with liraglutide in patients with eGFR less than 60 ml/min/1.72 m2 compared with those with higher eGFRs; the benefit also appeared greater in patients with established CVD compared to patients with risk factors for CVD (Marso et al. 2016a). In total, 66 patients had to be treated for 3 years to prevent 1 primary endpoint and 98 patients to prevent 1 death from any cause (Marso et al. 2016a). A secondary analysis shows that liraglutide resulted in lower rates of development and progression of diabetic kidney disease than placebo (Mann et al. 2017). This result was driven primarily by the new onset of persistent macroalbuminuria, which occurred in fewer participants in the liraglutide group than in the placebo group (HR, 0.74).
In SUSTAIN-6, semaglutide for once-weekly administration was evaluated in 2 doses (0.5 mg or 1.0 mg) versus placebo in 3297 type 2 diabetic patients (Marso et al. 2016b). At baseline 83% had established cardiovascular disease, chronic kidney disease, or both. The primary outcome: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, was after 104 weeks follow-up reduced by 26% (p < 0.001), nonfatal myocardial infarction by 26% (p = 0.12), and nonfatal stroke by 39% (p = 0.04) (Marso et al. 2016b). Rates of death, including cardiovascular death, were similar in the two groups. In total 45 patients would need to be treated for 2 years to prevent 1 primary endpoint. Revascularization surgery rates were also greatly reduced by semaglutide compared with placebo. Semaglutide is in late phase 3 development and will probably enter the market within the next few years.
In the EXSCEL trial, 14,752 patients (of whom 10,782 (73%) had previous cardiovascular disease) were randomized to treatment with exenatide once weekly or placebo as add-on to usual therapy and followed for a median of 3.2 years (Holman et al. 2017). The primary composite endpoint: death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, occurred in 839 versus 905 participants in the exenatide and placebo groups (HR, 0.91, P = 0.06 for superiority). Once-weekly exenatide did not increase risk of hospitalization for heart failure. Cardiovascular death did not differ between exenatide and placebo groups, but exenatide reduced total mortality by 14%, which was statistically significant (Holman et al. 2017). The incidence of acute pancreatitis, pancreas cancer, and thyroid carcinoma did not differ between the groups.
Taken together, the short-acting lixisenatide had a neutral effect on cardiovascular risk, whereas liraglutide and semaglutide showed a benefit. Liraglutide reduced cardiovascular and total mortality. Nonfatal stroke was reduced with semaglutide but not with liraglutide. Exenatide OW also reduced cardiovascular risk and total mortality significantly. The GLP-1 receptor agonist had no effect on heart failure in the four endpoint trials.
The mechanism of the cardiovascular benefits is unknown. One suggestion is that GLP-1 RAs have some beneficial effects on the progression of atherosclerosis by reducing the plaque burden or increasing plaque stability. The GLP-1 RAs also have beneficial effects on blood pressure, weight and postprandial lipids, low-grade inflammation, and on the myocardium, but these effects do not readily explain the findings. Therefore, the mechanisms of action of GLP-1 RAs have yet to be elucidated. It is also debated how the four randomized studies with lixisenatide, liraglutide, semaglutide, and exenatide could generate so different results (Marso et al. 2016a, b; Pfeffer et al. 2015; Holman et al. 2017)? First, the patients in ELIXA appeared to be at higher risk for further cardiovascular disease progression than the patients in LEADER, SUSTAIN-6, and EXSCEL, meaning that even a significant beneficial effect of lixisenatide might not be able to influence the very high event rate in this group of patients. In addition, lixisenatide has a short half-life and covers only about 8 h of the day, while liraglutide, semaglutide, and exenatide QW cover all 24 h. In addition, the duration of the trials differ significantly. Moreover, the molecules are quite different and differ in their receptor signalling capacity and biological effects (see Table 1). It is an ongoing discussion, whether the CV benefit of the long-acting human GLP-1 RAs in LEADER and SUSTAIN-6 versus EXSCEL trials can be considered a class effect or might be specific for the liraglutide/semaglutide and exenatide molecules. Additional cardiovascular endpoint studies will be published in the future with FREEDOM-CVO (ITCA 659) and REWIND (dulaglutide). At any rate liraglutide, semaglutide, and exenatide QW have demonstrated beneficial effects on cardiovascular events and mortality in type 2 patients with cardiovascular disease or at high risk for a future cardiovascular events, which is important for the treatment of these patients .
Head-To-Head Comparisons of GLP-1 RAs
In general, baseline characteristics were similar across trial populations and between treatment groups (Ostergaard et al. 2016; Madsbad et al. 2011; Madsbad 2016). The mean age of participants ranged from 55 to 61 years across the studies, with mean duration of diabetes ranging from 6 to 9 years (Ostergaard et al. 2016; Madsbad et al. 2011; Madsbad 2016). Mean baseline HbA1c levels were in the range of 8.0 (64 mmol/mol) to 8.7% (72 mmol/mol) across the studies (Ostergaard et al. 2016; Madsbad et al. 2011; Madsbad 2016). Fasting glucose concentrations ranged from 9.1 to 9.9 mmol/l, and mean baseline body weight was consistently in the range 91–102 kg (Ostergaard et al. 2016; Madsbad et al. 2011; Madsbad 2016).
