Drug Review - GLP-1 Receptor Agonists

Mode of action 

Pharmacology

Glycaemic efficacy and clinical use

Microvascular outcomes

Macrovascular and mortality outcomes

Adverse events and precautions

Recommendations

The incretin effect is discussed in the introduction to incretin based therapies (See: Drug Review - Dipeptidyl peptidase-4 Inhibitors .) The main advantage of GLP-1 receptor agonists (GLP-1RA) is glycaemic efficacy without weight gain or hypoglycaemia. Their non-glycaemic benefits include positive effects on weight loss, blood pressure and cholesterol levels.

MODE OF ACTION 

GLP-1RAs are modified GLP-1 molecules that have structural homology with endogenous GLP-1 but are resistant to the enzymatic cleavage by DPP-4, resulting in a longer duration of action. Pharmacological dosing and prolongation of the half-life results in persistent supra- physiological levels of GLP-1, which increases insulin secretion, decreases glucagon release, enhances satiety and delays gastric emptying.

PHARMACOLOGY 

Table I below compares  the  pharmacological  and  other  properties of the two available in South Africa. They are both available only as injectables in the form of multi-dose pens, and are administered by subcutaneous injection; liraglutide is dosed once daily while exenatide is administered twice daily. The peak exenatide concentrations after meals results in a better post- prandial glucose lowering compared to liraglutide which has better efficacy at lowering fasting glucose^.1 This difference can be useful therapeutically in selected patients.

Table I: Comparison of available GLP-1 receptor agonists

When using a GLP-1RA in combination with sulphonylureas, a lower dose of sulphonylurea may be required as hypoglycaemia may occur more frequently.
**Post-marketing reports of acute kidney injury reported in patients with pre-existing kidney disease. Use with caution in patients with chronic kidney disease.

GLYCAEMIC EFFICACY AND CLINICAL USE 

Exenatide and liraglutide are examples of GLP-1RAs that are currently available in South Africa. The main advantage is that unlike most other diabetes drugs, the GLP-1RAs promote weight loss and do not cause hypoglycaemia when used alone. The GLP-1RAs are approved for combination therapy with metformin and/or sulphonylureas. However, adding a GLP-1RA also remains an attractive option to intensify insulin therapy, especially when basal insulin is failing. Advantages of adding a GLP-1RA may include a reduction in total insulin requirements, lower risk of hypoglycaemia and possible weight-loss/prevention of weight gain when compared to intensifying insulin therapy with premix, basal-plus or basal-bolus. A systematic review and meta-analysis of randomised control trials comparing the combination of GLP-1RA and basal inulin to intensifying insulin therapy alone found greater reductions in  HbA_1C with combination therapy (WMD -0.47%; 95% CI -0.59 to -0.35) and a significant weight-loss advantage (WMD -2.5 kg; 95% CI -3.3 to -1.7).⁵ Exenatide is registered for add-on therapy to basal insulin with or without oral antidiabetic therapy in South Africa. Exenatide is initiated at a dose of 5 ug BD, any time within 60 minutes before the morning and evening meals, but the maximum and most effective dose is 10ug BD. The most cost-effective dose of liraglutide is 1.2 mg, as the 1.8 mg is only marginally more effective in lowering HbA_1C.^6,7,8

The LEAD 6 study compared Liraglutide 1.8 mg and exenatide 10 ug twice daily as add-on therapy to metformin + sulphonylurea¹ .The mean HbA_1C reduction was  -1.1%  for liraglutide vs. -0.8% for exenatide. Mean weight loss was similar (~3kg). Discontinuation rates for liraglutide and exenatide were 14% and 19%, and more subjects experienced severe and serious adverse events with liraglutide (29/235) than exenatide (17/232); nausea was less persistent with liraglutide.¹ There are no clinical trials comparing liraglutide 1.2 mg OD with exenatide 10 ug BD.

MICROVASCULAR OUTCOMES

There are no dedicated microvascular outcome studies for GLP-1RAs. In the LEADER trial the incidence of a composite exploratory outcome of renal or retinal microvascular events was lower in the liraglutide group than in the placebo group (hazard ratio, 0.84; 95% CI, 0.73 to 0.97; P=0.02).⁹ This benefit was driven by lower rates of renal outcomes, such as new-onset persistent macroalbuminuria. With moderate differences in glycaemic control between the trial groups over a median 3.8 years of follow-up, the achievement of renal microvascular benefits raises uncertainty about whether this is related to better glycaemic control or a drug effect. In the LEADER trial, there was also a higher rate of retinopathy events with liraglutide than with placebo (HR 1.15), although the difference was not significant⁹.However, in the SUSTAIN 6 trial (using the GLP-1RA semaglutide), there was an unexpected higher rate of retinopathy complications in the semaglutide group though the actual overall numbers were small.¹⁰ There remains uncertainty about the microvascular effects of GLP-1RAs and more long-term studies addressing this issue are needed.

