drugs used in the treatment of type 2 diabetes mellitus Flashcards
Why do we even need to treat hyperglycaemia?
For every decrease of 10 mmol/mol in HbA1c you reduce the risk of microvascular complications by 25%/
Treatment of T2DM
1st line= metformin
2nd line= dual therapy with METFORMIN PLUS A sulfonylurea or pioglitazone or GLP-1 agent or SGLT-2 inhibitor
3rd line= triple therapy
4th line= insulin therapy
What class of drug does metformin belong to?
Metformin is a biguanide.
What is the mechanism of action of metformin?
- reduces hepatic gluconeogenesis by stimulating AMP-activated protein (AMPK)
- increases glucose uptake and utilisation by skeletal muscle by increasing insulin signalling
- reduces carbohydrat absorption
- increases fatty acid metabolism
desirable affects of metformin
- reduces HbA1c by 15-20mmol/mol
- does not cause hypoglycaemia when used as a mono therapy
- reduces microvascular and macrovascualr complication
- causes weight loss
- reduces triglycerides and LDL
- safe to use in pregnancy and used to treat polycystic ovarian syndrome
adverse affects of metformin
- GI side affects can occur in up to 25% of people, but only 5% cannot tolerate the drug because of nausea, vomiting, diarrhoea and taste disturbances
- lactic acidosis is a rare side effect but can occur so should not be used in people with significant renal or hepatic disease
use of metformin in renal disease
metformin dose should be halved when EGFR is between 30-45 ml/min and when EGFR falls to 30ml/min metformin should be stooped completely
prescribing metformin
start with 500mg od or bd ad slowly titrate up to the maximum dose of 1g bd to reduce the risk of GI intolerance
examples of sulfonylureas
gliclazide, glibenclamide, glimepiride
mechanism of action of sulfonylureas
- displaces the binding of ADP-Mg2+ from the SUR1 subunit which closes the KATP channel causing depolarisation and subsequent insulin release
desirable affects of sulfonylureas
- works quicker than metformin
- reduces HbA1c by 15-20mmol.mol
- reduces risk of microvascular complications
adverse affects of sulfonylureas
- hypoglycaemia due to excessive insulin secretion even when blood glucose levels are low, more common in elderly, alcoholics and those with chronic kidney and liver disease
- weight gain due to the anabolic affect of insulin which is increased, increase in appetite and urinary loss of glucose decreased
prescribing a sulfonylurea
- only used first line where metformin is contra-indicated, mostly used second line with metformin
- should be avoided in the frail elderly, severely obese, and not safe in pregnancy
which sulfonylurea is safe in pregnancy
glibenclamide as it does not cross the placenta
only example of thiazolidinediones
pioglitazone
mechanism of action of pioglitazone
exogenous agonist of PPAR- GAMMA
- PPAR gamma associated with retinoid receptor X (RXR) to form a complex which acts as a transcription factor that binds to DNA to promote the expression of genes encoding several proteins involves in insulin signalling and lipid metabolism
desirable affects of pioglitazone
- reduces HbA1c by 15-20mmol/mol by increasing insulin sensitivity
- does not cause hypoglycaemia
- promotes fatty acid uptake and storage in adipocytes rather than in skeletal muscle and liver
adverse affects of pioglitazone
- increases the risk of hip fractures by 20% per year of use therefor should not be used in those over 65
- causes fluid retention as they promote sodium reabsorption in the kidneys so is contra-indicated in people with heart failure
whats the downside of pioglitazone
it does not reduce the risk of microvascular or macrovascular complications
prescribing pioglitazone
15-45mg od not really used as much anymore due to newer better agents
What is the incretin affect?
The incretin affect is the affect which describes how insulin responds to oral glucose greater than the insulin response which will be elicited in response to IV gludoce/
the ingestion of food
stimulus the release of glucagon like peptide 1 (GLP-1) AND glucose dependant insulinotropic peptide (GIP) from enteroendocrine cells in the small intestine (K cells in the duodenum, L cells in the ileum)
GLP-1 and GIP then
enter the portal blood and enhance insulin release from pancreatic beta cells and delay gastric emptying which enhances glucose uptake and utilisation
GLP-1 also
decreases glucagon release from pancreatic alpha cells causing decreased production of glucose
both of these actions
decrease blood glucose
incretin analogues known as
GLP-1 AGONISTS
List examles of GLP-1 Agonists>
exenatide and liraglutide
mechanism of action of GLP-1 AGONISTS
bind as agonist to GPCR GLP-1 receptors that increase intra-cellular cAMP concentration in pancreatic beta cells to stimulate insulin expression and excretion
desirable affects of GLP-1 agonists
- promotes insulin secretion but will not cause hypoglycaemia
- surpasses secretion of glucagon
- delayed gastric emptying causes early satiety
- acts on hypothalamus to reduce apetite
What are the adverse affects of GLP-1 Agonists and GIP[
- they have to be injected
- increases risk of acute pancreatitis
the action of GLP-1 and GIP is
very rapidly terminated by the enzyme dipeptidyl peptidase-4 (DPP-4)
examples of DPP-4 inhibitors
saxalgliptin, vildagliptin, linagliptin, alogliptin
mechanism of action
gliptins competitively inhibit DPP-4 prolonging the action of endogenous GLP-1 and GIP and increasing plasma insulin
desirable affects
- promotes insulin secretion from pancreas without hypoglycaemia
- surpasses glucagon
adverse affects
- they’re not potent at all because they only work on the endogenous GLP-1 AND GIP but in type 2 diabetes the levels of there 2 enzymes in already low so inhibiting there breakdown doesn’t have a massive affects on HbA1c levels
- may increase risk of acute pancreatitis
examples of SGLT-2 inhibitors
dapagliflozin, empagliflozin, canagliflozin
mechanism of action of SGLT-2 inhibitors
selectively blocks the SGLT-2 transported in the proximal tubule of the kidney by blocking the reabsorption of glucose directly causes glucosuria
desirable affects of SGLT-2 inhibitors
- reduces blood glucose but unlikely to cause hypoglycaemia
- causes wight loss for the first 3-4 weeks
adverse affects
- increased incidence of though and urinary tract infections
anyone who has type 2 diabetes and has had a myocardial infarction should be given
empagliflozin independent of there HbA1c levels as it reduces the risk of cardiovascular death
Who can you not use SGLT-2 in?
You cannot use SGLT-2 inhibit
