type 2 diabetes

1. Type 2
Diabetes

2. TABLE OF CONTENTS
01
02
03
04
Case Study
• Overview
• key measures of diabetes management
- Glycemic control
- Weight
• GLP-1 and GIP
Type 2 Diabetes
• SURPASS studies
Newly approved FDA drug: Tirzepatide
• SURMOUNT studies
• SURPASS-CVOT
Future studies

3. Case Study
Failure of Metformin Monotherapy
Rami is a 58-year-old obese male patient with T2DM of 8 years' duration
presents with poor glycemic control (HbA1c of 8.2%) despite receiving
optimal metformin monotherapy for the last 2 years and tolerates the
treatment well. Hypoglycemia has not been an issue to date.
He has mild hypertension, which is well- controlled on a thiazide plus an
angiotensin-converting enzyme inhibitor. His blood lipids are well-
controlled on atorvastatin 10 mg daily.
His body mass index (BMI) is 30 kg/m2. He has been following his diet
and exercise schedule very strictly. He is also concerned about his weight
and wants advice on which class of antidiabetic drug would be best suited
in his case that may provide efficacious glycemic control, and weight loss.

4. Case Study
Choose the most appropriate answer:
A) Add sulfonylurea to metformin
B) Discontinue metformin and initiate sulfonylurea
C) Add tirzepatide (Mounjaro) SQ injection once weekly to metformin
D) Add semaglutide (OZEMPIC) SQ injection once weekly to metformin

5. Main types
Symptoms
Prevention
Organs affected
Treatment
Diabetes
Type 1 Type 2 Gestational
Risk Factors / Causes

6. What is the A1C test?
What does weight have to do with type 2 diabetes?
According to the American Diabetes Association
(ADA), sometimes, losing just 5%-7% of your body
weight is enough to improve diabetes control.
Type 2 diabetes, the most common form of
diabetes, is a chronic and progressive condition in
which the body either doesn’t make enough insulin
or can’t effectively use the insulin it does make,
leading to high levels of glucose in the blood.
Despite the availability of many medications to
treat diabetes, many patients do not achieve the
recommended blood glucose levels.
The current type 2 diabetes (T2D) epidemic is
closely associated with a parallel obesity epidemic,
with more than 85% of patients with diabetes being
overweight or obese.

7. GIP (glucose-dependent insulinotropic polypeptide) Is 1 of 2 Incretin
Hormones—Along With GLP-1 (Glucagon-like peptide-1)—That Has
Diverse Metabolic Roles1
• These hormones are secreted by the gut in response to nutrient load. They are responsible
for the incretin effect, which enhances the secretion of insulin after a meal.2
• GIP is responsible for nearly two-thirds of the incretin effect in healthy humans, contributing
more to insulin secretion than GLP-1.1
The incretin effect is diminished in patients with Type 2 Diabetes (T2D)1
A diminished incretin effect is associated with
hyperglycemia. Over time, hyperglycemia is associated
with nephropathy, retinopathy, neuropathy, and
cardiovascular disease.1,3

8. Comparison of Proposed Actions of GIP And GLP-14

9. Discover Once-Weekly Mounjaro (Tirzepatide):
In a New Class of T2D Treatment
• In May 2022, the FDA approved Lilly’s new medication Mounjaro (also
known as tirzepatide) for type 2 diabetes management, in addition to diet
and exercise to improve glycemic control.
• Tirzepatide has a mean half-life of ~5 days, enabling once-weekly dosing.
• The medication has been studied in a number of clinical trials, most
notably the SURPASS trials (which includes five completed studies and
two ongoing studies).
• In the trials submitted to the FDA for this approval – all three doses of the
medication were compared to a placebo, a GLP-1 receptor agonist
(semaglutide – also known as Ozempic), and two different long-acting
insulins (insulin degludec and insulin glargine).

