Rezvan Salehidoost, M.D. Endocrinologist Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus Rezvan Salehidoost, M.D. Endocrinologist Version December 2014

خانم 52 ساله،کارمندبازنشسته ودرحال حاضر معاون یک شرکت، باسابقه12ساله دیابت، برای پیگیری به مطب شمامراجعه کرده است. درحال حاضرتحت درمانهای زیر قرار دارد: متفورمین روزانه 2 گرم، گلی کلازید 120mg آتورواستاتین 40mg لوزارتان 12.5mg BD آسپیرین 80mg وسابقه CABG سه سال قبل داشته و احساس خستگی وتنگی نفس هنگام فعالیت شکایت دارد. آخرین نتایج بررسی به شرح زیراست: HbA1c=9.5, Cr=1.1, ALT=38, FBS=182, BMI=33, چه تغییر برنامه درمانی برای وی پیشنهاد می کنید؟

GLUCAGON-LIKE PEPTIDE-1

GLUCAGON-LIKE PEPTIDE-1 GLP-1 exhibits a short half-life of one to two minutes due to N-terminal degradation by the enzyme dipeptidyl peptidase-4 (DPP-4). This necessitates continuous infusion of GLP-1 to achieve steady-state levels in pharmacologic studies. Research has focused on GLP-1-like agonists that are resistant to DPP-4 degradation and on agents that increase GLP-1 via inhibition of DPP-4.

GLP-1 RECEPTOR AGONISTS GLP-1 receptor agonists (exenatide, liraglutide, albiglutide, taspoglutide, lixisenatide) In comparison with placebo, all GLP-1 receptor agonists reduced glycated hemoglobin (A1C) by approximately 1 percentage point (treatment difference 0.47 to 1.56 percent).

LONG-ACTING GLP-1 RECEPTOR AGONISTS Liraglutide Liraglutide is a GLP-1 receptor agonist that has been modified to noncovalently bind to serum albumin through a lipid side chain, resulting in slower degradation (half-life 11 to 15 hours) and allowing for once-daily, subcutaneous dosing.

LONG-ACTING GLP-1 RECEPTOR AGONISTS Liraglutide Liraglutide is available in prefilled pens. The initial dose is 0.6 mg once daily for one week to reduce gastrointestinal side effects. After one week, the dose should be increased to 1.2 mg once daily for one week. If blood glucoses remain above the goal range, the dose can be increased to 1.8 mg once daily.

GLP-1 RECEPTOR AGONISTS Cardiovascular effects In patients with type 2 diabetes and CVD, there was a reduction in CVD outcomes with liraglutide and semaglutide compared with placebo, whereas lixisenatide and exenatide did not increase or decrease CVD outcomes. Liraglutide had no effect on heart failure outcomes in patients with established heart failure.

GLP-1 RECEPTOR AGONISTS Microvascular outcomes There are no trials evaluating microvascular disease as the primary outcome in patients taking GLP-1 receptor agonists. In trials designed to assess cardiovascular outcomes in patients with or at high risk for CVD, liraglutide and semaglutide reduced nephropathy outcomes.

GLP-1 RECEPTOR AGONISTS Mortality The effect of GLP-1 receptor agonists on overall mortality is uncertain. In a systematic review and meta-analysis of 189 trials, there was no difference in all-cause mortality between any incretin drug and control. In a subgroup analysis of the GLP-1 receptor agonist cardiovascular outcomes trials, there was a suggestion of reduced all-cause mortality with GLP-1 receptor agonists versus placebo (7.0 versus 7.8 percent, odds ratio [OR] 0.89, 95% CI 0.80-0.99).

GLP-1 RECEPTOR AGONISTS Weight loss Weight loss is common with GLP-1 receptor agonists. In a systematic review of 17 randomized trials comparing GLP-1 receptor agonists with placebo or an active comparator in patients with type 2 diabetes, patients randomly assigned to GLP-1 receptor agonists had a weight reduction of approximately 1.5 to 2.5 kg over 30 weeks.

