Growing experience with GLP-1 receptor agonists



by J. F. Raposo, Portugal

Sten MADSBAD, DMSc
Department of Endocrinology
Hvidovre Hospital
University of Copenhagen
DENMARK

Over the last decade, the development of glucagon-like peptide-1 (GLP-1) receptor agonists has increased the treatment options for patients with type 2 diabetes mellitus. GLP-1 receptor agonists mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases satiety, and slows gastric emptying. All GLP-1 receptor agonists decrease HbA1c, fasting plasma glucose, and lead to a reduction in body weight in the majority of trials. Head-to-head trials report that the long-acting liraglutide and dulaglutide show the most consistent superiority in lowering HbA1c, while the weight loss is quite similar to short-acting and long-acting receptor agonists. The most common adverse events are nausea and other gastrointestinal discomfort, while hypoglycemia is rarely reported when GLP-1 receptor agonists are not combined with sulfonylurea or insulin. Treatment options in the near future will include continuous subcutaneous delivery of exenatide via an osmotic pump and coformulations of basal insulin and a GLP-1 receptor agonist. The of GLP-1 receptor agonists in patients with type 1 diabetes and the treatment of obesity is also discussed in the review.

The use of glucagon-like peptide-1 (GLP-1) receptor agonists has expanded the treatment options for type 2 diabetes over the last decade.1 GLP-1 receptor agonists have become popular because of their efficacy and durability in relation to glycemic control, which is associated with weight loss in most patients.2 GLP-1 receptor agonists mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases satiety, and slows gastric emptying.2 The most common adverse events are nausea and other gastrointestinal discomforts, while hypoglycemia is rarely reported when GLP-1 receptor agonists are not combined with sulfonylurea or insulin.2 The drawbacks of GLP-1 receptor agonists include the subcutaneous administration, gastrointestinal side effects, and cost.2

The six GLP-1 receptor agonists approved in Europe and the US are included in the present review. GLP-1 receptor agonists differ substantially in their molecular structures and sizes, chemical and physiological properties, and duration of action (Table I, page 220).3 Exenatide twice daily and lixisenatide once daily are short-acting agents. Liraglutide is, from a physiological point of view, considered long-acting, and it is administered once daily, while the very long-acting agents, including exenatide long-acting release, albiglutide, and dulaglutide, are administered once weekly.3

This review will first present the head-to-head comparisons of GLP-1 receptor agonists and will subsequently discuss the cardiovascular end point trials with GLP-1 receptor agonists. The use of GLP-1 receptor agonists in the treatment of patients with type 1 diabetes or obesity will also be examined. Lastly, the future aspects of GLP-1-based therapy will be mentioned, including fixed combinations of basal insulin and GLP-1 receptor agonists and the continuous administration of exenatide for months using a small osmotic minipump.

Head-to-head comparisons of GLP-1 receptor antagonists

Currently, six GLP-1 receptor agonists are approved for treating type 2 diabetes3: the short-acting exenatide twice daily and lixisenatide once daily; and the longer-acting liraglutide once daily, exenatide once weekly, albiglutide once weekly, and dulaglutide once weekly (Table I). The phase 3 trial of a seventh GLP-1 receptor antagonist, taspoglutide once weekly, was stopped due to unacceptable adverse events.3

Table I. Characteristics of GLP-1 receptor agonists.
Abbreviations: DPP-4, dipeptidyl peptidase-4 inhibitor; GLP-1, glucagon-like peptide 1.
From reference 3: Madsbad S. Diabetes Obes Metab. 2016;18:317-332. © 2016, The Authors.

Ten phase 3 head-to-head trials with a duration of 24 to 30 weeks have compared the efficacy and safety of these seven GLP-1 receptor agonists.4-13 All trials were associated with notable reductions in HbA1c, although liraglutide led to greater decreases than exenatide formulations and albiglutide. The HbA1c reductions did not differ between liraglutide and dulaglutide (Figure 1, page 222).3-13 As the short-acting GLP-1 receptor agonists delay gastric emptying, they had greater effects on postprandial glucose levels than the longer-acting agents, whereas the longer-acting compounds reduced plasma glucose throughout the 24-hour period studied.3 The reduction in HbA1c ranged from 0.3% to 1.9% (Figure 1).4-13 Liraglutide was associated with weight reductions similar to those with exenatide twice daily, but greater than those with exenatide once weekly, albiglutide and dulaglutide (Figure 2, page 223).3-13 The mean weight loss was between 1.4 kg and 4.3 kg (Figure 2).

