LT4 Precision Medicine in Diabetes

Question 1

What is precision medicine?

Answer 1

Using information about an individual or group to be more precise about how we treat our patients to maximise benefits from a treatment and minimize harm

Question 2

What information is used in precision medicine?

Answer 2

New technology/methods allow new data to be gathered

‘Simple’ clinical phenotype enhanced by modern molecular phenotyping

Question 3

Why is precision medicine important?

Answer 3

In general, the older we get the more drugs are accumulated to treat different issues

With precision medicine, can use genotyping to see which drug will be most effective for a specific individual (try to decrease drug burden)

Question 4

What is drug burden?

Answer 4

Increased age correlates to increased number of drugs taken

Taking more drugs increases the drug-drug interaction that can occur (potential for harm increases)

Question 5

What is polypharmacy?

Answer 5

People taking many drugs

Question 6

What do we mean by improving the balance of harm and benefit?

Answer 6

Having a good benefit to risk ratio

Meaning the drug will give a lot of benefit while having few or no side effects (this is ideal)

Question 7

What is Clopidogrel?

Answer 7

Anti-platelet drug = decrease risk of stroke (blood clots)

It prevents platelets (a type of blood cell) from sticking together and forming a dangerous blood clot

Question 8

How are clots normally dealt with and what is a novel approach?

Answer 8

Normally removed by thrombolysis

But Tayside is the first place to do thrombectomy

Question 9

What are potential treatments for hypertension?

Answer 9

ACE inhibitors

Diuretics
Calcium-channel blockers
Angiotensin-2 receptor blockers (ARBs)

Question 10

What does GORD stand for and what is a treatment for it?

Answer 10

Gastro-oesophageal reflux disease, a condition where stomach acid flows back up into the esophagus, causing symptoms like heartburn and acid reflux

Omeprazole

Question 12

What does Omeprazole do?

Answer 12

Omeprazole reduces the amount of acid your stomach makes

It’s widely used to treat indigestion and heartburn, and acid reflux

Question 13

What is the mechanism of action of Clopidogrel?

Answer 13

Clopidogrel is absorbed in GI

Metabolized in the liver, Clopidogrel is cleaved into an active metabolite by CYP2C19

Active metabolite inhibits the P2RY12 ADP receptor on PLATELETS

Normally, ADP causes platelet activation and aggregation so inhibiting it prevents this = thereby reducing the risk of thrombosis

Question 14

What characteristic does CYP2C19 have and what does this do?

Answer 14

CYP2C19 is polymorphic = meaning there are many genetic variants in the population

25%-30% carry one or more reduced function alleles

Question 15

What is the issue with only giving every patient with ischaemic stroke Clopidogrel?

Answer 15

People with the reduced function CYP2C19 cannot cleave Clopidogrel to the active metabolite meaning that the drug does not cause anti-platelet properties

This means that the drug does not work for 25%-30% of patients = increasing their risk of recurring stroke

Can’t tell if the drug works until later when someone has sufferent another stroke

Question 16

What is the solution for people with reduced functioning CYP2C19?

Answer 16

Using genotyping to see which alleles are present in the patient

If they have a reduced funciton allele then give them alternate drug that can be metabolized or has efficacy

Question 17

What was correlated for MACE and haemorrhage in patients with both CYP2C19 loss of funciton alleles?

Answer 17

Inidivduals who received clopidogrel, that had both loss of funtion alleles has a higher incidence of Major Adverse Cardiovascular Events (MACE) but lower risk of haemorrhage

Question 18

What genetic variant can cause issues with taking simvastatin and what symptoms can this cause?

Answer 18

Altered SLCO1B1 gene decreases OATP1B transport = increase risk of rhabdomyolysis and intolerance

Rhabdomyolysis is a condition that causes your muscles to break down (disintegrate), which leads to muscle death. When this happens, toxic components of your muscle fibers (MYOGLOBIN) enter your circulation system and kidneys. This can cause kidney damage.

Question 19

What is rhabdomyolysis?

Answer 19

Rhabdomyolysis is a condition that causes your muscles to break down (disintegrate), which leads to muscle death. When this happens, toxic components of your muscle fibers enter your circulation system and kidneys. This can cause kidney damage.

Question 20

How can statins cause rhabdomyolysis?

Answer 20

If there is reduce SLCO transporter efficiency

They cannot enter the liver to be broken down so they build up in the bloodstream

This can lead to higher levels of the drug in muscles, which may cause muscle damage.

Question 21

What genotype should be considered with Abacavir?

Answer 21

Abacavir is a medication used to treat HIV, but in individuals with this genetic variant, it can trigger an immune system response that leads to severe side effects

For people carrying the HLA-B*57:01 allele, the immune system recognizes abacavir as a harmful substance, even though it’s not. This causes the immune system to react abnormally, leading to an allergic or hypersensitivity reaction.

Question 22

What genotype should be considered with Codeine?

Answer 22

Codeine is a painkiller that is part of a group of medicines called opiates

Codeine is metabolized in the liver, primarily by the enzyme CYP2D6, into its active metabolite morphine, which is responsible for codeine’s analgesic effects.

Ultrametabolizers have many copies of the gene CYP2D6 = causing huge analgesic effects

If breastfeeding mothers are ultemetabolizers = then baby will die because overexposed to morphine

Question 23

What genotype should be considered with Azathiaprine?

