Liraglutide GLP-1 analogue with 97% homology to the human natural GLP.
Significance Better than natural GLP in Human body Longer half life periodHalf life period Natural GLP-1 -> 1.5 minutes Liraglutide -> 13 hours Therefore, can control blood glucose level for a longer period.
Advantages Helps promoting weight loss Increase insulin secretion Will not cause hypoglycaemia Reduce glucagon secretion
Severe -Pancreatitis -Allergic reactions (Rashes, difficulty in breathing, tightness of chest, swelling of mouth, face, lips or tongue) -Symptoms of thyroid Cancer (Lump or swelling in neck, trouble swallowing, hoarseness of voice)
Critic Phase III LEAD studies LEAD- Liraglutide Effect and Action in Diabetes)LEAD 1 & 2 – Add on therapyLEAD 3 - MonotherapyLEAD 4 & 5 - Triple TherapyLEAD 6 - Liraglutide Vs Exenatide (another GLP-1 analogue)
Inclusion criteria Type 2 diabetic patients Age 18-80 years Under Oral Glucose lowering agents(OGLA) for the past 3 months or more BMI <or= 45 kg/m2 and HbA1C 7-11%
Exclusion criteria Impaired renal or liver functions Proliferative retinopathy Usage of any other drugs apart from OGLA that could affect blood glucose levels Getting treated with systemic cortico-steroids Pregnant women (Animal studies have revealed evidence of foetal harm)
Outcome MeasuresPrimary outcome Measure - HbA1CSecondary outcome Measures - Fasting & Post Prandial Blood Glucose - Fasting Insulin and Glucagon Levels - Fasting C-peptide levels - Fasting pro insulin-insulin ratio - Body Weight - Blood pressure & - Lipid Profile
LEAD 1 Combined Glimepride With -Liraglutide -Rosiglitazone & -Placebo Studies are Double – blind, Double – dummy, Five – armed Parallel Randomised Controlled Trials .
Critique Glimepride increases weight Liraglutide helps to decrease weight In combination...... -Only maximum dose of 1.8 mg liraglutide reduced body weight by 0.2kg - But, there was a increase in weight in other doses of 0.6 mg (+ 0.7kg) & 1.2 mg (+0.3kg)
Critique 3 important factors in patho-physiology of elevated glucose level Insulin resistance Decrease in Beta-cell function Increased production of glucose in liver (which is partially mediated by increased glucagon levels)
LEAD 4 Trial Claims that the triple therapy (metformin+ rosiglitazone + liraglutide) has the potential to promote weight loss (action of metformin and liraglutide) reduce insulin resistance (action of metformin and rosiglitazone) decreased production of glucagon (liraglutide)
LEAD 5 Metformin & Glimepiride withInsulin GlargineLiraglutidePlacebo (Triple Therapy)
Outcome Measures HbA1C Similar reduction - 1.33% (liraglutide) - 1.09 % (Insulin)But, Significant loss of body weight and systolic Blood pressure
LEAD 6 Compared Liraglutide Vs Exenatide - a Double-blind, parallel group, multinational randomised control trial.
LiraglutideIn comparison with exenatide, Reduced HbA1C significantly (p<0.001) Reduced mean fasting glucose Lesser hypoglycaemic episodes Nausea complaints were lesser Weight loss slightly better (3.24 kg liraglutide Vs. 2.87 kg in Exenatide)
Therefore...This paper suggests the use of liraglutide over exenatide
Discussion Trial Design : Conducted in 600 centres in 40 countries. Lesser chances of bias Proves that research is repeatable Efficacy for a wider group of people, irrespective of ethnicity and country.
Aim:1. To address the issue that current drugs do not control the diabetes in the long run and not able to overcome the decline of beta cell function2. To reduce the adverse effects of current Oral Glucose Lowering Agents(OGLA)  Clearly defined
Inclusion Criteria Exclusion Criteria Primary & Secondary outcome Measures HbA1c was measured using high-performance liquid chromatography Statistics : ANCOVA – Analysis of Covariance Missing Data were imputed with Last Observation Carried Forward (LOCF)
Adverse events Only mild gastro intestinal symptoms were common Severe adverse event related to liraglutide like PANCREATITIS or others was rare - Only 3 out of the total 4456 participants got acute pancreatitis.
But, Buse et al 2009 claims that as obesity, hypertryglyceridemia and gallstones are risk factors of pancreatitis which is also associated with diabetes mellitus. So, we cannot conclude that liraglutide as the cause of pancreatitis. It MIGHT be because of the progressive nature of diabetes.
Conclusion Though Liraglutide proves effective for a shorter period of 26 weeks. Its long term effects on blood glucose levels, complications of diabetes and the beta cell function has to be studied further.