Effect on Glycemic Control
All of the phase 3 trials examined changes in HbA1c as the primary endpoint (Ostergaard et al. 2016; Madsbad et al. 2011; Madsbad 2016). All trials were associated with notable reductions in HbA1c, although liraglutide led to greater decreases than exenatide formulations, lixisenatide, and albiglutide (Fig. 4; Ostergaard et al. 2016; Madsbad 2016). HbA1c reductions did not differ between liraglutide and dulaglutide after 26 weeks (Fig. 4; Dungan et al. 2014). Exenatide once weekly produced more consistent and significantly greater reductions in HbA1c than exenatide twice daily (Drucker et al. 2008; Blevins et al. 2011; Ji et al. 2013). In the T-emerge 2 study, taspoglutide at 10 and 20 mg led to greater reductions in HbA1c than exenatide 10 μg BID (Rosenstock et al. 2013b). In the SUSTAIN-7 trial, semaglutide and dulaglutide as add-on to metformin during 40 weeks were compared (Pratley RE et al. Lancet Diabetes Endocrinol 2018, Jan 31 Epub ahead of print). Patients in the 0.5 mg semaglutide group had a reduction in HbA1c of 1.5% against a 1.1% reduction in the 0.75 mg dulaglutide group. Additionally, 1.0 mg of semaglutide reduced HbA1c with 1.8% compared with a decrease of 1.4% among patients treated with 1.5 mg dulaglutide. The reductions in HbA1c thus ranged from 0.3 to 1.9% (Fig. 4; Buse et al. 2009, 2013; Drucker et al. 2008; Rosenstock et al. 2013a, b; Nauck et al. 2016b; Pratley et al. 2014; Dungan et al. 2014; Blevins et al. 2011; Ji et al. 2013).
The postprandial glucose excursions and fasting plasma glucose were also assessed in many of these trials. As expected, based on the delayed gastric emptying seen with the short-acting GLP-1 RAs, exenatide BID and lixisenatide demonstrated greater effects on postprandial glucose excursions than the longer-acting GLP-1 RAs, but this improvement was seen mainly after the meal following the injection, whereas the longer-acting compounds reduced plasma glucose throughout the 24-h period studied (Fig. 2; Ostergaard et al. 2016; Madsbad 2016; Nauck et al. 2016b). Hence the longer acting resulted in greater improvements in HbA1c compared with the short-acting GLP-1 RAs (Ostergaard et al. 2016; Madsbad 2016; Dungan et al. 2014).
Effect on Weight
Liraglutide was associated with weight reductions similar to those with exenatide BID (3.2 and 2.9 kg, respectively) but greater than those with exenatide OW, albiglutide, and dulaglutide (Fig. 5; Buse et al. 2009, 2013; Drucker et al. 2008; Rosenstock et al. 2013a, b; Nauck et al. 2016b; Pratley et al. 2014; Dungan et al. 2014; Blevins et al. 2011; Ji et al. 2013). Compared to lixisenatide, the weight loss tended to be greater with liraglutide (4.3 kg vs. 3.7 kg) (Nauck et al. 2016b). Weight loss was not significantly different between the two exenatide formulations. In the T-emerge 2 study, exenatide BID showed a greater (nonsignificant) reduction in weight than taspoglutide 10 mg OW but showed no difference in weight loss compared with taspoglutide 20 mg OW (Rosenstock et al. 2013b). Exenatide BID was associated with greater (nonsignificant) weight loss than lixisenatide. In SUSTAIN-7 those on 0.5 mg semaglutide lost on average 4.6 kg of body weight compared to 2.3 kg with 0.75 mg dulaglutide. The higher doses led to losses of 6.5 kg and 3.0 kg, respectively (Pratley RE et al. Lancet Diabetes Endocrinol 2018, Jan 31 Epub ahead of print). Taken together, all GLP-1 receptor agonists have weight-reduction effect (Fig. 5), and the head-to-head studies revealed significantly greater reduction in weight with liraglutide than the once-weekly GLP-1 RAs (except for semaglutide). The explanation for the different magnitude of weight loss is a matter of contention. It is unclear whether the large molecules albiglutide and dulaglutide hinder transport across the blood-brain barrier or through fenestrated capillaries around hypothalamus (Secher et al. 2014). Alternatively, suboptimal dosing of the once-weekly GLP-1 RAs may play a role; this may also explain the differences in reduction in HbA1c level of the GLP-1 RAs.
Effect on Blood Pressure
Head-to-head trials have not revealed significant differences in effects on blood pressure (BP) among different GLP-1 RAs (Madsbad 2016). However, in the extension phases of DURATION-1 and LEAD-6, which continued to 52 weeks, participants switching from exenatide BID to either exenatide OW or liraglutide experienced further reductions in SBP (–3.8 mmHg in both studies) (Ostergaard et al. 2016; Buse et al. 2010a, b). In a 26-week study, changes in blood pressure did not differ between lixisenatide and liraglutide (Nauck et al. 2016b). Effect on blood pressure did not differ between semaglutide and dulaglutide in SUSTAIN 7 trial (Pratley RE et al. Lancet Diabetes Endocrinol 2018, Jan 31 Epub ahead of print).
Head-to-head trials have suggested that heart rate increases may be smaller with exenatide twice daily than exenatide once weekly or liraglutide (Buse et al. 2009; Drucker et al. 2008). Dulaglutide is also associated with an increase in heart rate, of similar magnitude, to that with liraglutide (Dungan et al. 2014). Albiglutide did not appear to be associated with clinically relevant increases in heart rate (Pratley et al. 2014).