10. From This Day Forward,
The T2D Treatment Landscape Has A New Class
• Tirzepatide is the first and only approved treatment in a different class of
medication for type 2 diabetes.
• It is a single molecule that activates the GIP and GLP-1 receptors in the body
• It is called a "dual agonist" or a “dual GIP and GLP-1 receptor agonist.”
Superior A1C reduction across the five phase 3 SURPASS
studies, regardless of comparator
• A1C reductions were consistently seen across studies
vs Tresiba® (insulin degludec), insulin glargine, placebo,
and Ozempic 1 mg
Significant weight loss results across 5 clinical trials
• Tirzepatide is not indicated for weight loss.
• Change in weight was a secondary endpoint.

11. Tirzepatide
MOA

12. Study Designs
• SURPASS-1 was a 40-week, double-blind, placebo-controlled, phase 3 trial that randomized 478
adult patients with T2D who had inadequate glycemic control with diet and exercise to receive once-
weekly SC Tirzepatide 5 mg, 10 mg, or 15 mg, or placebo 5
Tirzepatide vs Placebo (AS MONOTHERAPY)

13. Study Designs
• SURPASS-2 was a 40-week, open-label, active-controlled, phase 3 trial that randomized 1879 adult
patients with T2D who had inadequate glycemic control on stable doses of metformin alone to receive once-
weekly SC Tirzepatide 5 mg, 10 mg, or 15 mg or once-weekly SC Semaglutide 1 mg, all in combination with
metformin ≥1.5 g per day 6
Tirzepatide vs Semaglutide

14. Study Designs
• SURPASS-3 was a 52-week, open-label, active-controlled, phase 3 trial that randomized 1444 adult
patients with T2D who had inadequate glycemic control on stable doses of metformin with or without an
SGLT2i to once-weekly SC Tirzepatide 5 mg, 10 mg, 15 mg, or once-daily SC Tresiba 100 U/mL 7
Tirzepatide vs Tresiba (insulin degludec)

15. Study Designs
• SURPASS-4 was a 104-week, open-label, active-controlled, phase 3 trial that randomized 2002 adult
patients on once-weekly SC Tirzepatide 5 mg, 10 mg, 15 mg, or once-daily SC insulin glargine 100 U/mL
,on background metformin (95%), and/or sulfonylureas (54%) and/or an SGLT2i (25%) 8
Tirzepatide vs insulin glargine

16. Study Designs
• SURPASS-5 was a 40-week, double-blind, placebo-controlled, phase 3 trial that randomized 475 adult
patients with T2D who had inadequate glycemic control on insulin glargine 100 U/mL, with or without
metformin (≥1500 mg/day), to receive once-weekly SC Tirzepatide 5 mg, 10 mg, 15 mg, or placebo 9
Tirzepatide vs Placebo (+BASAL INSULIN ± METFORMIN)

17. Overview of the SURPASS Studies
 Titles: are concise and non conclusive. They include the intervention, the population
and the comparator
 Journals :
- The lancet (SURPASS 1, 3, 4): Impact Factor of 202.731. The Lancet is ranking first
among all general and internal medicine journals globally.
- The NEJM (SURPASS 2): Impact Factor of 91.245.
- The JAMA (SURPASS 5) : Impact Factor of 157.3
 Authors: are credible and knowledgeable in the field of publication.
 Funding sources: Funded by Eli Lilly, the manufacturing company of Tirzepatide.
 Enrollment : explained with enough details, with no sign of bias. Patients signed an
informed consent before participation.

18. Study
Design:
Randomized  eliminates selection
bias
Open-Label (SURPASS 2,3,4)  risk
of Reporter’s bias
Double-blinded (SURPASS 1,5) 
reduces performance bias
Multicenter  improves external
validity

19. Inclusion/Exclusion
Inclusion criteria's
- An age of 18 years or older and type 2
diabetes that was inadequately
controlled with metformin at a dose of at
least 1.5 g per day.
- Eligible patients had a glycated
hemoglobin level of 7% to 10.5% and a
body mass index (BMI) of at least 25,
and they had stable weight (±5%)
during the previous 3 months.
Exclusion criteria's
- Type 1 diabetes;
- An estimated glomerular filtration rate
<45 ml/min
- A history of pancreatitis;
- A history of thyroid diseases,
- A history of nonproliferative diabetic
nephropathy that warranted urgent
treatment, proliferative diabetic
retinopathy or diabetic maculopathy.

