Drugs and Their Targets in T2DM Flashcards
If a drug is insulin dependent, what does this mean?
In order to have an effect, enough insulin must be present
Which drugs can be described as insulin independent?
- α-glucosidase inhibitors
- SGLT2 inhibitors
Name two drug classes involved in increasing insulins sensitivity
- Biguanides
- Thiazolidinediones (glitazones)
As well as impacting insulin sensitivity, what other action do the biguanides and thiazolidinediones share?
Decrease hepatic gluconeogenesis
Which drugs will increase insulin secretion?
- Sulphonylureas
- Incretin mimetics
- Glinides
- DPP-4 inhibitors
Biguanides are insulin ____________
Biguanides are insulin dependent
Glinides are insulin ___________
Glinides are insulin dependent
α-glucosidase inhibitors are insulin ___________
α-glucosidase inhibitors are insulin independent
SGLT2 inhibitors are insulin _____________
SGLT2 inhibitors are insulin independent
DPP-4 inhibitors are insulin ______________
DPP-4 inhibitors are insulin dependent
GLUT4 is a glucose transport protein associated with which tissues?
Target tissues
(e.g. adipose and skeletal muscle)
Describe the process by which insulin is released
- Elevated BGL
- GLUT2 allows entry of glucose to cell cytoplasm
- Glucokinase converts glucose to glucose-6-phosphate
- Glucose-6-phosphate is converted to ATP
- ATP acts on KATP channel
- KATP channel closes and depolarisation of cell occurs
- Volages activated Ca2+ channels open
- Ca2+ influx triggers exocytosis of insulin storage granules
Which drug class works by slowing glucose absorption from the GI tract?
α-glucosidase inhibitors
During the insulin secretion mechanism, what exactly causes KATP channel to close?
The ratio of ATP:ADP
How many subunits make up the KATP channel?
8
Which two types of subunit are involved in the KATP channel?
- Kir6.2
- SUR1
To which subunit will ATP bind to in order to close the KATP channel?
Kir6.2
Which substance can bind to the KATP channel in order to keep it open and to which subunit will it bind?
ADP-Mg2+
SUR1
To which subunit will the sulphonylurea drug class bind to in the KATP channel and what is the useful effect of this?
SUR1
This induces depolarisation leading to insulin release regardless of whether blood sugars are high or low
In order for the sulphonylureas to be of use what is required?
Pancreatic β cells
(this is why this drug class is useless in T1DM)
Why may the effect of the sulphonylureas decrease over time in a patient?
β cells decrease over time, even in T2DM
Give 4 examples of sulphonylureas
- Tolbutamide (1st gen - rarely used)
- Glibenclamide
- Gliclazide
- Glipizide
How do the sulphonylureas act?
Displacement of the ADP-Mg2+ from the SUR1 subunit causing closure of the KATP channel and subsequent depolarisation
Which risk is associated with sulphonylureas since they act independently to BGLs?
Hypoglycaemia
(BGLs may already be low when administered for example, which would reduce them further)
How can the sulphonylureas be administered?
Orally
What is the duration of action of the different sulphonylureas?
- Short acting - tolbutamide - 4-6 hours
- Long acting - glibenclamide, glipizide, gliclazide - 16-48 hours
Which type(s) of vascular risks associated with diabetes do the sulphonylureas reduce?
Microvascular complications
In which patients is hypoglycaemia a particular risk when taking sulphonylureas?
- Elderly (renal function decreases with age)
- Reduced hepatic or renal function
- Pregnant women
(N.b. Long acting agents pose a higher hypoglycaemic risk)
In a treatment algorithm, sulphonylureas will usually be _________ line therapy with __________
In a treatment algorithm, sulphonylureas will usually be second line therapy with metformin
(N.b Not in pregancy; they may also be used 3rd line with TZDs and metformin)
Sulphonylureas cause weight ________
Sulphonylureas cause weight gain
What are the main reasons sulphonylureas can cause weight gain?
- Increased appetite
- Glucose is lost which induces calorific retention
- Anabolic effect of insulin (glucose storage) is increased
Why are glinides less likely to cause hypoglycaemia when compared with sulphonylureas despite their mechansims being similar?
Action of the glinides increases with glycaemia
(sulphonylureas work the same regardless of glycaemic level)
Where do glinides bind and what is the result?
- SUR1 at the benzamido site
- KATP closes and depolarisation induced
- Insulin released
Give two examples of glinides
- Repaglinide
- Nateglinide
How are glinides administered?
Orally
Why may the glinides be useful in lowering post-prandial glucose levels?
Thay have a rapid onset of action
Why is it that glinides are safer in CKD than sulphonylureas?
Glinides are metabolised by the liver
When is the use of glinides contraindicated?
- Hepatic impairment
- Pregnancy
- Breast-feeding
Where are GLP-1 and GIP released from?