The most frequently observed adverse events with GLP-1 receptor agonists were gastrointestinal disorders, particularly nausea, vomiting, and diarrhea; however, nausea occurred less frequently with exenatide once weekly and albiglutide, than with exenatide twice daily and liraglutide.4-13 Both exenatide formulations and albiglutide may be associated with higher incidences of injection-site reactions than are liraglutide and dulaglutide.4-13 The GLP-1 receptor agonists used in clinical practice should be customized for individual patients, based on their clinical profile and patient preference.

Cardiovascular end point studies with GLP-1 receptor agonists

The ELIXA trial (Evaluation of LIXisenatide in Acute coronary syndrome) assessed the effect of the short-acting lixisenatide on cardiovascular outcomes in 6068 patients with type 2 diabetes and a recent acute coronary event.14 The primary end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina did not differ between the lixisenatide and placebo groups after a median 25-month follow- up.14up> There was also no differences in heart failure or death. Lixisenatide treatment was not associated with a higher risk of hypoglycemia, pancreatitis, or pancreatic neoplasm.14

The safety of liraglutide was evaluated in the LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results), a double-blind trial, including 9340 patients with type 2 diabetes with a mean 3.8-year follow- up.15 Patients included had cardiovascular disease or were at a high risk of developing cardiovascular disease. The primary end point of death, nonfatal myocardial infarction, and nonfatal stroke was reduced by 13% (P<0.001), mortality of cardiovascular disease by 22% (P=0.007), and death from any cause by 15%, (P=0.002).15 The incidence of pancreatitis was nonsignificantly lower in the liraglutide group. There was a significant reduction in severe hypoglycemic episodes in the liraglutide group. A subgroup analysis showed a benefit with liraglutide in patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.72 m2 compared with those with higher eGFR values and in patients with established cardiovascular disease compared with patients with risk factors for cardiovascular disease.15 In total, 66 patients should be treated for 3 years to prevent one primary end point and 98 patients to prevent one death from any cause.15

Figure 1. Reduction in HbA1c in published phase 3 randomized head-to-head studies of GLP-1 receptor agonists in type 2 diabetes.
Study durations ranged from 24 to 30 weeks. 1% change in HbA1c corresponds to a 10.93 mmol/mol change in The International Federation of Clinical Chemistry
units. *Noninferiority criteria met. †Noninferiority criteria not met.
Abbreviations: AWARD, Assessment of Weekly AdministRation of LY2189265 (dulaglutide) in Diabetes; BID, twice daily; DURATION, Diabetes therapy Utilization:
Researching changes in A1c , weight and other factors Through Intervention with exenatide ONce weekly; GetGoal-X, efficacy and safety of lixisenatide once daily
versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin; GLP-1, glucagon-like peptide-1; HARMONY, once-weekly albiglutide versus
once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs; LEAD, effect of Liraglutide or Exenatide Added to an ongoing treatment
on blood glucose control in subjects with type 2 Diabetes; OD, once daily; OW, once weekly; T-emerge 2, taspoglutide vs exenatide as add-on treatment to metformin
and/or thiazolidinediones in patients with type 2 diabetes mellitus.
Adapted from reference 3: Madsbad S. Diabetes Obes Metab. 2016;18:317-332. © 2016, The Authors.

The GLP-1 receptor agonist semaglutide once weekly was evaluated in two doses (0.5 mg or 1.0 mg) vs placebo in 3297 type 2 diabetic patients.16 At baseline, 83% had established cardiovascular disease, chronic kidney disease, or both. After a 104-week follow-up, the primary outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was reduced by 26% (P<0.001), nonfatal myocardial infarction by 26% (P=0.12), and nonfatal stroke by 39% (P=0.04).16 The rate of death was similar in the two groups. To prevent one primary end point, 45 patients would need to be treated for 2 years. With semaglutide, the rates of new or worsening nephropathy were lower, but the rates of retinopathy complications were significantly higher16; however, the reason why semaglutide causes worsening retinopathy is currently unknown. Semaglutide is in phase 3 development, and it will probably be on the market within the coming years.

