cardiac health

1. Dr Rupendra

2. Background
• Overweight is a BMI >25(23); and Obesity BMI >30(28).1
• 39% of adults >18 years were overweight in 2016, and 13% were obese
worldwide1
• 33% in Indian urban and 19% in Indian rural population are obese2
• 41% of BMI-related deaths and 34% of BMI-related disability-adjusted life-years
were caused by CVD among individuals with obesity3
• Obesity paradox-recently debunked in 20234
1..WHO 2016 OBESITY DAY 22
2.NHFS 2019-’21
3.GBD 2015 Obesity Collaborators et al Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med. 2017 Jul 6;377(1).
4. Anthropometric measures and adverse outcomes in heart failure with reduced ejection fraction: revisiting the obesity paradox”, by Jaward H. Butt et al. European Heart Journal

3. Background
• Glucagon like peptide 1 agonists are incretin stimulates insulin secretion after oral
glucose load
• Promote weight loss by mimicking action of glucagon decreasing gut motility and
increasing satiety1
• Only two GLP-1 receptor agonists have been approved for weight management
• liraglutide (3.0 mg once daily) and Semaglutide (2.4 mg once weekly)
• Oral formulation of Semaglutide isn’t as efficacious2,3
• Side-effects- anaphylaxis, GI side effects, pancreatitis, thyroid cancer
• Orforglipron is a potent non peptide partial agonist of the GLP-1 receptor that has
a greater effect on cyclic AMP (cAMP) signalling
• Half-life of 29 to 49 hours and lower receptor desensitization
1. Jepsen MM, Emerging glucagon-like peptide 1 receptor agonists for the treatment of obesity. Expert Opin Emerg Drugs. 2021 Sep;26.
2. Pi-Sunyer X,, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med 2015;373:
3. Wilding JPH, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021;384:989-1002

4. Mechanism of action:
GLP-1 receptor
agonist behaves like
incretin
Decreases appetite
and delays gastric
emptying
Weight reduction

5. Trial design
• Phase 2, Multicenter, randomized, double-blind, placebo-controlled,
parallel group trial.
• Trial sponsor (Eli Lilly) designed and oversaw the conduct of the trial
• Conducted in Canada, Hungary, and the United States
• September 2021 to November 2022

6. Objective and Methodology
• To evaluate the efficacy and safety of orforglipron in adults with obesity, or
with overweight plus at least one weight-related coexisting condition, and
without diabetes and optimise dosing.
INCLUSION CRITERIA:
18-75yrs age
HbA1c<6.5%
Obese(BMI>30)
Overweight(BMI=25-30) + weight related co-existing conditions(HTN,
cardiovascular disease, OSA)
Stable body weight (<5% gain or loss) 3 months prior to randomization

7. Procedure
PHASE 1
2 weeks
Screening + lead in
phase
PHASE 2
36 weeks
Treatment period
PHASE 3
2 weeks
Follow up period

8. • During the treatment period, dose escalation was performed in all the orforglipron dose
cohorts.
• The dose-escalation phase had a duration of up to 16 weeks, depending on the dose cohort.
• The starting dose was 2 mg or 3 mg, and additional dose-escalation steps were specific to
the dose cohort.
• Orforglipron or matching placebo was administered once daily by oral capsule in the
morning without meal-timing restrictions.
• Throughout the trial, education regarding healthy eating and exercise was provided by trial
person
Treatment period:

9. Procedure

10. End points
Primary
• Percentage change from baseline
in body weight at week 26.
Secondary
Percentage change from baseline
in body weight at week 36.
The absolute change from baseline
in body weight, BMI, and waist
circumference at week 26 and
week 36.
Weight reductions of at least 5%
and at least 10% by week 26 and
week 36.

14. OUTCOMES
WEIGHT BASED CARDIOMETABOLIC SAFETY
Dose dependent
• Reduction in body weight
(orforglipron= 8.6-14.7%
placebo= 2.3%)
Duration dependent
absolute change from baseline in
body weight ranged from −6.9 kg
to −11.2 kg at week 26 and
ranged from −7.4 kg to −13.0 kg
at week 36
Mean change from baseline in
the systolic blood pressure was
up to −10.5 mm Hg at week 26
and was up to −10.5 mm Hg at
week 36 with orforglipron, as
compared with −3.6 mm Hg and
−1.8 mm Hg,
• No change in diastolic BP
• Beneficial effect on lipid
profile
Side effects:
Nausea, vomiting
(directly proportional to the
starting dose and inversely
proportional to the duration of
dose escalation)

16. Comparison with other GLP-1 agonists
PARAMETERS LIRAGLUTIDE SEMAGLUTIDE ORFORGLIPRON
Route of administration Injectable Injectable Oral
Weight reduction 9.2%1 16.9%2 9.4-14.7%
Duration 56 weeks 68 weeks 36 weeks
Safety profile Similar safety profile- main side effects- Gastrointestinal S/E
1. Pi-Sunyer X, et al A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med 2015; 373: 11-22
2. Wilding JPH et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021;384:989-1002.

17. Strengths and limitations of the trial
STRENGTHS
Randomized, double-blind, placebo-
controlled design
Exploration of dose range
Good levels of adherence and
participant retention
LIMITATIONS
Relatively few people in each trial
group
The homogeneous trial population,
which was enrolled in only three
countries and included a high
percentage of women and White
participants(Limits generalizability)
Gastrointestinal events occurred at a
higher incidence than desired because
of the need for exploration of
alternative dose-escalation regimens.

18. CONCLUSION
Similar to other GLP-1 receptor agonists, orforglipron produced
improvements in the blood pressure and levels of circulating lipids.
Lower starting doses and slower dose escalation are indicated for
reducing gastrointestinal events and reaching the target dose
Daily oral orforglipron was associated with weight reduction and
related benefits that appeared to be similar to the efficacy outcomes
observed with injectable GLP-1 receptor agonists.

19. THANK YOU