Individualized Diabetes Management by Barnett Anthony Grice Jenny

Author:Barnett, Anthony, Grice, Jenny
Language: eng
Format: epub
Publisher: CRC Press
Published: 2017-04-09T04:00:00+00:00

GLP-1 receptor agonists

GLP-1 RAs provide pharmacological levels of GLP-1, activating GLP-1 receptors in the pancreas and mimicking the actions of endogenous GLP-1: glucose-dependent increase in insulin release and decrease in glucagon release with a consequent low risk for hypoglycaemia. These agents are also associated with weight reduction by their effects on delaying gastric emptying and increasing satiety.

There are currently six GLP-1 RAs approved for use in the European Union, which can be classified as short-acting (exenatide twice daily, lixisenatide once daily) or long-acting (liraglutide once daily, exenatide once weekly, albiglutide once weekly and dulaglutide once weekly) (Table 4.1). All of the GLP-1 RAs are administered as subcutaneous injections and are available as prefilled injection pens.

To date, nine phase III head-to-head trials and one large phase II study have compared the efficacy and safety of these drugs (Madsbad, 2016). All trials were associated with HbA1c reductions of between 0.8% (9 mmol/mol) and 1.9% (21 mmol/mol). In general, longer acting GLP-1 RAs (which include liraglutide despite the fact it is licensed only for once daily use) lower HbA1c to a greater extent. Exenatide twice daily partially restores the first-phase insulin response, and injections should be administered within the 60-min window PRIOR TO eating the two main meals of the day. Lixisenatide should also be given prior to the main meal of the day. The other GLP-1 RAs can be administered at any time of the day with or without meals.

In addition to improved coverage of post-prandial hyperglycaemia, the short-acting GLP-1 RAs offer greater weight reductions. The potential advantages of long-acting GLP-1 RAs include a greater action on fasting plasma glucose, less frequent injections and lower rates of nausea (Table 4.1).

GLP-1 receptors are also expressed in the heart and vasculature, and preclinical studies with GLP-1 RAs indicate that they have favourable effects on endothelial function, recovery from ischaemic injury and myocardial function (Chilton, 2015). In the first cardiovascular outcome trial to be reported with a GLP-1 RA (Evaluation of Lixisenatide in Acute Coronary Syndrome [ELIXA]), there was no increased cardiac risk (cardiovascular death, MI, stroke, unstable angina or heart failure) for lixisenatide compared with placebo in over 6000 people with type 2 diabetes who had recently experienced acute coronary syndrome events (Pfeffer et al., 2015).

The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, which was launched in 2010 to meet FDA requirements for post-marketing cardiovascular analysis of new diabetes therapies, has also recently completed (Marso et al., 2016a). This double-blind trial randomized 9340 patients with type 2 diabetes at high risk of major adverse cardiovascular events to either 1.8 mg of liraglutide or placebo in addition to standard care. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, non-fatal MI or non-fatal stroke. The average duration of disease was 12.9 years for placebo and 12.8 years for the liraglutide arm, and patients had a mean HbA1c of 8.7% (71.6 mmol/mol). Patients were followed for a median of 3.8 years. In

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