The short-acting lixisenatide has a neutral effect on the risk of cardiovascular disease, whereas liraglutide and semaglutide reduced this risk; however, the mechanism is unknown. One suggestion is that liraglutide and semaglutide have some beneficial effects on the progression of atherosclerosis. The GLP-1 receptor agonists also have beneficial effects on blood pressure, weight, and postprandial lipid disturbances, but these effects do not seem to explain the findings. How did the randomized studies—ELIXA, LEADER, and SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes)—on lixisenatide and liraglutide achieve such different results?14-16

First, the patients in ELIXA appeared to be at a higher risk for cardiovascular disease than did the patients in LEADER and SUSTAIN-6. Lixisenatide has a shorter half-life, with only 8 hours of coverage per day, while liraglutide and semaglutide provide 24-hour coverage. Further molecular differences also exist (Table I). An ongoing discussion is whether the cardiovascular benefits in LEADER and SUSTAIN-6 can be considered a class effect of the long-acting human GLP-1 receptor agonists or whether they might be specific for the liraglutide molecule. Results from additional end-point studies—EXSCEL (EXenatide Study of Cardiovascular Event Lowering trial; Exenatide once weekly), FREEDOM-CVO (Evaluate Cardiovascular Outcomes in Patients With Type 2 Diabetes Treated With ITCA 650), and REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes; dulaglutide)—will be published in the future.

Figure 2. Reduction in weight in published phase 3 randomized head-to-head studies of GLP-1 receptor agonists in type 2 diabetes.
Study durations ranged from 24 to 30 weeks. *Difference was not significant at week 24, although it was significant at week 20. †Not stated if difference was significant.
‡Data shown at week 24; however, at week 52, weight loss was significantly lower in the taspoglutide 10 mg versus exenatide group (P=0.01).
Abbreviations: AWARD, Assessment of Weekly AdministRation of LY2189265 (dulaglutide) in Diabetes; BID, twice daily; DURATION, Diabetes therapy Utilization:
Researching changes in A1c, weight and other factors Through Intervention with exenatide ONce weekly; GetGoal-X, efficacy and safety of lixisenatide once daily
versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin; GLP-1, glucagon-like peptide-1; HARMONY, once-weekly albiglutide versus
once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs; LEAD, effect of Liraglutide or Exenatide Added to an ongoing treatment
on blood glucose control in subjects with type 2 Diabetes; OD, once daily; OW, once weekly; T-emerge 2, taspoglutide vs exenatide as add-on treatment to metformin
and/or thiazolidinediones in patients with type 2 diabetes mellitus.
Adapted from reference 3: Madsbad S. Diabetes Obes Metab. 2016;18:317-332. © 2016, The Authors.

GLP-1 receptor agonists: a new option to treat obesity

Obesity is known as a risk factor for common diseases, such as cardiovascular disease, type 2 diabetes, cancer, osteoarthritis, and it reduces the quality of life.17 Obesity guidelines recommend that pharmacological therapy is a possible adjunctive therapy to diet, exercise, and behavior modification in certain patients.18 Weight loss medications can be considered in adults with a BMI ≥30 kg/m2 or in patients with a BMI of 27 kg/m2 and at least one weight-related comorbidity, ie, hypertension, dyslipidemia, or type 2 diabetes.18 The response should be evaluated after 3 months of treatment; however, if the weight loss is <5%, the treatment should be stopped.

Liraglutide 3.0 mg has been developed to treat obesity. In the 56-week SCALE–obesity and prediabetes study (Satiety and Clinical Adiposity — Liraglutide Evidence in nondiabetic and diabetic individuals), 3731 subjects were included, 2285 with prediabetes and a baseline weight around 106 kg.19 The prediabetes group was followed-up for 160 weeks to assess the ability of liraglutide to delay the onset of progression to type 2 diabetes. After 160 weeks, 3% of participants developed type 2 diabetes in the liraglutide group vs 11% in the placebo group. 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% vs 27.1% and 33.1% vs 10.6% lost more than 5% and 10% of weight in the liraglutide and placebo groups, respectively.19 In total, 9.9% and 3.8% withdrew due to adverse events in the liraglutide and placebo groups.19

In the 56-week SCALE-Diabetes study, 846 patients with type 2 diabetes were randomized to liraglutide 3.0 mg, liraglutide 1.8 mg, or placebo.20 The weight loss was 6.4 kg, 5.0 kg, and 2.0 kg, which corresponded to the 54.3%, 40.4%, and 21.4% who obtained a weight loss of at least 5%, and the 25.2%, 15.9%, and 6.7% with a weight loss >10%. The reduction in HbA1c was –1.3%, –1.1%, and –0.3%, respectively.20 The adverse events of liraglutide 3.0 mg included the usual gastrointestinal events, such as nausea, diarrhea, constipation, and vomiting, and gallbladder disease. Hypoglycemia was not a problem during the studies.19,20

