Recent advances in antiobesity drugs

1. Recent advances in Antiobesity
drugs
Dr Monica Jain
Senior Professor
Department of Pharmacology

2. Introduction
• Obesity, a serious chronic disease, results from
an imbalance between energy intake and
expenditure, which is caused by a multitude of
factors including genetic, behavioural and
social factors
• several co-morbidities, such as type 2 diabetes
(T2D), cardiovascular (CV) disease, kidney
disease and liver disease, contribute to the
shorter life expectancy in obese patients

3. Estimated obesity
• Based on current trends, it is estimated that
38% of the world’s adult population will
become overweight and 20 % obese by 2030
• a 5% weight loss is considered to clinically
signifcant, as it improves insulin resistance, all
components of the metabolic syndrome and
co-morbid conditions

5. • The currently available pharmacological
options for long-term treatment of obesity in
the USA and/ or EU have the following effects
• Phentermine/topiramate Provides the
greatest relative weight loss and improves
cardiometabolic risk factors and T2Ds.

6. Fenfluramine and dexfenfluramine
• stimulate the release of 5-hydroxytryptamine
(5-​HT; also known as serotonin) and inhibit its
reuptake in the synaptic cleft.
Dexfenfluramine was purported to be more
selective in biological action, with fewer
adverse effects than fenfluramine
• concerns for valvular heart disease and
primary pulmonary hypertension (PPH). A

7. • These adverse events were mechanistically
linked to direct stimulation of 5-​HT2B
receptors on the interstitial cells of the mitral
and aortic valves

8. Sibutramine
• Sibutramine — a norepinephrine and
serotonin reuptake inhibitor that reduces
appetite and promotes thermogenesis
• In cardiovascular disease patient- Alarmingly,
the incidence of non-fatal myocardial
infarction and non-fatal stroke was
significantly higher in patients treated with
sibutramine

9. RIMONABANT
• Rimonabant, an endocannabinoid 1 receptor
(CB1) antagonist shown to decrease appetite,
enhance thermogenesis and diminish
lipogenesis preclinically and in numerous
human trials333. Upon emerging reports of
suicidal ideation and serious depression, the
FDA rejected its registration in 2007 (ref. 334)

10. Liraglutide
• Liraglutide Provides weight loss that is
superior to that with orlistat and similar to
that with naltrexone/bupropion.
• Improves CV risk factors, blood glucose levels,
insulin sensitivity and pancreatic β-cell
function.

12. Semaglutide
• Semaglutide) injection (2.4 mg once weekly) for
chronic weight management in adults with
obesity or overweight with at least one weight-
related condition (such as high blood pressure,
type 2 diabetes, or high cholesterol), for use in
addition to a reduced calorie diet and increased
physical activit
• Indicated body mass index (BMI) of 27 kg/m2 or
greater who have at least one weight-related
ailment or in patients with a BMI of 30 kg/m2 or
greater.

13. ADR
• nausea, diarrhea, vomiting, constipation,
abdominal (stomach) pain, headache, fatigue,
dyspepsia (indigestion), dizziness, abdominal
distension, eructation (belching),
hypoglycemia (low blood sugar) in patients
with type 2 diabetes,

14. Tirzepatide
• Tirzepatide is a 39 amino acid synthetic
peptide with agonist activity at both the
glucose-dependent insulinotropic polypeptide
(GIP) and glucagon-like peptide-1 (GLP-1)
receptors, with a greater affinity to GIP
receptors

15. • Reductions in proinsulin levels, proinsulin/C-
peptide ratios, and proinsulin/insulin ratios in
response to treatment with tirzepatide
collectively suggest improvements in insulin
protein processing and may reflect reduced
pancreatic beta-cell stress

16. Orlistat
• Orlistat Has a moderate efect on weight loss,
improves CV risk factors and long-term treatment
decreases the incidence of T2D.
• the use of orlistat is well-established with the
drug having an acceptable safety profle
• Limitation -it is poorly tolerated as it causes
steatorrhea and faecal incontinence, especially
when patients ingest high-fat foods.
• Modifying the diet to avoid ingesting high-fat
foods may be considered as a potential beneft of
orlistat