- L cells in the ileum and colon
- K cells in the duodenum and jejunum
What is the effect of the incretins?
- Enhanced glucose uptake and utilisation (GLP-1 and GIP)
- Decreased hepatic gluconeogenesis (GLP-1 only)
How do the incretins cause enhanced glucose uptake and utilisation?
- Enhance insulin release
- Delay gastric emptying
How do the incretins cause decreased glucose production from the liver?
Decrease glucagon release
Give an example of an incretin analogue
Extenatide
Liraglutide (long acting)
What are the main effects of extenatide?
- Increase insulin secretion
- Decrease glucagon secretion
- Slow gastric emptying
Extenatide will cause weight _______ by ____________ appetite and increasing _________ by acting on the ___________
Extenatide will cause weight loss by decreasing appetite and increasing satiety by acting on the hypothalamus
How are the incretin analogues administered?
Subcutaneous injection
What are the side effects of the incretin analogues?
- Nausea
- Hypoglycaemia
- Pancreatitis (rare)
In which two ways can the incretin effect be maximised/maintained pharmacologically?
- Reduce endogenous incretin breakdown (via DPP-4 inhibitors)
- Exogenous incretin analogues
Why will more insulin be released if the same amount of glucose is taken orally versus by IV?
Incretin effect
Incretins (GLP-1 and GIP) increase insulin release
Which class of drugs can competitively inhibit the enzymatic breakdown of the incretins to maintain the incretin effect (and keep insulin levels higher)?
DPP-4 inhibitors (Gliptins)
Actions of GLP-1 and GIP are very rapidly terminated by which enzyme?
Dipeptidyl peptidase-4 (DPP-4)
Give an example of a DPP-4 inhibitor
- Sitagliptin
- Saxigliptin
- Vildagliptin
What effect do DPP-4 inhibitors have on weight?
They are weight neutral
How are DPP-4 inhibitors administered?
Orally
What are the side effects of DPP-4 inhibitors?
Generally well tolerated
Nausea, yet NO hypoglycaemia (when used as a monotherapy)
As well as causing a mild weight loss, the actions of fat distribution are desirable in incretin analogue use, why?
Fat is redistributed from the liver to subcutaneous tissue
This reduces organ complications and is essentially healthier
What is α-glucosidase and what is its role?
A brush border enzyme in the small intestine
Breaks down CHOs to monosaccharides
Why are α-glucosidase inhibitors useful in T2DM?
Slow the breakdown of CHOs to monosaccharides
Reduces peak glucose levels in the blood
Name an α-glucosidase inhibitor
Acarbose
What are the adverse effects of α-glucosidase inhibitors?
- Flatulence
- Bloating
- Abdominal pain
- Diarrhoea
(occur as excess CHOs build up causing increased bacterial activity)
There is a risk of hypoglycaemia with α-glucosidase inhibitors
True or false?
False
What is the only therapeutic agent in the biguanide class of drugs?
Metformin
Generally metformin is considered the _______ line drug for T2DM
Generally metformin is considered the first line drug for T2DM
In which instances would metformin be contraindicated?
- Hepatic dysfunction
- CKD or reduced kidney function
What are the key effects of metformin?
- Reduce hepatic gluconeogenesis
- Increase glucose uptake and utilisation by skeletal muscle
- Reduce CHO absorption
- Increase fatty acid oxidation
Why is metformin a desirable drug for use in T2DM?
- Reduces hyperlgycaemia
- Do not cause hypoglycaemia
- Can be used with other agents
- Reduces micro and macrovascular complications of diabetes
- Causes weight loss
- Can be used in pregnancy
- Can be taken orally
- Minor BP reduction
- Reduces triglycerides and LDL
What are the side effects of metformin?
- GI side effects are most common - nausea, anorexia, diarrhoea
- Metallic taste in the mouth
Generally these effects subside with time
Lactic acidosis (much more serious, yet rare) implicated in patients with hepatic or CKD. Alcohol excess may also induce this.
What dose is metformin
a) Generally started at
b) Rarely prescribed more than?
a) 500mg
b) 1g
(Metformin can be prescribed up to 3g/day yet there is not much added benefit of doing this vs 1g - adding another drug is more effective)
What is the main priciple behind the action of the thiazolidinediones (TZDs)?
Enhance the action of insulin
(this reduces the amount of insulin required to have an effect)
TZDs are agonists of _________ receptor ________-___________ ____________ _
TZDs are agonists of nuclear receptor proliferator-activated receptor γ
(proliferator-activated receptor γ = PPARγ)
What occurs when TZDs bind to proliferator-activated receptor γ?
- PPARγ which associates with retinoid receptor X (RXR)
- Activated PPARγ-RXR complex acts as a transcription factor that binds to DNA
- This promotes expression of genes encoding several proteins involved in insulin signalling etc.
Examples include:
- Lipoprotein lipase
- Fatty acid transport protein
- GLUT4
What are the desirable effects of the TZDs?