Liraglutide 3.0 mg provided a superior weight loss than orlistat, but these results have not been compared with other weight loss medications.21 Tolerability may be problematic for some patients, although it can be partly avoided by using an uptitration that is slower than 0.6 mg/week. Liraglutide 3.0 mg is expensive; it is currently priced much higher than other pharmacological agents for the treatment of obesity. Patients with prediabetes may particularly benefit from liraglutide 3.0 mg because of its glucose-lowering effect and its potential to delay the progression from prediabetes to diabetes.19 The appropriate duration of treatment has not been established, but obesity is a chronic disease, and the effects of weight loss are only sustained for as long as liraglutide is taken.

Treatment of patients with type 1 diabetes using GLP-1 receptor agonists

Type 1 diabetes is characterized by severely impaired or absent insulin secretion combined with abnormal α-cell function with excess glucagon in the fasting and postprandial state.22,23 Insulin treatment only partly addresses the pathophysiological excess of glucagon and even the most rapid-acting mealtime insulin peaks too late to match the postprandial glucose absorption resulting in large postprandial glucose excursions. Intensive insulin treatment is associated with weight gain, and, in patients with type 1 diabetes, approximately 50% are overweight in economically developed countries.24 In theory, treatment regimens in type 1 diabetes may be improved by combining insulin with a GLP-1 receptor agonist. Results from open-label, short, and small clinical trials indicate that GLP-1 receptor agonist treatment induces weight loss and reduces insulin requirements, with either improved or unaltered glycemic control.25 Liraglutide was tested in most of the trials.

In the first placebo-controlled trial of patients with a normal weight and type 1 diabetes, liraglutide 1.2 mg once daily had no effect on HbA1c or glycemic variation compared with placebo.26 The change in body weight was –3.13 kg vs +1.12 kg (P<0.0001) with liraglutide vs placebo, respectively. The bolus insulin dose decreased in liraglutide-treated patients, but it did not change with placebo treatment (–4.0±1.3 IU vs 0.0± 1.0 IU; P=0.02), and systolic blood pressure decreased vs placebo (between-group difference, 3.21 mm Hg; P=0.04).26 The incidence of hypoglycemia did not differ between groups.

In the second trial with obese patients with type 1 diabetes, HbA1c and glycemic variability did not differ between liraglutide 1.8 mg and placebo after 24 weeks of treatment, but liraglutide reduced the number of hypoglycemic events,27 bolus insulin (difference, –5.8 IU),and body weight (difference, –6.8 kg) compared with placebo. However, liraglutide increased heart rate, with a between-group difference of 7.5 bpm.27

In the randomized, double-blind, placebo-controlled ADJUNCT ONE trial (efficacy and safety of liraglutide as ADJUNCT therapy to insulin in the treatment of type 1 diabetes), liraglutide 0.6 mg, 1.2 mg, 1.8 mg, and placebo as an adjunct to insulin treatment were investigated in 1398 patients with type 1 diabetes for 52 weeks.28 From a mean baseline HbA1c of 8.2%, those treated with 1.2 mg and 1.8 mg showed a numerically greater improvement in HbA1c (0.5%) compared with placebo (0.3%).28 From a baseline body weight of 86 kg, patients treated with 1.2 mg and 1.8 mg achieved a statistically significant 3 to 4 kg weight loss, whereas the placebo groups experienced an approximate 1 kg weight gain.28 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 patients treated with liraglutide 1.2 mg and 1.8 mg compared with those treated with placebo.28

In the 26-week, double-blind, placebo-controlled ADJUNCT TWO trial (efficacy and safety of liraglutide ADJUNCT to insulin treatment in type 1 diabetes), 835 participants were enrolled in and assigned to liraglutide 0.6 mg, 1.2 mg, 1.8 mg, or placebo. 29 The maximum insulin dose was fixed for all treatment arms. From a baseline HbA1c of 8.1%, there was a statistically significant improvement in HbA1c of 0.23%, 0.22%, and 0.33% for the groups treated with liraglutide 0.6 mg, 1.2 mg, and 1.8 mg, respectively, compared with unaltered glycemic control in the placebo-treated group.29 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 kg to 5 kg, whereas the weight was stable in the placebo-treated patients.29 A higher rate of symptomatic hypoglycemia was observed among patients treated with liraglutide 1.2 mg compared with placebo treatment. The incidence of severe hypoglycemia and nocturnal hypoglycemia did not differ between groups.29