Since heart rate was mostly estimated during daytime, 24-h monitoring was needed to understand the different effects of the short- and long-acting GLP-1 RAs on heart rate. In a 8-week study, liraglutide doses increased the mean ± SE 24-h heart rate from baseline by 9 ± 1 bpm versus 3 ± 1 bpm with lixisenatide (P < 0.001) (Meier et al. 2015). Greater heart rate increases at week 8 with liraglutide were observed at nighttime, while heart rate increases with lixisenatide were greatest during the day (Meier et al. 2015). In another comparison between lixisenatide and liraglutide, the increase in pulse was 2.5 bpm with liraglutide, while a decrease by 1.1 bpm was reported with lixisenatide after 26 weeks (Seino et al. 2012). Note that heart rate primarily has been estimated during daytime in an ambulatory consultation; 24 h monitoring is needed to understand the different effects of short- and long-acting GLP-1 receptor agonists on heart rate. In one study, liraglutide increased 24-h heart rate from baseline by 9 bpm versus 3 bpm with lixisenatide (Meier et al. 2015). Greater heart rate increases with liraglutide were observed at nighttime (Meier et al. 2015). Increase in heart rate was greater with semaglutide 1.0 mg compared with dulaglutide 1.5 mg (4.0 vs 2.4 bpm), while the increase did not differ with the lowest doses (Pratley RE et al. Lancet Diabetes Endocrinol 2018, Jan 31 Epub ahead of print).
Gastrointestinal Adverse Effects
The most frequently observed AEs with GLP-1 RAs were gastrointestinal disorders, particularly nausea, vomiting, and diarrhea; nausea, however, occurred less frequently with exenatide OW and albiglutide than exenatide BID and liraglutide (Buse et al. 2009, 2013; Drucker et al. 2008; Rosenstock et al. 2013a, b; Nauck et al. 2016b; Pratley et al. 2014; Dungan et al. 2014; Blevins et al. 2011; Ji et al. 2013). However, by far the highest rates of nausea were observed with taspoglutide: 53% and 59% with 10 and 20 mg OW, respectively, compared with 35% among participants treated with exenatide BID (Rosenstock et al. 2013b). In a meta-analysis of 32 phase 3 clinical trials with GLP-1 RAs, it was concluded that presence of a background treatment with metformin was associated with more nausea and vomiting (Bettge et al. 2017). Compared to exenatide BID, there was less nausea and diarrhea with lixisenatide (Bettge et al. 2017). Compared to liraglutide, there was a similar risk associated with dulaglutide and less with exenatide QW and albiglutide (Bettge et al. 2017). Long-acting GLP-1 RAs were associated with less nausea and vomiting but with more diarrhea than short-acting agents (Bettge et al. 2017). More premature discontinuation, mostly due to gastrointestinal adverse events was observed with semaglutide compared with dulaglutide in SUSTAIN 7 (Pratley RE et al. Lancet Diabetes Endocrinol 2018, Jan 31 Epub ahead of print).
Injection Site Reactions
Both exenatide formulations and albiglutide may be associated with higher incidences of injection site reactions than liraglutide and dulaglutide (Buse et al. 2009, 2013; Drucker et al. 2008; Rosenstock et al. 2013a, b; Nauck et al. 2016b; Pratley et al. 2014; Dungan et al. 2014; Blevins et al. 2011; Ji et al. 2013), but the once-weekly GLP-1 RAs appear to be associated with higher incidences of injection site reaction than exenatide BID or liraglutide OD. The exception appears to be dulaglutide OW, in AWARD-6, which was associated with low rates (<1%) of injection site reactions, comparable to those observed with liraglutide (Dungan et al. 2014). Injection site reaction did not differ between semaglutide and dulaglutide in SUSTAIN 7 (Pratley RE et al. Lancet Diabetes Endocrinol 2018, Jan 31 Epub ahead of print).
In head-to-head studies, anti-exenatide antibodies were more common – and titers were higher – with exenatide OW than with exenatide BID (Drucker et al. 2008; Blevins et al. 2011; Ji et al. 2013). However, reductions in HbA1c were still significant in participants with or without antibodies, and the presence of antibodies did not correlate with reported rates of AEs (Drucker et al. 2008; Blevins et al. 2011; Ji et al. 2013).
Antibody formation has also been reported in liraglutide clinical trials, although a meta-analysis of the LEAD studies found lower immunogenicity with liraglutide than with exenatide BID and no effect of antibodies on glycemic efficacy with liraglutide (Buse et al. 2011). Development of antibodies was reported in 56–60% of participants (undergoing different treatment regimens) treated with 20 μg lixisenatide OD (Rosenstock et al. 2013a; Nauck et al. 2016b). In another study, antibodies were found in 43% and 71% of participants treated with 10 μg lixisenatide once daily and 20 μg twice daily, respectively (Ratner et al. 2010; Fonseca et al. 2012). No notable differences were reported in terms of safety and efficacy between antibody-positive and negative participants (Ratner et al. 2010; Fonseca et al. 2012).
Antibody formation occurred relatively rarely in phase 3 trials of dulaglutide and albiglutide, but no comparison could be made with liraglutide in these studies, as anti-liraglutide antibodies were not assessed (Pratley et al. 2014; Dungan et al. 2014).
Finally, in the T-emerge 2 study, anti-taspoglutide antibodies were detected in 49% of participants. In this trial, levels of systemic allergic reactions were also considered to be unacceptably high (6% of participants in each of the taspoglutide groups) (Rosenstock et al. 2013b).
The immunogenicity reported in the trials of exenatide, lixisenatide, and liraglutide appeared to have little impact on the efficacy and safety of these GLP-1 RAs .
