Liraglutide: Present and Future
Pp. 67-120 (54)
Dan Mircea Cheţa, Cristian Serafinceanu and Cornelia Zetu
The conventional treatment of type 2 diabetes cannot stop the declining of betacell
function. Weight gain and hypoglycemia represent frequent side effects. These
important limitations justify the search for new therapeutic options, one of them being
incretin-mimetics GIP and GLP-1 analogues.The incretin phenomenon comprises up to 60%
of the postprandial insulin secretion via the stimulation of the pancreatic islet cells. The first
incretin identified, glucose-dependent insulinotropic polypeptide (GIP), exhibits weak
effects on gastric acid secretion but more potent insulinotropic actions. Its release is
stimulated by both fat and glucose ingestion. The second incretin hormone, glucagon-like
peptide 1 (GLP-1) stimulates insulin and suppresses glucagon secretion, inhibits gastric
emptying and reduces appetite and food intake. Both GLP-1 and GIP receptor activation
lead to a rapid insulin release in a glucose dependent manner, and also promote resistance to
apoptosis as well as enhance beta-cell survival. Most pharmaceutical efforts related to
incretin action in the treatment of type 2 diabetes were focused on GLP-1 agonists, due to
considerable loss of GIP activity at these patients. Both ADA (American Diabetes
Association)/EASD (European Association for the Study of Diabetes) and AACE
(American Association of Clinical Endocrinologists) guidelines recognize GLP-1 analogues
as efficient agents for patients who do not achieve metabolic control through lifestyle
changes and selected oral drugs. Liraglutide, a new Novo Nordisk therapy, is the first human
GLP-1 analogue sharing 97% of its amino acid sequence with native human GLP-1.
Furthermore, the prolonged half-life of liraglutide makes it the first human GLP-1 analogue
suitable for once-daily administration. An extensive series of preclinical and clinical studies
have revealed considerable potential benefits for liraglutide, i.e. reducing fasting and
postprandial glucose, decreasing HbA1c levels by up to 1, 75% at 18-month follow up,
preventing weight gain and inducing weight loss. Moreover, this agent showed positive
influence both on beta-cell function and mass preservation, and cardiac function by
increasing cardiomyocyte survival and reducing systolic blood pressure. The phase 3 clinical
trial program (LEAD studies) has demonstrated that the glycemic benefits of liraglutide are
not associated with an increased risk of hypoglycemia, or with an increased risk of
pancreatitis. In terms of tolerability, gastrointestinal adverse effects were less persistent with
liraglutide when compared with an active comparator in a large head-to-head study.
Practitioners can consider liraglutide as a very promising option for type 2 diabetes.
However, new large trials are still necessary to evaluate its long-term clinical outcomes.
Agonists, beta-cell function, blood pressure, DPP-4 inhibitors, fasting
plasma glucose, gastric emptying, glucagon, glucagon-like peptide 1 (GLP-1),
HbA1C, hypoglycemia, incretin phenomenon, incretin-mimetics, LEAD trials,
liraglutide, nausea, Novo Nordisk A/S, postprandial plasma glucose, type 2
diabetes, Victoza, weight loss.
National Institute of Diabetes, Nutrition and Metabolic Disease “N. C. Paulescu”, Bucharest, Romania.