In C-peptide positive patients, a significant effect of liraglutide was found in relation to the reduction in HbA1c (–0.77% and –0.69% for 1.8 mg and 1.2 mg liraglutide, respectively).29

Thus, GLP-1 receptor agonists reduce body weight and insulin dose with improved or unaltered glycemic control, without an increased risk of hypoglycemia.25 The effect on HbA1c is conflicting with small, uncontrolled studies showing the most positive findings.25 In the randomized, placebo-controlled studies, no effect on HbA1c and glucose variability was reported compared with placebo treatment.25 One area of interest is treatment with a GLP-1 receptor agonist from the time of diagnosis to improve and prolong the remission phase during the first years after diagnosis. Animal and in vitro human models show that GLP-1 receptor agonists preserve β cells from destruction.30 As a result, the use of GLP-1 receptor agonists in new-onset type 1 diabetes is currently being investigated in clinical trials. It is unknown whether treatment with a GLP-1 receptor agonist has a future in C-peptide–negative type 1 diabetes, especially when considering the costs.

Fixed-ratio combination therapy with a GLP-1 receptor agonist and basal insulin

Combination therapy with basal insulin and a GLP-1 receptor agonist is very popular, and a recent meta-analysis suggests that basal insulin in combination with a GLP-1 receptor agonist provides superior glycemic control, with no increase in hypoglycemic episodes or weight gain, as compared with basal insulin alone.31 The fixed-ratio combinations of basal insulin and GLP-1 receptor agonists—degludec and liraglutide (IDeg- Lira; 50 units degludec/1.8 mg liraglutide) under the brand name Xultophy 100/3.6; glargine and lixisenatide (100 units glargine/33 μg lixisenatide) under the brand name Soliqua 100/33—have been developed as once-daily injections for the treatment of type 2 diabetes. Both combinations have been approved by the FDA and EMA.

Figure 3. ITCA 650 utilizes a novel drug-delivery technology to provide a continuous and controlled subcutaneous delivery of exenatide
for as long as 1 year of treatment at a precise and predetermined rate.
Initiating treatment with ITCA 650 involves the subcutaneous placement of a matchstick-sized osmotic mini-pump, which is done during a short office procedure that
can be performed by a physician, physician’s assistant, or other licensed practitioner. ITCA 650 consists of a cylindrical titanium alloy reservoir with external dimensions
of 4 mm in diameter by 44 mm in length. The reservoir is capped at one end by a controlled-rate, semi-permeable membrane and capped at the other end by
a diffusion moderator through which the drug formulation is released from the drug reservoir. The drug formulation, piston, and osmotic engine are contained inside
the cylinder. ITCA 650 releases the drug at a predetermined rate based on the principle of osmosis. Water from the extracellular space enters through the semipermeable
membrane directly into the osmotic engine that expands to drive the piston at a slow and consistent rate of travel.
From reference 40: Henry et al. Clin Ther. 2013;35:634-645. © 2013, The Authors. Published by Elsevier Inc. Credit: Intarcia Therapeutics, Inc.

IDegLira reduces HbA1c more than monotherapy with either a GLP-1 receptor agonist (liraglutide) or insulin (degludec or glargine).32-35 Furthermore, combination therapy leads to weight loss or a stable body weight, with no increase in hypoglycemia. These results are found in both insulin-naive and insulin-treated patients with type 2 diabetes, independent of diabetes duration and baseline HbA1c.32-35 Rates of adverse events did not differ between treatment groups; however, there were fewer gastrointestinal side effects with IDegLira compared with liraglutide treatment alone.32-35

The combination of once-daily insulin glargine and the shortacting GLP-1 receptor agonist lixisenatide (iGlarLixi, formerly known as LixiLan) should be injected about 1 hour before the biggest meal.36-38 In a phase 3 program, Soliqua 100/33 demonstrated a better HbA1c reduction vs glargine in the majority of patients (55% vs 30% achieving the target of <7%).36-38Patients in the Soliqua 100/33 arm had similar rates of hypoglycemia than the patients in the glargine arm. Soliqua 100/33 will be available as a single prefilled pen covering 15 to 60 units of insulin glargine and 5 to 20 μg of lixisenatide.36-38 Compared with liraglutide, lixisenatide is a short-acting GLP-1 receptor agonist that is based on the structure of exendin-4, with a half-life of approximately 3 hours. Lixisenatide has a more pronounced effect on postprandial plasma glucose excursions in relation to the meal following the injection than liraglutide. Adding a short-acting GLP-1 receptor agonist may be a more convenient intensification strategy compared with adding rapid-acting insulin at mealtime because the fixed dosing does not require adjustments for meal size and carbohydrate content. A limitation with iGlarLixi may be the short duration of action of lixisenatide and the once-daily administration given 30 to 60 minutes before one of the main meals, while IDegLira can be taken independently of meals. A head-to-head comparison with LixiLan and IDeglirawill be of interest.