Fixed-Ratio Combination Therapy with a GLP-1 Receptor Agonist and Basal Insulin
The complex pathophysiology of type 2 diabetes (T2D) is associated with insulin resistance, obesity, and declining beta-cell function (DeFronzo 2009). It also includes defects in glucagon secretion and a severely impaired incretin effect of glucagon-like peptide-1 (GLP-1) and glucose-independent polypeptide (GIP) in response to a meal (Holst et al. 2011). Consequently, combination therapies, addressing several of the underlying abnormalities and effectively reducing glycated hemoglobin A1c (HbA1c), mitigating weight gain or inducing weight loss, combined with an impact on the comorbidities associated with T2D are of high interest (Balena et al. 2013; Eng et al. 2014). On this background, in the real world, combination therapy with basal insulin and a GLP-1 RA has turned out to be very popular, and a recent meta-analysis suggests that basal insulin in combination with a GLP-1 RA results in superior glycemic control with no increase in hypoglycemic episodes or weight gain, as compared with basal insulin alone (Eng et al. 2014).
A fixed-ratio combination of the basal insulin degludec and the GLP-1 RA, liraglutide (IDegLira, 50 units degludec/1.8 mg liraglutide), has been approved under the brand name Xultophy 100/3.6 as a once-daily injection for the treatment of type 2 diabetes (T2D). Insulin degludec is an ultra-long-acting basal insulin analogue with a half-life of approximately 25 h and a duration of action of about 41 h compared with about 12 h for insulin glargine (Haahr and Heise 2014). Steady state is obtained within 2–3 days of treatment (Haahr and Heise 2014). Insulin degludec has demonstrated lower intraindividual glycemic variability and lower risk of hypoglycemia as compared to the shorter-acting insulin glargine (Haahr and Heise 2014; Vora et al. 2014). IDegLira has been approved by FDA to improve glycemic control in patients inadequately controlled on basal insulin in doses of up to 50 units/day or a GLP-1 RA. IDegLira has also been approved for use in Europe for the treatment of type 2 diabetes in combination with oral glucose-lowering agents alone or combined with basal insulin.
IDegLira is available in prefilled pen injectors which contain 3 ml, equivalent to 300 units of insulin degludec and 10.8 mg of liraglutide. Each dose step is 1 unit of insulin degludec and 0.036 mg of liraglutide. Administration is by once-daily injection, independent of meal intake or time of day (although it should ideally be injected at the same time each day). The maximal dose is 50 steps corresponding to 50 units of insulin degludec and 1.8 mg of liraglutide. The recommended starting dose in patients treated with OADs alone is 10 dose steps (10 units/0.36 mg), whereas the starting dose is 16 dose steps (16 units/0.6 mg) in patients that were already treated with a GLP-1 RA or insulin.
IDegLira has been investigated in eight 26-week randomized trials (the DUAL™ program) (Buse et al. 2014; Gough et al. 2014; Lingvay et al. 2016; Linjawi et al. 2017; Rodbard et al. 2017). IDegLira reduces HbA1c more than monotherapy with a GLP-1 RA (liraglutide) or insulin (degludec or glargine) despite the fact that IDegLira and insulin degludec or insulin glargine were titrated to similar FPG levels, indicating that the further improvement also includes better PPG control effected by the liraglutide component of the combination therapy (Buse et al. 2014; Gough et al. 2014, 2015; Lingvay et al. 2016; Linjawi et al. 2017; Rodbard et al. 2017). Furthermore, combination therapy leads to weight loss, or a stable body weight, with no increase in hypoglycemia despite the lower HbA1c in the IDegLira group (Buse et al. 2014; Gough et al. 2014, 2015; Lingvay et al. 2016; Linjawi et al. 2017; Rodbard et al. 2017). These results were found in both insulin-naïve and insulin-treated patients with T2D, independent of diabetes duration and baseline HbA1c (Buse et al. 2014; Gough et al. 2014, 2015; Lingvay et al. 2016; Linjawi et al. 2017; Rodbard et al. 2017). In DUAL VII, IDegLira was compared with basal-bolus insulin therapy (glargine plus insulin aspart up to four times daily) in patients uncontrolled on metformin and insulin glargine. After 26 weeks the HbA1c did not differ between groups (6.7%), but body weight decreased with IDegLira (−0.9 kg) and increased with basal-bolus therapy (+2.6 kg); the rate of hypoglycemia was eightfold lower with IDegLira (Billings LK et al. Diabetes Care 2018; Feb, Epub ahead of print). Daily dose of insulin was 40 units in the IDegLira group compared with 84 units (basal 52 units and bolus 32 units) in the patients treated with basal-bolus. Notably, these results were obtained by one injection and one fasting blood glucose measurement in the IDegLira group compared with multiple injections and multiple blood glucose measurements in the basal-bolus group.
In the DUAL studies, rates of adverse events did not differ between treatment groups; however, gastrointestinal side effects were fewer with IDegLira compared with liraglutide treatment alone, which was titrated using the recommended dose escalation of 0.6 mg per week until a dose of 1.8 mg (Gough et al. 2014, 2015) (although, because of insulin titration, only a maximum dose of 1.4 mg was actually achieved in the large DUAL 1 study). IDegLira may be of more limited value in patient populations that are challenging to manage, e.g., patients with HbA1c values >10%, BMI >40 kg/m2, or patients receiving insulin doses in excess of 50 U/day. This has to be taken into consideration when switching people treated with large doses of insulin; potentially this may lead to a transient worsening of glycemic control .
