Type 2 Diabetes Treatments Flashcards
What is the main aim of treatment in type 2 diabetes?
Reduce the risk of microvascular complications
The KATP channel involved in insulin secretion is an octomeric complex composed of what?
4 potassium inward rectifier (Kir) 6.2 subunits // 4 sulphonylurea receptor (SUR) 1 subunits
In the KATP channel involved in insulin secretion, what forms the potassium selective ion channel?
Tetramer of Kir 6.2 subunits
In the KATP channel involved in insulin secretion, what regulates potassium channel activity?
SUR1 subunits
Where does ATP bind to the KATP channel involved in insulin secretion?
Each of the Kir 6.2 subunits
What happens in the KATP channel involved in insulin secretion, to maintain the resting potential of the beta cell and inhibit insulin secretion until ATP is bound?
ADP-Mg++ binds to the SUR1 subunits to keep the channel open
Which type 2 diabetes drugs have their action at the KATP channel which regulates insulin secretion?
Sulphonylureas
What type of drug is a biguanide?
Metformin
What is the 1st line agent for type 2 diabetes?
Metformin
In what dosages is metformin available?
500mg, 850mg, 1g
Metformin should usually be started on what dose?
500mg once or twice daily
There is little evidence for taking more than how much metformin daily?
1g
Where does metformin act? What is its role there?
Liver // Lower glucose production
How does metformin lower glucose production at the liver?
Decrease hepatic gluconeogenesis // Increase peripheral glucose uptake
What are some other functions that metformin is said to have?
Reduced absorption of glucose from the gut // Enhanced anaerobic glycolysis
How effective is metformin at hyperglycaemia management?
Reduces HbA1c by 15-20mmol/l by lowering insulin resistance
How likely is metformin to cause hypoglycaemia?
Very unlikely (when used as monotherapy)
What effect does metformin have on weight?
Weight loss (suppresses appetite)
Does metformin prevent microvascular complications?
Yes
What is the only drug to prevent macrovascular complications of type 2 diabetes?
Metformin
Is metformin safe in pregnancy?
Yes
What are some minor effects of metformin which may contribute to its ability to decrease risk of macrovascular complications?
Reduces triglycerides and LDL, minor reduction in BP
What other conditions can metformin be used in?
PCOS and NAFLD
Where are the main metformin side effects? Give examples.
GI tract: anorexia, nausea, vomiting, diarrhoea, abdominal pain, taste disturbance
How common are GI side effects from metformin? How often can people not tolerate them?
25% will have side effects, 5% will be intolerable
Metformin can interfere with the absorption of which vitamins?
B12 and folic acid
What are some very rare side effects of metformin?
Lactic acidosis, liver failure, rash
When may lactic acidosis occur in a patient on metformin?
Co-existing renal failure or acute illness
How can adverse effects of metformin be reduced?
Slow release formulations and start low go slow methods
Does metformin cause renal toxicity?
Not directly, only if there is underlying renal disease
With regards to renal toxicity, when should metformin be stopped?
If eGFR < 30ml/min // Serum creatinine > 150macromol/l
If a patient is on metformin and their eGFR is between 30-45ml/min, what should be done?
Halved dose
When should metformin be temporarily withheld?
If a patient is getting IV contrast
If a patient is on metformin and is acutely unwell or having elective surgery, what should they be put on instead?
Insulin
With regards to liver toxicity, when should metformin be stopped?
If there is advanced cirrhosis/liver failure // Risk of lactic acidosis e.g. encephalopathy or alcohol excess
When are sulphonylureas used as treatment for type 1 diabetes?
1st line in underweight type 2 diabetics, or those intolerant to metformin // 2nd line as an add on to metformin
Chlopropramide and tolbutamide are examples of what?
1st generation sulphonylureas (rarely used now)
2nd generation sulphonylureas are used in practice now. Give 2 examples? Why are these better than 1st generation?
Gliclazide, glibenclamide // Shorter acting
What is the time taken until peak release of insulin, following a sulphonylurea?
1-2 hours
What is the dosage of gliclazide?
40mg od - 160mg bd
What is the dosage of glibenclamide?
5mg - 15mg od
What must still be functioning in order for sulphonylureas to work?
Beta cells
How do sulphonylureas work?
Displace the binding of ADP-Mg++ from the SUR1 subunit thus closing the beta cell KATP channel to depolarise the cell and increase insulin secretion
Is there a risk of hypoglycaemia with sulphonylureas?
Yes
How effective are sulphonylureas at hyperglycaemia management?
15-20mmol/mol decrease in HbA1c by increasing insulin secretion and rapid reduction in hyperglycaemia
Which type(s) of complications do sulphonylureas prevent?
Microvascular only
Who should sulphonylureas be given with care in, because of the risk of hypoglycaemia?
Elderly/frail, alcohol excess, liver disease
What effect do sulphonylureas have on weight?
Weight gain
Apart from hypoglycaemia, what are some side effects of sulphonylureas?
GI upset, headache (rarely hypersensitivity and liver dysfunction)
When should sulphonylureas be avoided?
Hepatic or renal failure, pregnancy
What other drugs will impede the actions of biguanides and sulphonylureas due to their own effects on insulin action?
Corticosteroids and thiazides
What type of drug are thiazolidinediones?
PPAR gamma agonists
What is the only available thiazolidinedione agent?
Pioglitazone 15-45mg once daily
What is PPAR gamma?