17. Locaserin
• Locaserin Provides relatively low weight loss, but
improves fasting glucose and glycated haemoglobin
(HbA1c) levels
• Lorcaserin is a 5-​HT2C receptor agonist with much
reduced affinity for other serotonergic receptors.
• Approval for lorcaserin for the treatment of chronic
severe epilepsy in children (Dravet syndrome).
• The mechanism of action of locaserin may result in
cardiac valvulopathy and hallucinations due to
activation of the 5-HT2A and 5-HT2B receptors,

18. • Naltrexone/bupropion Provides clinically
significant weight loss and improves HbA1c
and blood lipid levels.
• Act by inhibiting NA and dopamine reuptake

19. Type 2 diabetes mellitus
• Promote weight loss -metformin, glucagon-
like peptide-1 receptor agonists and sodium-
glucose co-transporter 2 inhibitors
• Weight neutral -dipeptidyl peptidase-4
inhibitors and acarbose
• Weight gain- insulin, sulfonylureas,
metiglinides and thiazolidinediones promote
weight gain

20. Drugs withdrawn
• mazindol, amfepramone and fenproporex have
been withdrawn or restricted to short-term use
due to concerns over addiction
• Sibutramine has been withdrawn due to an
increase in the incidence of non-fatal myocardial
infraction and strokes
• The mechanism of action of locaserin may result
in cardiac valvulopathy and hallucinations due to
activation of the 5-HT2A and 5-HT2B receptors,

21. • Naltrexone/bupropion is contraindicated in
patients with CV disease, as changes in heart
rate and blood pressure have been reported
• phentermine/topiramate is not recommended
in patients with a history of CV disease

22. Approved drug
• . Liraglutide is associated with a decrease in
CV risk, but the need for daily subcutaneous
injections may be an issue for some patients

23. Tesofensine
• Has a mechanism of action similar to that of
sibutramine, leading to concerns about its CV
safety.
• However, as weight loss from tesofensine was
independent from cardiac effects in animals, it
may be possible to correct its CV effects while
retaining its weight-loss effects.

24. • Tesofensine, which is a multimode inhibitor of
norepinephrine, serotonin and dopamine
reuptake that was initially advanced for
treatment of Alzheimer disease.
• In a phase II study, it was reported to dose-
dependently decrease body weight by 4.4–
10.4%166,330.
• Tesofensine also improved LDL cholesterol and
triglyceride levels, but led to increased heart rate.

25. GSK1521498
• Inhibits β-endorphin in the same manner as
naltrexone, but is also an inverse agonist that
increases the activity of anorexigenic neurons,
in addition to reducing the pleasure derived
from food.
• Generally well tolerated, but obese patients
did not lose weight in early clinical trials

26. • Cetilistat Lipase inhibitor that is better
tolerated than orl - istat, though
gastrointestinal tolerability remains an issue
for some patients.

27. • Semaglutide
• Weight loss efects are superior to those with
liraglutide and its oral or once-weekly
subcutaneous injection administration
regimen may be more convenient for patients.
Efficacy needs to be confirmed phase 3 trials

28. Potential new anti-obesity drugs
• Potential new anti-obesity drugs with novel
mechanisms of action are also being
developed
• Prohibitin-TP01 Has the potential to modify
metabolism instead of hunger and satiety.
Animal studies show weight loss and
improvement in insulin resistance, but trials in
patients with obesity are required.
Administration will likely be via injections.

29. • Dapagliflozin- Originally developed to treat
T2D. Although treatment decreased renal and
hepatic damage, HbA1c levels and systolic
blood pressure, weight loss was low in early
clinical trials. Urinary tract infections may
occur due to glycosuria.
• Livoletide- Counteracts the action of ghrelin
that increases hunger. Well tolerated, but
weight loss is low