The combination of once-daily insulin glargine and the short-acting GLP-1 RA lixisenatide (iGlarLixi, formerly known as LixiLan) is recommended to be injected about 1 h before the largest meal (Aroda et al. 2016; Rosenstock et al. 2016a, b). iGlarLixi has been approved by FDA to improve glycemic control in patients inadequately controlled on basal insulin up to 60 units/day or a GLP-1 RA alone. iGlarLixi has also been approved for use in Europe for the treatment of type 2 diabetes in combination with oral glucose-lowering agents alone or combined with basal insulin. iGlarLixi will be available as prefilled pens for dosing of 10–40 units of glargine with 5–20 mcg of lixisenatide or 30–60 units of glargine with 10–20 mcg of lixisenatide. Each dose step contains 1 unit of glargine and 0.33 mcg of lixisenatide.
In the phase 3 program, iGlarLixi demonstrated better HbA1c reduction versus insulin glargine in patients treated with metformin and reduced weight by approximately 1 kg versus an increase of 0.5 kg for those who received glargine (Rosenstock et al. 2016a). Final dose of insulin was 36 versus 39 units and risk of hypoglycemia did not differ between groups. In the second trial including patients inadequately controlled on basal insulin and with up to 2 oral glucose-lowering agents, iGlarLixi compared to glargine demonstrated better reduction in HbA1c over 30 weeks and a greater proportion of patients (55% vs. 30%) achieving target of <7%. Body weight was reduced with 0.7 kg versus + 0.7 kg, respectively, while final dose of insulin (47 units) and risk of hypoglycemia did not differ between groups (Aroda et al. 2016). In a third study including patients on metformin with or without a second oral glucose-lowering agents, iGlarLixi reduced HbA1c significantly more than with either glargine or lixisenatide alone (−1.6%, −1.3%, and −0.9%, respectively) without increased risk of hypoglycemia with iGlarLixi compared with glargine alone (Rosenstock et al. 2016b). Insulin dose was 39.8 units in the iGlarLixi group and 40.3 units in the glargine group. Changes in body weight were −0.3 kg, +1.1 kg, and −2.3 kg, respectively.
Lixisenatide has a more pronounced effect on PPG excursions in relation to the meal following the injection when compared with liraglutide. Thus, addition of a short-acting GLP-1 RA may be a more convenient intensification strategy compared to adding mealtime rapid-acting insulin, because the fixed dosing does not require adjustments for meal size and carbohydrate content. A limitation with iGlarLixi may be the short duration of lixisenatide and the once-daily administration given 30–60 min before one of the main meals, while IDegLira can be taken independent of meals. A head-to-head comparison with LixiLan and IDegLira will be of interest.
A possible drawback of the combination therapies is the fixed-dose principle, which reduces the flexibility to adjust insulin and GLP-1 RA treatment in an individualized manner. In patients where weight loss is a major aim, a more optimal treatment may be to titrate liraglutide to the maximal dose of 1.8 mg and then add basal insulin (Balena et al. 2013). Thereby less insulin is probably also needed. Nevertheless, the fixed-ratio combinations have been shown to be very effective at lowering glycemia while being associated with lower rate of hypoglycemia and weight gain compared to basal insulin alone and lower gastrointestinal side effects than liraglutide and lixisenatide alone .
GLP-1 RA: Place in Therapy of Type 2 Diabetes
Metformin is considered the first-line therapy in the treatment of type 2 diabetes, but ADA, EASD, and AACE recommend GLP-1 receptor agonists as potential add-on therapy for patients with uncontrolled type 2 diabetes (Garber et al. 2016; Inzucchi et al. 2015). They also may be considered as monotherapy for patients with metformin intolerance. GLP-1 RAs are becoming increasingly popular for the treatment of T2DM because of their excellent HbA1c lowering, positive effects on weight loss, low risk of hypoglycemia, and influence on cardiovascular risk factors (Ostergaard et al. 2016). Their superiority to OADs has been demonstrated in most studies, with greater reductions in both HbA1c and weight (Ostergaard et al. 2016). The fear of injections will, in some patients, remain a barrier for the use of GLP-1 RAs, but this problem can be reduced by using the long-acting agonists for once-weekly injection or ITCA 650 infusion pump. Compared with insulin, GLP-1 RAs are much easier to initiate, with less need for dose titration and blood glucose monitoring (Ostergaard et al. 2016). Furthermore, in patients in whom weight loss is advisable, GLP-1 RA treatment could be an option instead of insulin, which for many patients is associated with weight gain (Inzucchi et al. 2015). The addition of a GLP-1 RA to insulin treatment has been demonstrated to improve glycemic control, help patients lose weight, and lower the need for insulin (Eng et al. 2014). The results from the degludec/liraglutide and the glargine/lixisenatide fixed combination studies support the concept that initiation of insulin therapy is best carried out as an insulin/GLP-1 combination rather than insulin alone. None of the GLP-1 RAs are marketed for use with basal-bolus regimens.
Recently the ADA and some other national guidelines have suggested that in patients with type 2 diabetes and established CVD treatment should begin with lifestyle management and metformin and subsequently in patients not achieving glycemic goal an agent proven to reduce major cardiovascular events and cardiovascular mortality (liraglutide and empagliflozin) is recommended (ADA Position Statement. Diabetes Care 2018; 41 (Suppl 1): S73–S85).
GLP-1 RA use in clinical practice should be customized for individual patients, based on the clinical profile and patient preferences. Survey data on patient preferences have revealed that efficacy (lowering of HbA1c) is the most important attribute influencing patient preference, followed by absence of nausea and hypoglycemia and simplicity of dosing schedule (Polster et al. 2010). In a survey more patients were likely to prefer once-weekly injection because of greater convenience (Polonsky et al. 2011).
