- The document discusses the GLP-1 analogue liraglutide and its effectiveness in treating type 2 diabetes based on results from the LEAD clinical trials. - Liraglutide was shown to lower A1C levels, promote weight loss, reduce blood pressure, and have a longer half-life compared to natural GLP-1. - The LEAD trials found liraglutide to be effective as monotherapy or in combination with other oral drugs in improving glycemic control and weight with a low risk of hypoglycemia. However, longer term studies are still needed to fully understand liraglutide's effects.

1. Glucagon Like Peptide-1 (GLP-1) Analogue

2. Liraglutide
 GLP-1 analogue with 97% homology to the human
natural GLP.

3. Significance
 Better than natural GLP in Human body
 Longer half life period
Half life period
Natural GLP-1 -> 1.5 minutes
Liraglutide -> 13 hours
 Therefore, can control blood glucose level for a longer
period.

4. Advantages
 Helps promoting weight loss
 Increase insulin secretion
 Will not cause hypoglycaemia
 Reduce glucagon secretion

5. Adverse Effects
 Mild
Nausea
Vomiting
Diarrhoea
Constipation

6.  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)

7. Critic
 Phase III LEAD studies
 LEAD- Liraglutide Effect and Action in Diabetes)
LEAD 1 & 2 – Add on therapy
LEAD 3 - Monotherapy
LEAD 4 & 5 - Triple Therapy
LEAD 6 - Liraglutide Vs Exenatide
(another GLP-1 analogue)

8. 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%

9. 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)

10. Outcome Measures
Primary outcome Measure
- HbA1C
Secondary 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

11. LEAD 1
 Combined Glimepride With
-Liraglutide
-Rosiglitazone &
-Placebo
 Studies are Double – blind, Double – dummy, Five –
armed Parallel Randomised Controlled Trials .

12. Outcome Measures
 HbA1C - -1.1% (Baseline 8.5%)
(p <0.001)
 Weight - -0.2 kg (1.8 mg lirag.)
- +0.3kg (1.2 mg lirag.)
- +0.7kg (0.6mg lirag.)

13. 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)

14. Graph

15. LEAD 2
 Combining Metformin with
- Liraglutide (Add-On Therapy)
- Glimepride
- Placebo
 Studies are Double – blind, Double – dummy, Five –
armed Parallel Randomised Controlled Trials

16. Outcome Measures
 HbA1C - -0.7 % (0.6 mg)
- -1.0 % (1.2 & 1.8 mg)
 Body Weight - 1.8 kg (0.6 mg)
- 2.6 kg (1.2 mg)
- 2.8 kg (1.8 mg)

17. Blood pressure
 Systolic Blood pressure
- 2-3 mm Hg (1.2 & 1.8 mg lirag)
- 0.6 mm Hg (0.6 mg lirag)
- 1.8 mm Hg (Placebo)
- +0.4 mm Hg (Glimepride)
 Diastolic Blood pressure
-Did not vary much from the baseline
value(80mmHg)

18. LEAD 3
 Compared
-Liraglutide Vs Glimepride (Monotherapy)
- a double-blind, double-dummy, active-
control, parallel-group study trial

19. Critique
Aim:
 New treatments for type 2 diabetes mellitus are
needed to retain insulin–glucose coupling and
lower the risk of weight gain and hypoglycaemia...

20. Outcome Measures
 Primary outcomes
HbA1C - 0.51% (8mg Glimp)
- 0.84 % (1.2 mg lirag)
- 1.14 % (1.8 mg lirag)
- Not available (Placebo)

21. Critique
 Symptoms of nausea was directly proportional to the
weight loss

22. LEAD 4
 Combined metformin and rosiglitazone with
- Liraglutide
- Placebo (Triple therapy)

23. Outcome measures
 HbA1C - 1.5%(Liraglutide)
- 0.5% (Placebo)
(Placebo+ Metformin+Rosiglitazone)

24. 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)

25. 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)

26. LEAD 5
 Metformin & Glimepiride with
Insulin Glargine
Liraglutide
Placebo (Triple Therapy)

27. Outcome Measures
 HbA1C
Similar reduction
- 1.33% (liraglutide)
- 1.09 % (Insulin)
But,
 Significant loss of body weight and systolic Blood
pressure

28. LEAD 6
 Compared
Liraglutide Vs Exenatide
- a Double-blind, parallel group, multinational
randomised control trial.

29. Liraglutide
In 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)

30.  Therefore...
This paper suggests the use of liraglutide over exenatide

31. 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.

32.  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 function
2. To reduce the adverse effects of current Oral
Glucose Lowering Agents(OGLA) [8]
 Clearly defined

33.  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)

34. 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.

35.  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.

36. 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.

37. Dr.V.Venugopal BNYS, FCR, M.Sc Diabetes
Yoga & Naturopathy Consultant
Diabetes Specialist