MACROVASCULAR AND MORTALITY OUTCOMES 

The cardiovascular outcomes trials with GLP-1RAs are all safety trials which have been mandated by regulatory authorities, and were primarily designed to demonstrate cardiovascular safety of the product when compared to conventional treatments plus placebo, at equivalent HbA_1C, i.e. the trials are meant to test the safety of the drug, not the effect of improved glycaemic control. All these trials recruited patients with either established cardiovascular disease or those who had multiple risk factors for cardiovascular disease. Results of these outcome trials are summarised in Table II. In the ELIXA trial, lixisenatide was non-inferior to conventional glucose lowering therapy.¹¹ In the LEADER trial liraglutide 1.8 mg was superior to conventional treatment, and was associated with a 13% relative risk reduction (RRR) in the primary composite outcome (death from cardiovascular causes,nonfatal myocardial infarction, or nonfatal stroke – 3 point MACE) compared to placebo.⁹ HbA_1C was not equivalent as there was a significant 0.4% HbA_1C difference in in favour of liraglutide, so it is not possible to conclude whether the improvement was the result of better glycaemic control or a specific effect of the drug. The beneficial effect on the composite outcome was driven by a reduction in cardiovascular mortality (RRR=22%) and all cause mortality (RRR=15%); there was no difference in rates of non-fatal myocardial infarction, non-fatal stroke, and hospitalisation for heart failure. The calculated numbers needed to treat (NNT) to prevent one MACE, CV death and all cause death with liraglutide 1.8 mg were 66, 104 and 98 respectively.

In the SUSTAIN-6 trial the treatment effect of semaglutide 0.5 and 1.0 mg (not yet available in South Africa) for a relatively short duration (2.1 years) in diabetic patients with high CV risk, resulted in a significant 26% lower risk of the primary composite outcome than did those receiving placebo.¹⁰ Similar to the LEADER trial, there was a significant HbA_1C difference between treatment groups. In both SUSTAIN-6 and LEADER, the subgroups of patients without established cardiovascular disease did not benefit significantly from the intervention. There are no cardiovascular outcomes trials with exenatide. The EXSCEL trial is currently underway to examine the long-term effects of exenatide-LAR 2 mg weekly on cardiovascular and mortality outcomes.

GLP-1RAs are consistently associated with slight blood pressure lowering. The conclusion is that liraglutide and semaglutide have proven cardiovascular safety, and has evidence for improved cardiovascular outcomes when used to improve glycaemic control in patients with established cardiovascular disease.

ADVERSE EVENTS AND PRECAUTIONS 

Common: The common side-effect on initiating GLP-1RA therapy is nausea and vomiting in up to 25% patients and this can be severe in some cases, leading to discontinuation in some (5-10%). It is usually transient (four to eight weeks), can be minimised by titrating up the dose slowly, and it responds to antiemetics. GLP- 1RAs should probably be avoided in patients with significant gastrointestinal disease, particularly gastroparesis.

Rare but serious: Post-marketing reports of pancreatitis (<0.2%) with GLP-1RA therapy have emerged, but it is not clear whether pancreatitis is directly related to therapy. A possible association with cholelithiasis may exist. Among the available GLP-1RA outcome studies which include SUSTAIN 6, LEADER and ELIXA studies, there were numerically higher numbers of patients with cancer of the pancreas in the GLP-1 treated groups compared to placebo, but this was not statistically significant.^9,10,11 Therefore until further information becomes available, these drugs are best avoided in patients with a past history of acute or chronic pancreatitis and pancreatic cancer, and in those at risk for pancreatitis (gallstones, pancreatic or biliary obstruction, or planned manipulation such as ERCP, excessive alcohol intake). Consider excluding cholelithiasis in high risk patients before adding GLP-1RA therapy. Patients should be warned to report symptoms suggestive of pancreatitis and discontinue the drug immediately on suspicion, and not to restart a GLP-1RA if the diagnosis of pancreatitis is confirmed. In animal models, liraglutide was associated with the development of C cell tumours. This has not yet been reported in humans. Nevertheless, liraglutide is contraindicated in patients with a history of MTC or multiple endocrine neoplasia (MEN) syndrome type 2.