Answer 23

Poor metabolizers have increased risk of toxicity

Question 24

Why is cancer such an exciting area for precision medicine?

Answer 24

Because cancer is dictated by genetic mutations leading to tumours So it is easier for drugs to be designed for an individual person's genetics

Question 25

Why is diabetes not like cancer in terms of precision medicine?

Answer 25

Dangerous to bipsy the pancreatic tissue Diabetes is not caused by somatic mutations that we can target that are unique to the diseased tissue (most of the time)

Question 26

Why is the classification of diabetes not accurate?

Answer 26

T2D is just everything that is not T1D But in reality there are many more categories that fall under T2D

Question 27

What is the primary way of diagnosing T1D?

Answer 27

NO C-peptide levels produced because no insulin Onset occur in a timeframe that allows for development of an autoimmune disease (common age 4-7 years) Then look at autoantibody production (GAD antibody)

Question 28

What does HNF1A pathogenic mutation cause?

Answer 28

HNF1A is a TF that regulates genes involved in insulin production, secretion, and glucose metabolism in the pancreas, particularly in beta cells Since the HNF1A protein is essential for proper insulin regulation, a mutation in this gene causes beta cell dysfunction and leads to insulin deficiency. The condition tends to be autosomal dominant, meaning that having one copy of the mutated gene is enough to cause the disease. This means if a person inherits the mutation from one parent, they have a 50% chance of developing MODY.

Question 29

What drug is best treatment for HNF1A MODY and why?

Answer 29

Sulphonylureas because it works directly on the K_ATP channel allowing insulin secretion Whereas metformin works by reducing hepatic glucose production = which helps lower blood glucose but not by increasing insulin This is because HNF1A MODY means that the body cannot secrete insulin

Question 30

What is the KCNJ11 mutation?

Answer 30

Kir6.2 subunit of K_ATP channel mutation Channel cannot close in response to increased glucose = so hyperpolarized (no depolarization) No calcium influx = no insulin secretion If this occurs at 6 weeks old = neonatal diabetes

Question 31

What drug is best treatment for KCNJ11 mutation and why?

Answer 31

Again, a problem with opening of K_ATP channel = so use sulphonylureas

Question 32

What evidence is there that prescription is not optimized?

Answer 32

Open prescribing Different regions prescribe diferently = shows that there is no uniform/logical reason for these things Newcastle has highest rate of SU prescription = doesn't mean that people in Newcastle respond best to SUs

Question 33

Can we predict the best and worst repsonders to a given drug?

Answer 33

Yes, using clinical phenotype for stratification (grouping)

Question 34

What is the flowchart for evaluating differential HbA1c response?

Answer 34

Use routine data for discovery analysis = ID characteristsics associated with differential drug response Use trial data for validation analysis = using primary outcome of trial where possible (not biased because randomized trial) Evalutation of mechanism and other outcomes

Question 35

Do clinical features show differential HbA1c response to TZD and SU therapy?

Answer 35

Yes showed that sex and BMI are differential factors for TZD and SU Age affected both drugs

Question 36

Splitting the group in 4 looking at sex and BMI, what groups responded best to TZDs ad SUs?

Answer 36

Obese females HbA1c levels repsond better to TZDs Non-obese males HbA1c levels repsond better to SUs

Question 37

What did the trial data valid about TZDs and SUs in these two groups? (obese females, non-obese males)

Answer 37

For non-obese males: although SU kept glucose levels lower for the first few years after 5 years they reached the same place This is still beneficial because didn't need insulin for those few extra years For obese females: TZD kept glucose levels constantly lower than SUs during the 5 years

Question 38

What were the side effects of TZDs and SUs in non-obese males and obese females, repectively?

Answer 38

Sulphonylureas had no effect on weight for the non-obese males TZDs caused weight gain in obese females

Question 39

What is the 1st line and 2nd line therapy for T2D patients?

Answer 39

1st line = Metformin 2nd line = 5 possibilities GLP1-RA, SU, TZD, SGLT2 inhibitors, DPP4inhibitors

Question 40

What clinical features were needed to be taken into account?

Answer 40

Baseline HbA1c, duration of diabetes Age, sex, and BMI HDL Kidney function (eGFR) ALT = Alanine aminotransferase levels are measured in units per liter (U/L) and are used to assess liver health

Question 41

What are the improvements seen when precision medicine for 2nd line T2D therapy was applied?

Answer 41

Less than 20% currently initiated model optimal therapy 5mM average HbA1c beenfit 40% longer before treatment intensification Lower risks of T2D micro- and macrovascular complications

Question 42

What are the interpretations of the model predictions?

Answer 42

The model informs ONLY on HbA1c reduction There are many factors that need to be considered in choosing the best drug for an individual = CV risk, renal risk, heart failure, side effects, weigh change These predictions are an average At population level there is some error

Question 43

What is the polygenic risk score?

Answer 43

Thousands of genetic variants can contribute to risk of disease Sum up variants into a score Higher score = higher risk of developing disease

Question 44

What impacts the polygenic risk score more?

Answer 44

High genetic risk score more impactful than high clinical risk score Clinical risk score = looking at everything else execpt genetics