Drugs for obesity

Question 1

What is type 2 diabetes?

Answer 1

• high blood sugar and insulin resistance
• organs are unresponsive to insulin; less glucose is being stored and/or used
• 422 million people in 2014

Question 2

What group of people seem to have rising cases of type 2 diabetes?

Answer 2

rising more rapidly in low- and middle-income countries than in high-income countries

Question 3

What are some major side effects of diabetes?

Answer 3

• blindness
• kidney failure
• heart attacks
• stroke
• lower limb amputation

Question 4

How many people are affected by obesity?

Answer 4

• over 50% of the world’s population will be overweight by 2035
• 4 billion people affected (mainly children)

Question 5

What are some drivers of obesity?

Answer 5

• dietary preferences towards processed foods
• greater levels of sedentary behaviour
• weaker policies to control food supply and marketing
• decrease in healthcare resources for weight management and education

Question 6

What is fueling the rise of type 2 diabetes?

Answer 6

• obesity
• 1 in 3 will be obese by 2034
• 1 in 10 will develop type 2 diabetes

Question 7

How are obesity and type 2 diabetes connected?

Answer 7

• high body mass index
• type 2 diabetes diagnosis
• risk for microvascular damage increase (small blood vessels; kidneys, nerves, eyes)

Question 8

If obesity was reduced, what other diseases might also decrease?

Answer 8

• underactive thyroid
• depression
• insomnia
• heart disease
• fatty liver
• breast cancer

Question 9

What were some weight loss drugs in the 1950s and 1960s?

Answer 9

diet pills based on amphetamines (“uppers”, buzzed)
- the popularity of these lowered due to addiction

Question 10

What weight loss drug was recalled in 1997?

Answer 10

fen-fen (recalled after 24 years on market)
- damages heart valves
- legal fees: $14 billion, over 50,000 people (most costly liability cases in history)

Question 11

What are hormones?

Answer 11

chemical messengers
- many are carried through the blood and act at a distance (act on a different organ than the one which produces them)
- act via hormone receptors (often on the cell membrane )

Question 12

How does glucagon work?

Answer 12

regulating blood sugar raising it:
- pancreas gets a low blood sugar signal
- glucagon is released from the pancreas into the liver
- glucagon stimulates glycogen breakdown in the liver
- raises blood sugar

Question 13

How does insulin work?

Answer 13

regulating blood sugar by lowering it:
- pancreas gets a high blood sugar signal
- insulin is released; then it either stimulates glucose uptake from the blood or it goes into the liver and simulates glycogen formation
- lowers blood sugar

Question 14

What is glucagon-like peptide 1?

Answer 14

small chain of amino acids that act on the GLP-1 receptor to regulate insulin levels (which affects many organs)

Question 15

What do GLP-1 receptors recognize?

Answer 15

a GLP-1 analog

• weight loss drug is free in the solution cell membrane

Question 16

Where does GLP-1 act?

Answer 16

• liver (increase glycogen storage)
• brain (increase neurogenesis and memory)
• Heart
• pancreas
• skeletal muscle
• blood vessel
• kidney
• fat cells

Question 17

What kind of regions are involved in GLP-1 signaling?

Answer 17

brain regions, giving rise to certain behaviors

Question 18

What is Ghrelin?

Answer 18

• different types of hormone
• released by the stomach
• hunger cues

Question 19

What is GLP-1 released from?

Answer 19

the intestine and by neurons

Question 20

When are Ghrelin signals high, and GLP-1 low?

Answer 20

• reactivity to food cues
• meal anticipation
• food motivation
  -preference for palatable food

Question 21

When are Ghrelin signals low, and GLP-1 high?

Answer 21

• taste sensitivity
• nausea and aversion

Question 22

What research was done in the 1970s?

Answer 22

• research on gut ulcers
• look at hormones that are secreted when people eat
• GLP-1 identified as a powerful hormone

Question 23

What are the actions of GLP-1?

Answer 23

• stimulate insulin secretion
• inhibit glucagon secretion

this is a double action for regulating blood sugar

Question 24

What was a challenge with the human GLP-1 hormone?

Answer 24

it disappears very quickly

Question 25

What was found after experimenting on Glia monsters?

Answer 25

they have genes for Exendin-4, the protein that became the first diabetes GLP-1 treatment (it’s similar to GLP-1, but breaks down much slower)

Question 26

What was the impact of GLP-1 medication?

Answer 26

impacted over 100 million people with type 2 diabetes, over 1 billion with obesity and over 3 million with short bowel syndrome
- 2023, over 20 million doses used

Question 27

What is the future for GLP medication?

Answer 27

GLPs has propelled the research and development of new treatments for cardiovascular disease and neurodegenerative conditions

Question 28

How was GLP-1 used in clinical research?

Answer 28

1993
- infused people with type 2 diabetes with GLP-1
- blood sugar level returns to normal in 4 hours
- insulin secretion stimulated
- glucagon inhibited
- GLP-1 is working differently due to dual action

Question 29

What was the design of the study done on GLP-1 trials?

Answer 29

• early studies focused on keeping the dose low
• treat people with GLP-1
• people eat a meal
• 30 min later, researchers check blood glucose level

Question 30

What was the problem with the GLP-1 trials?

Answer 30

• people didn’t want to finish their meal (nauseous)
• low appetite

Question 31

How are GLP-1 agonist drugs different from GLP-1?

Answer 31

• change amino acids
• prevent degradation of the peptide
• clues from nature

Question 32

What was the landmark phase 3 clinical trail with semaglutide in 2021?

Answer 32

• 1961 people
• inclusion criteria: body mass index of over 30
• exclusion criteria: Diabetes
• lasted 75 weeks

people overweight or obese had clinically relevant weight loss (15%) with weekly injections of semaglutide (GLP-1 agonist) added to lifestyle changes

Question 33

After the semaglutide clinical trial, what were some hypotheses made about people with type 2 diabetes?

Answer 33

for people with type 2 diabetes, if decrease weight by 15%, 86% of these people will have remission of their diabetes (indirect impact)

Question 34

Why are peptides not stable when taken orally?

Answer 34

easily broken down by the stomach

Question 35

How was an oral peptide created?

Answer 35

an oral formulation mixed with an absorption enhancer

Question 36

What are some problems with oral peptides?

Answer 36

• needs to be taken on an empty stomach
• 1 hour before other meds
• 30 before food

Question 37

What was the efficacy of the oral version of semaglutide?

Answer 37

• 68 weeks
• 15% weight loss
• 2.5% in placebo

Question 38

What were some side effects of the oral version of semaglutide?

Answer 38

• gastrointestinal adverse events

Question 39

What is “food noise” and how was this affected by people on GLP-1 agonists?

Answer 39

• frequent thoughts about food
• communication between brain and gut
• many people say the “food noise” is quieter
• reduced pleasure in eating

Question 40

What happens if people stop taking GLP-1 agonists?

Answer 40

people regain 2/3 of their weight within 2 years of stopping

Question 41

How long do people stay of GLP-1 agonists?

Answer 41

• half of the people stopped after 1 year
• 70% after 2 years
• missed the pleasure of eating

Question 42

What are some future areas for GLP-1 receptor agonists?

Answer 42

• chemical versions of GLP-1 receptor agonists
• GLP-1 receptor agonist - effects on cognition
• health revolution or cosmetic procedure for the wealthy
• deepen social stigma around body size
• off label use, eventual over-the-counter, (but they have strong side effects)