20. Endpoints
Secondary Endpoints
Primary Endpoints
- The primary end point was the change in
the glycated hemoglobin level from baseline
to week 40.
- The key secondary end points were the
change in body weight from baseline to
week 40
- and the attainment of glycated
hemoglobin level targets of less than
7.0% and less than 5.7%.
Composite Endpoints
- A composite end point of A1C level of 6.5% or
less with at least 10% weight loss and without
clinically significant glycemia (BGL, <54 mg/dl)
and severe hypoglycemia events were also
assessed.
Safety Endpoints
- The safety end points were pancreatic adverse
events; the incidence of hypersensitivity
reactions; the mean changes in the pulse rate
and the systolic and diastolic blood pressure; and
the occurrence of hypoglycemia events.

21. Tirzepatide vs Placebo (AS MONOTHERAPY)
See how Tirzepatide did in studies ( SURPASS 1)
Mean change in A1C at 40 weeks
was -1.8%, -1.7%, -1.7%, and -
0.1% for Mounjaro 5 mg, 10 mg,
15 mg, and placebo, respectively.

22. Tirzepatide vs Semaglutide (Ozempic)
See how Tirzepatide did in studies (SURPASS 2)
In a 40-week study, Mounjaro 5-mg, 10-
mg, and 15-mg doses were compared to
Ozempic 1 mg in 1879 adults with type 2
diabetes who were also taking metformin
and had a baseline A1C of 8.3%.

23. Mounjaro vs Ozempic
Significantly more patients achieved
the ADA guideline-recommended
A1C target of <7% with Tirzepatide
10 mg and 15 mg

24. Tirzepatide vs Tresiba (insulin degludec)
See how Tirzepatide did in studies (SURPASS 3)
In a 52-week study, the Mounjaro 5-mg,
10-mg, and 15-mg doses were compared
to titrated Tresiba, a basal insulin, in
1444 adults with type 2 diabetes who
were also taking metformin with or
without another oral diabetes medication.
They had an average starting A1C of 8.1
to 8.2%.

25. Tirzepatide vs insulin glargine
See how Tirzepatide did in studies (SURPASS 4)
Mean change in A1C at 52 weeks was -
2.1%, -2.3%, -2.4%, and -1.4% for
Mounjaro 5 mg, 10 mg, 15 mg, and
insulin glargine, respectively.

26. Tirzepatide vs Placebo (+BASAL INSULIN ± METFORMIN)
See how Tirzepatide did in studies (SURPASS 5)
In a 40-week study, the Mounjaro 5-mg,
10-mg, and 15-mg doses were compared
to placebo in 475 adults with type 2
diabetes who were also taking insulin
glargine. Some study participants were
also taking metformin. They had a
starting A1C of 8.2% to 8.4%.

27. Tirzepatide demonstrated significant weight reduction across
all 3 doses vs Placebo (AS MONOTHERAPY) - SURPASS 1

28. Tirzepatide demonstrated significant weight reduction across
all 3 doses vs Semaglutide 1 mg – SURPASS 2

29. Tirzepatide demonstrated significant weight reduction across
all 3 doses vs Tresiba (insulin degludec) – SURPASS 3

30. Tirzepatide demonstrated significant weight reduction across
all 3 doses vs insulin glargine – SURPASS 4

31. Tirzepatide demonstrated significant weight reduction across all
3 doses vs Placebo (+BASAL INSULIN ± METFORMIN) – SURPASS 5

