treatment of type 2 diabetes Flashcards
aims of management
- treat symptoms
- prevent microvascular complications
- prevent cardiovascular complications
- screen for complications early while treatable
diet changes
- aim is to lose 5-10kg in one year
- reduce refined sugar intake
- reducing fat intake
- increase fruit and veg intake
- reducing salt
- safe and sensible alcohol consumption
how low should glucose aim to be
- low enough to stop symptoms
- prevent complications - HbA1c <7%
aim of HbA1c target for type 2
53mmol/mol (7%)
what are some insulin secretagogues
- sulphonylureas
- DPP4 inhibitors
- GLP-1RA
what are some insulin sensitizers
- metformin
- thiazolidinediones
molecular mechanism of metformin
- inhibition of complex 1 of the mitochondrial respiratory chain
- fall in cellular ATP
- rise in ADP/ATP ratio
- lowers hepatic glucose production
- increases gut glucose utilisation and metabolism
where is metformins site of action
- requires active transport by organic cation transporters
- these are present in the intestines, liver and kidneys
what is the usual dose of metformin
500mg bd
max dose 1g bd
side effects of metformin
- GI intolerance
- diarrhoea
- bloating
- abdo pain
- dyspepsia
- metallic taste in mouth
- metformin associated lactic acidosis
what is done to reduce side effects of metformin
initiate slowly
-500mg od 1 week and increase by 500mg od per week
or use modified release formation
why does metformin associated lactic acidosis happen
metformin increases lactic acid production
- lactate is normally cleared by the liver and kidneys
- in acute kidney injury metformin is associated with greater risk of lactic acidosis
is metformin first line
yes
what are the 2nd generation sulphonylureas
- gliclazide
- glipizide
- glimepiride
- glibenclamide
mechanism of action of sulphonylureas
- SUs bind to SUR1
- closure of ATP sensitive K channels
- rise in membrane potential triggers voltage gated calcium channel
- calcium influx leads to insulin exocytosis
do sulphonylureas increase or decrease weight
increase
risk of sulphonylureas
hypoglycaemia
most common sulphonylurea in UK
gliclazide
who do we need to be cautious with when prescribing sulphonylureas
- elderly
- where hypoglycaemia would be a risk (driving, working up ladders etc)
what type of ligands are thiazolidinediones
PPARgamma
-results in switching on 100s on genes
what does TZDs mainly have an effect on
adipose tissue
what is TZDs effect on adipocytes
- increase differentiation from pre-adipocytes to adipocytes
- increased fat mass
- lipid seal - FFA (free fatty acids) uptake removed fat from liver and muscle, reduces lipotoxicity
- increases adiponectin which acts on liver to increase insulin sensitivity
- net result is increased insulin sensitivity
who are TZDs particularly potent in
obese women
TZDs affect on blood pressure and weight
increase in weight
reduction in blood pressure
what is the only available TZD called
Pioglitazone
usual dose of Pioglitazone
15-30mg od
side effects of TZDs
- weight gain
- fluid retention (doubles risk of cardiac failure)
- fracture risk (fat accumulation in bone marrow and reduction in bone density)
does Pioglitazone reduce cardiovascular risk
yes
what are incretins
intestinal secretion of insulin
what are the two incretin peptides
GIP from K cells
GLP-1 from L cells
incretins mechanisms of action
increase in cAMP acts in many ways to increase release of insulin
-can only work when pathway is triggered by either glucose or sulphonylureas
what do gliptins do (DPP4i)
- inhibit breakdown of GLP-1 and GIP
- augment insulin secretion so are insulin secretagogues
are DPP4i very potent?
no
-weak glucose lowering
side effects of DPP4i
very minimal
-possible risk of pancreatitis
what do GLP-1RA do
- they are GLP-1 like molecules modified to avoid breakdown by DPP4
- act directly on the GLP-1 receptor
- promote insulin secretion in a glucose dependent mechanism
- also lower glucagon
- act on hypothalamus to reduce appetite
- and intestines to reduce gastric emptying
effect of GLP-1RA on weight and bp
lose weight
reduce bp
increase heart rate
are GLP-1RA potent?
yes
name two GLP-1RA
liraglutide and semaglutide
side effects of GLP-1RA
- nausea and vomiting
- small increase in gallstones
how are GLP-1RA given
injection
-one is oral
what do SGLT2 inhibitors do
increase renal glucose loss resulting in glucose reduction and weight loss
what are the direct effects of SGLT2i
glucose loss results in osmotic diuresis
- inhibition of SGLT2i reduces Na absorption
- urate excretion is increased - reduction in plasma urate concentrations
- renal protection
indirect effects of SGLT2i
- reduction in insulin and increase in glucagon
- increase in FFA results in increase in ketone body production
- cardiac benefit
- BUT risk of ketosis and ketoacidosis
what does SGLT2i glucose lowering effect rely on
renal glucose filtration
name three commonly used SGLT2i’s
- dapagliflozin
- canagliflozin
- empagliflozin
side effects of SGLT2i
- thrush
- fournier gangrene
- hypovolemia and hypotension
- diabetic ketoacidosis
do SGLT2i’s have a CV benefit
yes