The GLP-1 RAs are generally well-tolerated. The main side effects are gastrointestinal, i.e., nausea and vomiting, which often are transient and can be partly avoided by slowly up-titrating the dose (Ostergaard et al. 2016; Gough et al. 2015). The GLP-1 RAs are not recommended for people with impaired kidney function (estimated glomerular filtration rate (eGFR) <30 ml/min) or for elderly people with reduced appetite and food intake. At present, no clear evidence of a causal relationship between GLP-1 RAs and pancreatitis and pancreatic cancer exists (Ostergaard et al. 2016; Marso et al. 2016a, b; Pfeffer et al. 2015).
The major drawback of GLP-1 RAs is the higher cost compared with that of other antidiabetic agents.
Treatment of Type 1 Diabetic Patients with GLP-1 Receptor Agonists
Type 1 diabetes (T1D) is characterized by severely impaired or absent or minimal insulin secretion (Madsbad 1983). Even the most rapid-acting insulin analogues peak too late when given with meals to match the postprandial glucose absorption resulting in large postprandial glucose excursions. Intensive insulin treatment is associated with weight gain, and about 50% of persons with T1D are overweight in economically developed countries (Conway et al. 2010). In theory, treatment regimens in T1D may be improved by combining a GLP-1 RA with insulin. Accordingly, acute infusions of native GLP-1 in C-peptide-negative patients with type 1 diabetes resulted in inhibition of gastric emptying, as well as reduction of glucagon levels, which seems to explain the glucose-regulating effect of GLP-1 during a meal, whereas in patients with residual beta-cell function, enhancement of the endogenous insulin secretion is probably also of importance (Kielgast et al. 2011).
Results from open-label short and small clinical trials indicate that GLP-1 RA treatment induces weight loss and reduces insulin requirements, with either improved or unaltered glycemic control, reviewed in Frandsen et al. (2016). In most of the trials, liraglutide has been used (Dejgaard et al. 2016a).
In the first placebo-controlled trial in normal weight type 1 patients with liraglutide 1.2 mg once daily, there was no effect on HbA1c or glycemic variation compared with placebo (Frandsen et al. 2015). Changes in body weight were −3.13 and +1.12 kg with liraglutide and placebo, respectively. The bolus insulin dose decreased in liraglutide-treated patients and did not change with placebo treatment (−4.0 ± 1.3 vs. 0.0 ± 1.0 IU), and systolic blood pressure decreased compared with placebo (between-group difference 3.21 mmHg) (Frandsen et al. 2015). The incidence of hypoglycemia did not differ between groups. Liraglutide does not compromise glycemic recovery, gastric emptying rate, or counterregulatory hormone responses in T1D during hypoglycemia (Frandsen et al. 2017).
In the second trial with obese type 1 patients, HbA1c and glycemic variability did not differ between liraglutide 1.8 mg and placebo after 24 weeks of treatment, but the number of hypoglycemic events was reduced with liraglutide (Dejgaard et al. 2016b). Both bolus insulin (difference −5·8 IU) and body weight (difference −6·8 kg) decreased with liraglutide treatment compared with placebo. Heart rate increased with liraglutide, with a difference between groups of 7·5 bpm (Dejgaard et al. 2016b). Daytime heart rate increased by 3.7 and nighttime heart rate by 7.5 pbm (Dejgaard et al. 2017).
In the randomized, double-blind, placebo-controlled trial ADJUNCT ONE™, liraglutide 0·6 mg, 1·2 mg, 1·8 mg, and placebo as adjunct to insulin treatment were investigated in 1,398 persons with T1D for 52 weeks (Mathieu et al. 2016). From a mean baseline HbA1c of around 8·2%, those treated with 1·2 mg and 1·8 mg showed a numerically greater improvement in HbA1c of around 0·5% compared with 0·3% for placebo (Mathieu et al. 2016). From a baseline body weight of 86 kg, persons treated with 1·2 mg and 1·8 mg achieved a statistically significantly greater weight loss between 3 kg and 4 kg, whereas the placebo groups experienced a weight gain of around 1 kg (Mathieu et al. 2016). The rates of severe hypoglycemia appeared numerically, but not statistically, lower for all doses of liraglutide compared with placebo. A statistically higher rate of confirmed symptomatic hypoglycemia was observed among persons treated with liraglutide 1·2 mg and 1·8 mg compared with those treated with placebo (Mathieu et al. 2016).
In the ADJUNCT TWO™ trial , 835 participants were enrolled in a 26-week, double-blind, placebo-controlled trial and assigned to liraglutide 0·6 mg, 1·2 mg, 1·8 mg, and placebo (Ahren et al. 2016). Maximum insulin dose was fixed for all treatment arms. From a baseline HbA1c of about 8·1%, the groups treated with liraglutide showed statistically significantly improvements of HbA1c by 0·2% and 0·3% compared with unaltered glycemic control in the placebo-treated group (Ahren et al. 2016). Additionally, the total insulin dose was reduced with liraglutide compared with placebo after 26 weeks. From a baseline body weight of 84 kg, the weight loss in the liraglutide groups was 1–5 kg, whereas the weight was stable in placebo-treated patients (Ahren et al. 2016). A higher rate of symptomatic hypoglycemia was observed among persons treated with liraglutide 1·2 mg (but not with the higher dose) compared with placebo treatment. The incidence of severe hypoglycemia and nocturnal hypoglycemia did not differ between groups (Ahren et al. 2016). Notable, in C-peptide positive patients, liraglutide reduced HbA1c by 0.77% and 0.69% for the 1.8 mg and 1.2 mg doses, respectively (Ahren et al. 2016).