Intarcia (ITCA) 650

ITCA 650 is a new and interesting concept, which provides a consistent and continuous subcutaneous delivery of exenatide via an osmotic minipump (the size of a matchstick, see Figure 3) to treat patients with type 2 diabetes.39-41 In the phase 3 FREEDOM program, which also included a cardiovascular end point study, more than 5000 patients with type 2 diabetes were enrolled.39-41 In the trials, the mini-pumps were given with a 3- month introductory dose of 20 μg/day followed by a 6-month maintenance dose of 60 μg/day. A 12-month mini-pump with a delivery dose of 60 μg/day is being developed with the goal to deliver exenatide with a once- or twice-yearly application of the pump. In FREEDOM 2, ITCA 650 (baseline HbA1c, 8.6%) reduced HbA1c by 1.5% vs 0.8% with sitagliptin. Weight changes were –4.0 kg and +1.3 kg, respectively. Regarding tolerability, ITCA 650 treatment is superior to exenatide twice daily.39 The adverse events were the well-known gastrointestinal events seen with GLP-1 receptor agonists; the placement and removal of ITCA were well tolerated.39-41

Commentary

GLP-1 receptor agonists are becoming increasingly popular for the treatment of type 2 diabetes due to their favorable profile for HbA1c lowering, positive effects on weight loss, low risk of hypoglycemia, and influence on cardiovascular risk factors.2 Their superiority to oral antidiabetic drugs has been demonstrated in most studies, with greater reductions in both HbA1c and weight.2 The fear of injections will, in some patients, remain a barrier to the use of GLP-1 receptor agonists, but this problem can be reduced by using the long-acting agonists for once-weekly injections or ITCA 650. Compared with insulin, GLP-1 receptor agonists are much easier to initiate, with a lower need for dose titration and blood glucose monitoring.2 Furthermore, for patients in whom weight loss is advisable, GLP-1 receptor agonists could be an option instead of insulin, which, for many patients, is associated with weight gain. The addition of a GLP-1 receptor agonist to insulin treatment has been suggested to improve glycemic control, help patients lose weight, and reduce the need for insulin.31

GLP-1 receptor agonists are generally well tolerated. The main side effects are gastrointestinal—ie, nausea and vomiting— which often are transient and can be partly avoided by slowly uptitrating the dose.2,33 GLP-1 receptor agonists are not recommended for patients with impaired kidney function (eGFR <30 mL/min) or elderly patients with a reduced appetite. At present, no clear evidence of a causal relationship between GLP-1 receptor agonists and pancreatitis or pancreatic cancer exists.2,14-16 The major drawback of GLP-1 receptor agonists is the higher cost compared with that of other antidiabetic agents.

Future perspective

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 receptor agonists will probably not provide much better efficacy. In the future, the oral administration of GLP-1 or GLP-1 enhancers may be of interest to increase treatment efficacy.42

Oral GLP-1 as a once-daily administration is in phase 3 development, and, in a dose-finding study, 40 mg of oral semaglutide reduced HbA1c by 1.9% from a baseline of 7.9%. Reduction in weight was 6.9 kg (Davies M et al; presented at the 2016 EASD congress).

In rodents, co-agonism at the GLP-1 and glucagon receptors has been investigated to achieve weight loss. The rodents treated with coagonism achieved superior weight loss without the induction of hyperglycemia compared with the rats treated with GLP-1 receptor–selective agonists.43 Peptide YY (PYY) is secreted from intestinal L-cells and reduces appetite; co-agonism that stimulates both the GLP-1 and PYY receptor pathways has been shown to reduce food intake in humans in preclinical studies.44,45 The co-agonism of several hormones may open up new treatments for type 2 diabetes and obesity. ■

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Keywords: cardiovascular trial; fixed-ratio insulin; GLP-1 receptor agonist; head-to-head comparison; ITCA 650; obesity; type 1 diabetes