- Promote fatty acid uptake and storage in adipocytes, rather than skeletal muscle and liver
- Reduced hepatic glucose output
What is the only TZD still in use?
Pioglitazone
What are the adverse effects of pioglitazone?
- Weight gain
- Fluid retention (Na+ resorption by kidneys promoted)
- Increased incidence of bone fractures
What are the only SGLT2 inhibitors currently licensed (2017)?
- Dapagliflozin
- Empagliflozin
What is the mode of action of the SGLT2 inhibitors?
- Resorption of glucose is blocked in the proximal kidney tubule
- Glucose is lost in the urine (glucosuria)
- Blood glucose levels are reduced
What are the key benefits to Dapagliflozin and other SGLT2 inhibitors?
- Weight loss (calorific loss)
- Glucose lost in urine causing reduced BGLs
- Osmotic diuresis (water follows glucose into urine ↑ weight loss)
- Reduces CV risk
- Reduces death by any cause
- Benefits micro and macrovascular complications of diabetes
In which instances should metformin be avoided?
- CKD
- Hepatic failure/cirrhosis
- Alcoholism
- CLD
- Cardiac failure
- Mitochondrial myopathy
- Other serious illness
What are the main side effects of SGLT2 inhibitors?
- UTI
- Thrush
- Polyuria
(due to increased glucose output in urine)
Due to osmotic diuresis, SGLT2 inhibitors may even reduce _______ ________
Due to osmotic diuresis, SGLT2 inhibitors may even reduce blood pressure
1/3rd of all T2DM patients will eventually require ________ as part of their treatment
1/3rd of all T2DM patients will eventually require insulin as part of their treatment
What is one key, unique benefit to insulin therapy?
There is no upper dose limit - it is used as much as required
What are the side effects of insulin treatment?
- Hypoglycaemia
- Hyperglycaemia
- Local reactions at injection site
- Loss of fatty tissue at injection site
- Insulin resistance
What happens to the required insulin doses in renal failure and why is this?
Required dose decreases
Insulin is usually excreted by the kidneys, yet this process becomes ineffective
Why can insulin induce hyperglycaemia?
Somogyi effect
There is overcompensation for induced hypoglycaemia
Which pathway can regulate glucose levels in insulin independent tissues?
Poyol pathway
Why are insulin independent tissues such as nerves, retina and blood vessel walls more susceptible to the effects of raised blood glucose?
They cannot regulate blood glucose levels through uptake
How does the Poyol (aldose reductase) function?
- When there is significant excess of glucose in the blood, aldose reductase activates
- Glucose is converted mostly to sorbitol yet some is converted to methylglyoxal and acetol
- Sorbitol exerts osmotic pressure on cells inducing damage
- Sorbitol dehydrogenase converts sorbitol to fructose so it can diffuse out of the cell
- Advanced glycation end products (AGEs) may also cause damage
- Glycating sugars and excess glucose bind to proteins forming AGES
- AGEs are less effective and HbA1c is an example
Why does aldose reductase only activate in significantly raised blood glucose?
It has a very high Km when compared with glucokinase
Why does metformin cause weight loss?
Suppresses appetite
Thiazolidinediones (TZDs) exert their effect in which tissues?
- Adipose
- Skeletal muscle
- Liver
How are GLP-1 (incretin) analogues administered?
Injected subcutaneously twice daily
(before first and last meals)
As well as T2DM, when else may metformin be used?
- NAFLD
- Polycystic ovary syndrome
Metformin may induce a deficiency in which 2 main things?
- Vitamin B12
- Folic acid
What is the normal dose range for glicazide, yet there is little therapeutic benefit above which dose?
40-160mg
80mg
Which sulphonylurea is preferentially used in pregnancy and why?
Glibenclamide
Does not cross placenta
(used at 5-15mg)
What is eGFR?
Estimated glomerular filtration rate (of kidneys)
At which eGFR levels will metformin doses need to be altered and in which way for each?
eGFR = 30-45ml/min, half dose given
eGFR < 30ml/min (or serum creatinine >150micromol/l), STOP medication
(eGFR should be >/= 90ml/min in a healthy patient)
In terms of beta cell function, what is a potential concern with using sulphonylureas?
It has been suggested they may be implicated in increased beta cell decline
How do GLP-1 agonists cause weight loss?
Act on hypothalamus to increase satiety
(suppress appetite)
What is the extent of weight loss in SGLT2 inhibitors?
3-5kg
(weight loss plateaus after this)
Which drug is very useful for a type 2 diabetic patient with high CV risk?
- Dapagliflozin
- Empagliflozin
Dapagliflozin should not be used if a patient has an eGFR below which level?
eGFR <60ml/min
Which drugs, when used with sulphonylureas may cause a reductive effect?
- Corticosteroids
- Thiazide diuretics