Lastly, efficacy of liraglutide 1.8 mg has also been evaluated in inadequately controlled (HbA1c 8.2%) insulin pump-treated type 1 patients (ADA 2017 abstract OR 71). After 26 weeks the reduction in HbA1c was −0.6% in the liraglutide group, while an increase of 0.2% was observed in the placebo group (between groups, p < 0.001), without increased risk of hypoglycemia. Doses of insulin were unchanged in both groups. Body weight was reduced with −7.3 kg in the groups treated with liraglutide and −0.6 kg in the placebo group.
Thus GLP-1 RAs (at least liraglutide) reduce body weight and insulin dose with improved or unaltered glycemic control, without increased risk of hypoglycemia (Frandsen et al. 2016). The effects on HbA1c are conflicting with small, uncontrolled studies showing the most positive findings (Frandsen et al. 2016). In the randomized, placebo-controlled studies, no effect on HbA1c and glucose variability was reported compared with placebo treatment (Frandsen et al. 2016). One area of interest is treatment with a GLP-1 RA from time of diagnosis with the aim to improve and prolong the remission phase, the first years after diagnosis. From animal and in vitro human models, there is evidence that GLP-1 RAs preserve beta cells from destruction as reviewed in Kielgast et al. (2009), which has initiated ongoing trials in new-onset T1D. Whether treatment with a GLP-1 RA has a future in C-peptide-negative T1D is questionable if the primary indication is to improve glycemic control, especially when taking cost into account.
GLP-1 RAs a New Option for Treatment of Obesity
The exact mechanism by which GLP-1 exerts its anorectic effects is a matter of controversy, but both peripheral and brain GLP-1 receptors seem to be involved (Secher et al. 2014; Madsbad 2014). Since albumin-conjugated GLP-1 which presumably does not cross the blood-brain barrier still reduces food intake, one would assume that a peripheral action on vagal afferent neurons could be involved (Madsbad 2016). On the other hand, it is possible that the reduced weight loss obtained with the large molecules, albiglutide and dulaglutide, compared with liraglutide, can be explained by less direct activation of the GLP-1 receptors in the hypothalamic areas and brain stem. Indeed, compared with liraglutide, the larger molecular sizes of albiglutide and dulaglutide may hinder transport across the blood-brain barrier or through fenestrated capillaries at the area of hypothalamus (Secher et al. 2014; Madsbad 2014). Liraglutide has been reported to directly stimulate pro-opiomelanocortin (POMC) neurons and inhibit neuropeptide-Y and Agouti-related peptide neurons in the hypothalamus resulting in appetite suppression (Secher et al. 2014). The weight-reducing effect may also be explained by attenuation of the decrease in the levels of the anorexigenic hormone, leptin, which accompanies weight loss (Iepsen et al. 2015). GLP-1 RAs do not influence energy expenditure in humans (Harder et al. 2004). Alternatively, however, it is possible that the once-weekly GLP-1 RAs have been suboptimally dosed (with respect to weight loss); in fact, this may also explain the differences with respect to reduction of HbA1c (Madsbad et al. 2011; Madsbad 2016).
Obesity is known as a risk factor for several common diseases including cardiovascular disease, type 2 diabetes, cancers, and osteoarthritis, and obesity is associated with reduced quality of life (Guh et al. 2009). Obesity guidelines mention the use of pharmacological therapy as a possible adjunctive therapy to diet, exercise, and behavior modification in certain patients (Jensen et al. 2014). Weight loss medications can be consider in adults, who have a BMI of 30 kg/m2 or higher or in patients with a BMI of 27 kg/m2 and having at least one overweight-related comorbid condition, e.g., hypertension, dyslipidemia, and type 2 diabetes (Jensen et al. 2014). The response should be evaluated after 3 months treatment, and if weight loss is less than 5%, the treatment should be stopped.
Liraglutide 3.0 mg has been developed for treatment of obesity and was approved in the USA in 2014 and in Europe in 2015. In a dose-finding study of 1.2, 1.8, 2.4, and 3.0 mg doses, it became clear that 3.0 mg was the most effective dose for inducing weight loss (4.8, 5.5, 6.3, and 7.2 kg, respectively) (Astrup et al. 2009).
In the SCALE-Obesity and Prediabetes study with a duration of 56 weeks, 3731 subjects were included, 2285 of whom had prediabetes, a baseline weight of about 106 kg, and BMI about 38 kg/m2 (Pi-Sunyer et al. 2015). The prediabetes group was followed for 160 weeks to assess the ability of liraglutide to delay the onset of progression to type 2 diabetes. After 56 weeks the weight loss was 8 kg in the liraglutide group compared with 2.6 kg in the placebo group. In total 63.2% versus 27.1% and 33.1% versus 10.6% lost more than 5% or 10% of body weight in the liraglutide and placebo group, respectively (Pi-Sunyer et al. 2015). In total 9.9% and 3.8% withdrew due to adverse events in the liraglutide and placebo groups (Pi-Sunyer et al. 2015). Liraglutide was associated with a reduced progression to prediabetes (7.2% vs. 20.7%) and increased reversal of prediabetes (69.2% vs. 32.7%).