Table II: Summary of GLP-1 agonist cardiovascular safety studies

CI=confidence interval; RCT= randomised controlled trial; CV=cardiovascular; pts= patients, no= number; ITT= intention to treat.
§95% Values <1.00 favour DPP-4 inhibitor safety; Confidence Interval: statistically significant if the interval does not cross 1.00.

RECOMMENDATIONS

GLP-1RAs are a useful addition to the currently available antihyperglycaemic therapies and have a novel mode of action with potential additional non-glycaemic benefits. They can be used as adjunctive therapy to the currently available oral agents to improve glycaemic control. Although they have been studied in combination with metformin as dual therapy, they do not offer substantial advantages over other less expensive therapeutic options in this circumstance, except in patients with established cardiovascular disease. Its routine use as a 2nd-line option for dual therapy is therefore not supported. However, they may be useful agents in selected patients as a 3^rd glucose lowering drug (in combination with metformin + sulphonylurea or metformin + TZD). Furthermore, GLP-1RAs can also be used to advance insulin therapy when added to basal insulin; exenatide is registered for this indication, and may improve post-prandial and overall glucose control in patients who are not controlled on basal insulin. Adding a GLP-1RA to basal insulin may be preferred to intensifying insulin in some patients.^13,14,15

Response to GLP-1RA therapy must be assessed at three and six months. Consider continuing GLP-1RA therapy only if there has been a reduction of at least 0.5% in HbA_1C and a weight loss of at least 3% of initial body weight at six months.

Because of their similar mode of action and lack of clinical trials, GLP-1RAs must not be combined with DPP-4 inhibitors. There are also no studies examining GLP-1RA combinations with SGLT2 inhibitors in type 2 diabetes.

Author: Imran Paruk 
Editor: Aslam Amod

References

1. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374(9683):39-47. doi:10.1016/ S0140-6736(09)60659-0.
2. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects  of exenatide (exendin-4) on glycemic control and weight over 30 weeks  in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28(5):1092-1100.
3. Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005;28(5):1083-1091.
4. Russell-Jones D, Vaag A, Schmitz O, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia. 2009;52(10):2046-2055. doi:10.1007/s00125-009-1472-y.
5. Maiorino MI, Chiodini P, Bellastella G, Capuano A, Esposito K, Giugliano D. Insulin and Glucagon-Like Peptide 1 Receptor Agonist Combination Therapy in Type 2 Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Diabetes Care. 2017;40(4):614-624. doi:10.2337/dc16-1957.
6. Nauck M, Frid A, Hermansen K, et al. Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, in Type 2 Diabetes: The LEAD (Liraglutide Effect and Action in Diabetes)-2 study. Diabetes Care. 2009;32(1):84-90. doi:10.2337/dc08-1355.
7. Marre M, Shaw J, Brändle M, et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med. 2009;26(3):268-278. doi:10.1111/j.1464-5491.2009.02666.x.
8. Zinman B, Gerich J, Buse JB, et al. Efficacy and Safety of the Human Glucagon- Like Peptide-1 Analog Liraglutide in Combination With Metformin and Thiazolidinedione in Patients With Type 2 Diabetes (LEAD-4 Met+TZD). Diabetes Care. 2009;32(7):1224-1230. doi:10.2337/dc08-2124.
9. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-322. doi:10.1056/ NEJMoa1603827.
10. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844. doi:10.1056/NEJMoa1607141.
11. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med. 2015;373(23):2247-2257. doi:10.1056/NEJMoa1509225.
12. Li L, Li S, Liu J, et al. Glucagon-like peptide-1 receptor agonists and heart failure in type 2 diabetes: systematic review and meta-analysis of randomized and observational studies. BMC Cardiovasc Disord. 2016;16(1):91. doi:10.1186/ s12872-016-0260-0.
13. Diamant M, Nauck MA, Shaginian R, et al. Glucagon-Like Peptide 1 Receptor Agonist or Bolus Insulin With Optimized Basal Insulin in Type 2 Diabetes. Diabetes Care. 2014;37(10):2763-2773. doi:10.2337/dc14-0876.
14. Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet. 2014;384(9961):2228- 2234. doi:10.1016/S0140-6736(14)61335-0.
15. Buse JB, Bergenstal RM, Glass LC, et al. Use of Twice-Daily Exenatide in Basal Insulin–Treated Patients With Type 2 Diabetes. Ann Intern Med. 2011;154(2):103. doi:10.7326/0003-4819-154-2-201101180-00300.