GLP-1 RECEPTOR AGONISTS Candidates GLP-1 receptor agonists are not considered as initial therapy for the majority of patients with type 2 diabetes. Initial therapy in most patients with type 2 diabetes should begin with diet, weight reduction, exercise, and metformin (in the absence of contraindications).

Considerations include: A patient-centered approach should be used to guide the choice of pharmacologic agents Considerations include: efficacy hypoglycemia risk history of atherosclerotic cardiovascular disease impact on weight potential side effects renal effects delivery method (oral versus subcutaneous) cost patient preferences Diabetes Care 2019;41(Suppl. 1):S73–S85

Adverse effects Gastrointestinal The side effects of GLP-1 receptor agonists are predominantly gastrointestinal, particularly nausea, vomiting, and diarrhea, and occur consistently in trials in 10 to 50 percent of patients. Nausea may wane with duration of therapy and can be reduced with dose titration. These agents are associated with decreased gastric transit and must be used with caution in those with gastroparesis.

Adverse effects Pancreas Acute pancreatitis has been reported in association with GLP-1 agonist treatment. At the current time, there are insuffcient data to know if there is a causal relationship. Pancreatitis should be considered in patients with persistent severe abdominal pain (with or without nausea), and GLP-1 receptor agonists should be discontinued in such patients. If pancreatitis is confirmed, it should not be restarted. In addition, GLP-1 receptor agonists should not be initiated in a patient with a history of pancreatitis.

Injection site reactions Adverse effects Injection site reactions In studies comparing insulin administration with once-weekly GLP-1 receptor agonists, including albiglutide and exenatide, local site reactions are more common with GLP-1 receptor agonists (approximately 10 percent), compared with 1 to 5 percent with insulin.

Adverse effects Immunogenicity Antibodies to GLP-1 receptor agonists may develop. In the majority of patients, the titer of antibodies decreases over time and does not affect glycemic control. However, some patients develop high titers of antibodies that may attenuate the glycemic response.

Adverse effects Renal Exenatide should not be used in patients with a creatinine clearance below 30 mL/min. There is limited experience in using liraglutide and dulaglutide in patients with severe renal impairment (eGFR 15 to 29 mL/min). In liraglutide trials, the presence of mild to moderate renal impairment did not affect treatment outcomes. However, there were too few patients with severe renal impairment to provide evidence for the safety and effcacy of these drugs in this population.

Adverse effects C-cell tumors In rodent studies, liraglutide and dulaglutide were associated with benign and malignant thyroid C-cell tumors. Stimulation of calcitonin release was reported in rats and mice exposed to exenatide and liraglutide. This effect is mediated by the GLP-1 receptor. It is unclear whether any effect is present in humans because humans have far fewer C-cells than rats, and expression of the GLP-1 receptor in human C-cells is very low. There were no changes in calcitonin levels in short-term human studies, but medullary thyroid carcinoma may take years to develop.

Adverse effects C-cell tumors GLP1 agonist are not recommended for use in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 2B.

خانم 52 ساله،کارمندبازنشسته ودرحال حاضر معاون یک شرکت، باسابقه12ساله دیابت، برای پیگیری به مطب شمامراجعه کرده است. درحال حاضرتحت درمانهای زیر قرار دارد: متفورمین روزانه 2 گرم، گلی کلازید 120mg آتورواستاتین 40mg لوزارتان 12.5mg BD آسپیرین 80mg وسابقه CABG سه سال قبل داشته و احساس خستگی وتنگی نفس هنگام فعالیت شکایت دارد. آخرین نتایج بررسی به شرح زیراست: HbA1c=9.5, Cr=1.1, ALT=38, FBS=182, BMI=33, چه تغییر برنامه درمانی برای وی پیشنهاد می کنید؟

Takeaway Glucagon-like peptide-1 (GLP-1)-based therapies reproduce or enhance the actions of the naturally occurring peptide GLP-1. GLP-1 receptor agonists are not considered as initial therapy for the majority of patients with type 2 diabetes. For patients who fail initial therapy, GLP1 agonist can be used with metformin. This decision therapy should be individualized based upon patient characteristics, preferences, and costs.