In a follow-up after 160 weeks, 2254 participants with prediabetes 1128 had completed the study (Roux et al. 2017). At week 160 2% in the liraglutide group compared with 6% in the placebo group were diagnosed with diabetes while on treatment. The time to onset of diabetes was 2.7 times longer with liraglutide than with placebo, corresponding to a hazard ratio of 0.21 (Roux et al. 2017). Weight loss was greater with liraglutide (−6.1% vs. −1.9%) than with placebo. In a post hoc analysis for individuals who lose >5% body weight after 16 weeks of treatment, the weight loss was 12% after 1 year and 8.6% at week 160, where 37% and 19% have a weight loss of 10% and 15%, respectively. Thus, early responders achieved greater long-term weight loss than non-responders, and fewer early responders developed type 2 diabetes, and more regressed to normoglycemia while on treatment.
In the SCALE-Diabetes study, 846 patients with type 2 diabetes and a BMI of 37 kg/m2 (106 kg) were followed for 56 weeks and randomized to liraglutide 3.0 mg, 1.8 mg, or placebo (Davies et al. 2015). The weight loss was 6.4 kg, 5.0 kg, and 2.0 kg, corresponding to 54.3%, 40.4%, and 21.4% obtaining a weight loss of at least 5% and 25.2%, 15.9%, and 6.7% obtaining a weight loss of more than 10%. The reduction in HbA1c was −1.3%, −1.1%, and −0.3%, respectively (Davies et al. 2015).
In the SCALE Maintenance trial, overweight subjects (BMI 38 kg/m2, 106 kg) undertook a 1200–1400 kcal/day diet (Wadden et al. 2015) and entered into the trial if they managed to lose >5% in body weight after 12 weeks. The mean weight loss at randomization was 6%. After 1 year, 6.2% more weight loss was obtained with liraglutide than those on placebo (−0.2%). An extra weight loss of >10% was obtained by 26.1% versus 6.3%, respectively (Wadden et al. 2015).
In a randomized study, liraglutide induced a significant reduction in obstructive sleep apnea compared with placebo (Blackman et al. 2016). Recently a 5-week trial that assesses safety and tolerability of 3.0 mg liraglutide in obese adolescents aged 12–17 years concluded that dosing regimen for adults may be appropriate for use in adolescents (Danne et al. 2017).
In the SCALE studies, small reductions in LDL, VLDL, triglycerides, and systolic and diastolic blood pressure were reported.
The adverse events to liraglutide 3.0 mg were the usual gastrointestinal events including nausea, diarrhea, constipation, and vomiting but also gallbladder disease. Nausea peaked after 4 weeks of treatment and subsided thereafter. Liraglutide was associated with a small increase in heart rate, between 2 and 4 beats/min. Gallbladder-related complications including cholelithiasis and cholecystitis were more common in the liraglutide arms. No incidence of medullary thyroid cancer was reported. Hypoglycemia was not a problem during the studies (Pi-Sunyer et al. 2015; Roux et al. 2017; Davies et al. 2015).
Liraglutide 3.0 mg has demonstrated superior weight loss compared with orlistat, but has not been compared with other weight loss medications (Astrup et al. 2012). Tolerability may be problematic for some patients, although it partly can be avoided by a slower up-titration than 0.6 mg per week. Liraglutide 3.0 mg is expensive, and it is currently priced much higher than other pharmacological agents for the treatment of obesity. Patients who may particularly benefit from liraglutide 3.0 mg are those who have prediabetes due to its glucose-lowering effect and potential to delay the progression from prediabetes to diabetes (Pi-Sunyer et al. 2015; Roux et al. 2017). The appropriate duration of treatment is not established, but obesity is a chronic disease, and the weight loss effects are only sustained as long as liraglutide is taken .
In a phase 2 study obese patients treated with semaglutide 0.4 mg daily lost up to 13.8% of body weight after 52 weeks compared with 2.3% in the placebo group. In the semaglutide group 65% lost more than 10% of their body weight (O’Neil PM et al. Presented at ENDO March 2018 (OR12)). Semaglutide is at present in phase 3 development as an obesity drug.
Future Perspective of GLP-1 RAs
In light of the relatively narrow therapeutic window defined by the balance between efficacy and gastrointestinal side effects, future subcutaneously administered long-acting GLP-1 RAs will probably not provide much better efficacy than observed with, for instance, semaglutide. In the future, the oral administration of GLP-1 or GLP-1 enhancers may be of interest to increase the treatment compliance (Meier and Nauck 2015). Oral GLP-1 for once-daily administration is in phase 3 development, and in a dose-finding study, 40 mg of oral semaglutide reduced HbA1c with 1.9% from a baseline of 7.9%. Reduction in weight was 6.9 kg (Davies M et al. JAMA 2017; 318: 1460–70).
In rodents, co-agonism at the GLP-1 and glucagon receptors has been investigated to achieve weight loss. Rats treated with co-agonism achieved superior weight loss without induction of hyperglycemia compared to rats treated with GLP-1 receptor-selective agonists (Day et al. 2012).
Peptide YY (PYY) is secreted from intestinal L cells and reduces appetite; co-agonism stimulating both the GLP-1 and PYY receptor pathways reduced food intake in humans in experimental studies (De et al. 2011; Tan et al. 2014). Similarly co-agonism with several hormones may open up new treatments for T2DM and obesity. Recently, the first 12 weeks clinical study in patients with type 2 diabetes was published showing sustained effects of a dual GIP/GLP-1 receptor agonist (Frias et al. 2017). The agonist significantly improved glycemic control and reduced body weight, total cholesterol, and leptin compared with placebo.
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