A nuclear receptor which is found predominantly in adipose tissue, but also in skeletal muscle and liver
How are thiazolidinediones taken into a cell? What do they bind with?
They are lipophilic and readily enter cells // Bind with PPAR gamma with high affinity
Thiazolidinediones acting on PPAR gamma has what effect?
Transcription of genes which encode lipoprotein lipase, fatty acid transport proteins, fatty acid CoA synthase and GLUT4
What is the role of lipoprotein lipase?
Hydrolyses the breakdown of lipids in lipoproteins into fatty acids and glycerol
Deficiency of lipoprotein lipase leads to what?
Hypertriglyceridaemia
What is the overall action of pioglitazone?
Enhance the action of insulin at target tissues
What effect do thiazolinediones have on hyperglycaemia management?
Reduces HbA1c by 15-20mmol/mol by increasing insulin sensitivity
What effect do thiazolinediones have on fatty acids?
Increase uptake and storage in adipocytes, rather than the skeletal muscle and liver
Do thiazolinediones cause hypoglycaemia?
Not unless used in combination with sulphonylureas
Do thiozolinediones prevent complications?
No (improvement in microalbuminaemia though)
What cardiac effect do thiazolinediones have?
Big risk of worsening heart failure due to fluid retention (in those with PRE-EXISTING heart failure)
Are thiazolinediones hepatotoxic?
Yes
What effect will thiazolinediones have on weight? Why?
Increase- increased subcutaneous fat and fluid retention
Who are thiazolinediones not recommended in and why?
Those over the age of 65 due to increased risk of hip fractures
Which two types of diabetes drugs act on the incretin pathway?
DPP-IV inhibitors and GLP-1 agonists
What happens to the incretin effect in type 2 diabetes?
It is reduced
Drugs involving the incretin effect will only work if there is what?
Some degree of insulin production present
GIP is one of the hormones involved in the incretin effect. Where is it secreted from? In response to what?
Secreted from endocrine K cells, in response to absorbable carbohydrates and lipids (hence increased after meals)
What action does GIP have in response to meals?
It binds with its receptor on the beta cells to increase cAMP and produce insulin
Where is GLP-1 expressed?
Pancreatic alpha cells and L cells of intestinal mucosa
The secretion of GLP-1 throughout the day is correlated with what?
Secretion of insulin
What is the function of GLP-1?
Binds to GPCRs on the beta cell to increase cAMP and release insulin. Also decreases glucagon so there is decreased glucose production.
Delayed gastric emptying is an action of which drugs? What is the advantage of this?
DDP-IV inhibitors and GLP-1 agonists, it means not as much CHO needs broken down at once
GLP-1 is metabolised by what?
DDP-IV
Do drugs acting on the incretin pathway cause hypos? Why/why not?
No- when glucose is in a normal range, incretin drugs do not bind
Give 2 examples of GLP-1 receptor agonist?
Exenatide and liraglutide
Which GLP-1 agonist drug has a shorter half life?
Exenatide
How often and how are GLP-1 agonists taken?
Exenatide = twice daily SC injection, liraglutide = once daily SC injection
What are the actions of GLP-1 agonists?
Increase insulin secretion from pancreas // decrease glucagon secretion // increase insulin sensitivity
What effect do GLP-1 agonists have on weight? Why?
Weight loss- acts on the hypothalamus to reduce appetite
What are the adverse effects of GLP-1 agonists?
Nausea (usually resolves), injections, potential pancreatic cancer/pancreatitis
What do all DDP-IV inhibitor drug names end in?
Gliptin
How are DDP-IV inhibitors administered? How often?
Once daily oral
DDP-IV inhibitors are usually used in combination with which other drugs? Can they be used as mono therapy?
Metformin and thiazolinediones // They can but not common
What is the action of DDP-IV inhibitors?
Increase the action of GLP-1, promote insulin secretion from the pancreas
What effect do DDP-IV inhibitors have on weight?
Neural
Which drug which acts on the incretin pathway has the biggest decrease in HbA1c?
GLP-1 agonists
Give 2 examples of SGLT2 inhibitors?
Canagliflozin, empagliflozin
What is the mechanism of action of SGLT2 inhibitors?
Selectively block the reabsorption of glucose by the SGLT2 transporter in the proximal tubule to deliberately cause glycosuria
Do SGLT2 inhibitors have a risk of hypoglycaemia?
No
What effect do SGLT2 inhibitors have on weight?
Weight loss (because you pee out the sugar i.e. calories)
Is the action of SGLT2 inhibitors dependent on insulin?
No
Apart from reduction in blood glucose, what are some other positive effects of SGLT2 inhibitors?
Reduces CV risk and hospitalisation for heart failure, beneficial for most renal outcomes
What are some adverse effects of SGLT2 inhibitors?
Thrush, and increased risk of UTIs
Who do SGLT2 inhibitors not work in?
Those with an eGFR < 60
Which type 2 diabetics receive insulin?
Those who fail on non-insulin therapies
What type of insulin is used in type 2 diabetes? What treatment is this added onto?
Intermediate acting insulin once daily, with metformin +/- sulphonylurea
What type of insulin (i.e. human or analogue) is used in type 2 diabetes?
Human
Is there an upper limit to the amount of insulin that can be given to a type 2 diabetic?
No, keep going until sugars are back to normal
What are some side effects of insulin treatment?
Hypo/hyperglycaemia, local reaction at injection site, loss of fatty tissue at injection site, insulin resistance
What should happen to insulin dose in a patient with renal failure?
Decreased (as it will take longer to be excreted)
