Liraglutide was the second GLP-1 RA approved for use in type 2 diabetes. The native hormone has been modified to develop a compound with pharmacokinetic properties suitable for once daily administration.

It is available for subcutaneous use in a single daily dose. It exhibits a 97 % structural similarity to endogenous GLP-1, and has a half-life of approximately 13 h. This pharmacokinetic profile is due to the combination of prolonged absorption at the site of injection, a rate of albumin binding greater than 98 % and a high resistance to degradation by DPP-IV [39].

The trials for the approval of liraglutide comprised the LEAD program (Liraglutide Effect and Action on Diabetes), which included six large randomized controlled trials, with a total of over 4,000 patients, conducted in over 600 centers in 40 countries [40–45]. The objectives of the LEAD studies were to evaluate the efficacy and safety of liraglutide and compare it with other treatments available for type 2 diabetes. The summary of the studies is found in Table 30.3.

In relation to glycemic control, a significant and sustained HbA1c reduction of around 1.1–1.5 % was obtained in all studies. Liraglutide also showed a lower risk of hypoglycemia. All the LEAD studies showed a significant reduction in body weight of approximately 1.0–3.2 kg. A reduction in systolic blood pressure of about 2.1–6.7 mmHg was also observed. The possibility of an improvement in metabolic control associated with decreased body weight is of paramount importance in the current scenario of a growing global prevalence of obesity and the forecast significant increase in the number of diabetics.

Liraglutide is, in general, well tolerated. The most common adverse events were related to the gastrointestinal tract, including nausea, vomiting, and diarrhea, occurring in 10–40 % of patients participating in the studies cited above. Most cases were mild and transient, occurring early in treatment and rarely resulting in discontinuation of the medication.

The effect on thyroid C cell in humans is unclear, since there are fewer C thyroid cells than in mice and the expression of GLP-1 receptors on those cells is very low [46]. A study was carried out to compare the levels of plasma calcitonin in humans using liraglutide versus a control group, and after two years of follow-up there were no consistent differences between the two groups, supporting the hypothesis that this drug does not increase the risk of follicular thyroid carcinoma in humans [47]. Until more definite data become available, the U.S. Food and Drug Administration (FDA) does not recommend its use in patients with a past or family history of medullary carcinoma of the thyroid or multiple endocrine neoplasia (MEN) type 2A or 2B.

Among the LEAD studies, there were seven cases of pancreatitis reported in 4,257 patients using liraglutide, while in the comparator group there were 2 cases. The small number of events hinders a proper conclusion involving causality. As previously mentioned, it is well established that diabetic patients show an increased risk of pancreatitis, a risk that can be three times higher than in the nondiabetic population, complicating data interpretation. The current recommendation of the FDA is to monitor the occurrence of abdominal pain and to immediately suspend the use of liraglutide use if pancreatitis is suspected.

In the LEAD studies, liraglutide was associated with a lower rate of major cardiovascular events compared with other therapies which served as comparators. It is possible that the beneficial effects of liraglutide on glycemic control, weight loss, and reduction in systolic blood pressure contributed to this result, but long-term studies are still being conducted to establish whether there are any real cardiovascular benefits.

Liraglutide is used initially at a dose of 0.6 mg, with progression to 1.2 mg. This gradual progression helps to minimize the side effects. To achieve a better glycemic control, it can be used at a dose of 1.8 mg. There is no need for dose adjustment according to age, gender, or ethnicity. It should be used with caution in patients with liver and kidney failure, although its phamacokynetics do not change significantly in the presence of advanced renal failure.

At the 2012 ADA/EASD position statement the indications for incretin-based therapies were greatly expanded in comparison with the previous document. In patients poorly controlled despite a proper diet, physical activity, and monotherapy with metformin, if the main objectives are to achieve good glycemic control with a low risk of hypoglycemia and leading to weight loss, GLP1 RA should be the first choice, although the costs and potential side effects should always be taken into consideration [48].

The World Health Organization estimates that the worldwide prevalence of overweight is 1.5 million adults, while 500 million are believed to be obese. It is known that the risk of developing T2DM is directly proportional to excessive body weight, increasing approximately threefold in overweight patients and 20-fold in obese ones when compared to individuals with a normal body mass index (BMI) [49]. Obesity, particularly when associated with increased visceral adipose tissue, is an independent risk factor for coronary heart disease, contributing to a substantial increase in cardiovascular morbidity and mortality. Considering that there is a global trend towards an increased prevalence of obesity and T2DM and that the therapies most widely available for T2DM induce weight gain (insulins, thiazolinediones, sulfonylureas), the prospect of drugs that act in glycemic control, leading to a better metabolic profile, is quite encouraging.