Physicians' Perspective: Gregory Peterson, MD, and Craig Spellman, MD
Gregory Peterson and Craig Spellman are two physicians who see a lot of diabetes patients in their practices, and are very familiar with the use of GLP-1 agonists. Both of them have written journal articles about the use of these newer medications....
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Glucagon-like peptide (GLP)-1 receptor agonists have several advantages over some older therapies, including reduction in body weight, low risk for hypoglycemia, improvement of beta-cell function and favorable effects on cardiovascular disease risk factors including blood pressure, and some measures of hyperlipidemia.
GLP-1 is an incretin hormone which is naturally occurring and is secreted by enteroendocrine L-cells and produces a glucose-dependent decrease in glucagon release. Native GLP-1 has a short biological half-life of approximately 1 to 2 minutes. GLP-1 receptor agonists are long-acting native GLP-1 analogs. Patients with Type 2 Diabetes Mellitus have reduced incretin-mediated insulin secretion. Studies in patients with Type 2 Diabetes Mellitus indicate GLP-1 based therapies effectively reduce glycosylated hemoglobin (A1C) with low rates of hypoglycemia.
Exenatide twice daily, liraglutide once daily and exenatide extended-release once weekly are the currently approved GLP-1 receptor agonists, with A1C reductions of 0.8 to 1.1%, 0.8 to 1.6%, and up to 1.9%, respectively.
According to Dr. Peterson, "Treatment for Type 2 Diabetes Mellitus must focus not only on elevated blood glucose, but also simultaneously on the underlying metabolic abnormalities of the disease." GLP-1 receptor agonists are currently recommended as a tier 2 intervention according to the American Diabetes Association/European Association for the Study of Diabetes consensus algorithm and also as add-on therapy to metformin and lifestyle changes in cases where hypoglycemia and weight gain are major concerns. On the other hand, the American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel recommends more aggressive and individualized therapy with a wider range of agents including GLP-1 receptor agonists as initial pharmacotherapy and in combination with oral anti-diabetics (except dipeptidyl peptidase-4 inhibitors which work on the same system) when A1C goal <6.5% is not met.
Exenatide and liraglutide are effective as monotherapy in patients with Type 2 Diabetes Mellitus to reduce levels of A1C, fasting plasma glucose and 2-hour postprandial glucose. Dr. Spellman concluded, according to data from studies of GLP-1 receptor agonists in combination with other oral anti-diabetics:
Exenatide and liraglutide are roughly equally effective in reducing A1C levels at doses of 10 µg twice daily and 1.2 mg daily;
GLP-1 receptor agonists show additional benefit in dual and triple-therapy regimens;
The benefit of adding a GLP-1 receptor agonist to achieve glycemic control follows the general rule for oral agents (i.e., the effects are additive), with a further A1C reduction of approximately 1%;
Liraglutide reduces FPG level to a greater extent than does exenatide." Spellman also mentioned that data from the LEAD-6 trial indicate exenatide decreased PPG levels more than liraglutide.
Substantial weight reduction was observed in monotherapy and combination therapy trials with both exenatide and liraglutide with weight loss of up to 3.1 kg and 2.5 kg, respectively. Weight loss was also sustained for more than 1 year in trials. Additionally, in an open-label trial lasting 3.5 years, exenatide showed statistically significant improvements in triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol. Blood pressure was also improved in the trial. The LEAD-6 trial showed liraglutide consistently decreased systolic blood pressure and triglyceride levels.
Most common adverse effects include nausea, vomiting and diarrhea, which generally decrease over time. GLP-1 receptor agonists are not to be used in patients with Type 1 Diabetes Mellitus and are contraindicated in patients with a history of pancreatitis and individuals with a history of medullary C-cell cancer or multiple endocrine neoplasia type 2.
Exenatide is initiated at 5 µg twice daily (60 minutes before meals) and increased to 10 µg twice daily after 1 month based on clinical response. Liraglutide is initiated at 0.6 mg once daily (independent of meals) for 1 week then increased to 1.2 mg once daily. Liraglutide may be increased to 1.8 mg if 1.2 mg does not result in acceptable glycemic control. Exenatide extended-release is initiated at 2 mg once weekly (independent of meals). A 50% dose reduction of a sulfonylurea should be considered if used in combination with GLP-1 agonist to avoid hypoglycemia. In addition, a basal insulin reduction of 20% is advised to minimize risk of hypoglycemia, if used in combination.
GLP-1 agonists can be used as monotherapy or in combination with other agents to improve glycemic control and reach A1C goals. Use is increasing due to safety and tolerability. In addition, GLP-1 agonists have demonstrated positive effects on common co-morbidities of diabetes including obesity, hypertension, and hyperlipidemia.
Dr. Peterson recommends "the utility of GLP-1 receptor agonists in combination therapy with oral anti-diabetics, especially after metformin failure, and their positive effects on beta-cell function support their use as part of initial and continuing treatment for patients with Type 2 Diabetes Mellitus."
Both Dr. Peterson and Dr. Spellman teach medical students at their respective hospitals and are constantly pushing the new professionals towards the use of GLP-1 therapy as a first line medication.
Prepared by Jacqueline Vogt, PharmD Candidate, UF College of Pharmacy
References:
Gregory Peterson. Current treatments and strategies for type 2 diabetes: Can we do better with GLP-1 receptor agonists? Annals of Medicine. 2012; 44:338-349.
Craig Spellman. Incorporating glucagon-like peptide-1 receptor agonists into clinical practice. J Am Osteopath Assoc. 2012 Jan; 112(No 1):S7-15.
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