32. Common adverse reactions in placebo-controlled trials

33. Common adverse events in a trial of Tirzepatide vs Semaglutide 1 mg

34. Percentage of patients who discontinued treatment due to GI adverse
reactions

35. Incidence of hypoglycemia with Tirzepatide in placebo-controlled trials
• Hypoglycemia adverse reactions in a placebo-controlled monotherapy trial, 40 weeks
• Hypoglycemia adverse reactions in a placebo-controlled trial as add-on to basal insulin with or without
metformin

36. Composite endpoint results

37. Strength/weakness
Strength
Weakness /
Limitations of
use
- The study design
- It included consent and ethics
- The results are consistent
- Active comparator
- A large sample size with a large number of patients (power set and met)
- The relatively short duration of 40 weeks, which allowed only 16 weeks at a
steady state for the assessment of the highest Tirzepatide dose.
- The number of black patients was low.
- Tirzepatide has not been studied in patients with a history of pancreatitis.
- Tirzepatide is not indicated for use in patients with type 1 diabetes mellitus.
- Higher doses of Semaglutide were not available as comparators at the time

38. On March 28, 2022, The FDA has approved a higher 2-mg dose of the GLP-1 agonist
semaglutide (Ozempic, Novo Nordisk) for adults with type 2 diabetes
Aim
To conduct an adjusted indirect treatment comparison (aITC) of the efficacy of Tirzepatide 5/10/15 mg
versus Semaglutide 2 mg in patients with type 2 diabetes.
Conclusions
HbA1c and weight reductions were significantly greater for tirzepatide 10 and 15 mg versus Semaglutide
2 mg and were similar for Tirzepatide 5 mg versus Semaglutide 2 mg.

39. Case Study
Choose the most appropriate answer:
A) Add sulfonylurea to metformin
B) Discontinue metformin and initiate sulfonylureas
C) Add Tirzepatide (Mounjaro) SQ injection once weekly to metformin
D) Add Semaglutide (OZEMPIC) SQ injection once weekly to metformin

40. Case Study
The Mounjaro Experience, Designed For Patients Like Rami
Unhappy with his A1C and weight, concerned about life with Type 2 Diabetes (T2D)

41. The medication is also being studied in
people with overweight or obesity without
type 2 diabetes (SURMOUNT), but those
trials are still ongoing and will require a
separate FDA approval.
Future Studies

42. Future Studies
Trial Name: A Study of Tirzepatide Compared with Dulaglutide on Major Cardiovascular Events in
Participants with Type 2 Diabetes (SURPASS-CVOT)
What is the trial testing?
The SURPASS-CVOT trial is comparing Tirzepatide and Dulaglutide, on their ability to effectively and safely
treat people with type 2 diabetes who also have an increased risk of heart complications.
While Dulaglutide is already used in people with type 2 diabetes and has demonstrated heart health
benefits, this study is evaluating which therapy has greater results for preventing heart disease
complications.
In this 54-month study, an estimated 12,500 participants with type 2 diabetes and confirmed atherosclerotic
heart disease will be randomized into two groups and treated with either Tirzepatide or Dulaglutide.
The main result being measured is the amount of time before one of three heart complications occurs –
heart attack, death, or stroke. Other outcomes being measured include changes in weight, A1C, and blood
lipid levels.

43. This approval marks the first new class of diabetes
medications in almost 10 years,” said Dr. Charles Alexander,
an endocrinologist and diaTribe’s scientific and medical
advisor. “We have known about the GIP receptor for over 50
years, but initial studies led scientists to believe that it
would not have any role in the treatment of diabetes. How
wrong they were! Many people with type 2 diabetes will
immensely benefit from this new class of medicines.
Conclusion
Tirzepatide and type 1 diabetes
So far, all clinical trials for Tirzepatide have
only included people with type 2 diabetes or
obesity, and the drug is not currently intended
for people with type 1 diabetes. However,
given that some people with type 1 can also
develop resistance to insulin and may benefit
from weight loss , experts emphasized that
they would like to see a study of Tirzepatide in
appropriate people with type 1 diabetes in the
near future.

44. THANK
YOU

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