diabetes medications

Question 1

what type of medication is metformin?

Answer 1

a biguanide

Question 2

how does metformin work (molecular mechanism)?

Answer 2

it is a weak cellular poison.

it inhibits complex 1 of mitochondrial respiratory chain
–> fall in cellular ATP (rise in ADP to ATP ratio)
–> rise in AMP : ATP , activation of AMPK and reduction of gluconeogenesis

Question 3

can metformin work passively?

Answer 3

no - Requires active transport by Organic Cation Transporters (OCTs)

Question 4

where does metformin become concentrated after an oral dose?

Answer 4

intestine
liver
kidney

Question 5

how does metformin help in diabetes?

Answer 5

lowers hepatic glucose production (in patients with poorly controlled diabetes)
&
increases gut glucose utilisation and metabolism

Question 6

when is metformin used and what dose?

Answer 6

potent glucose lowering in weight neutral or patients that need to lose weight
usually 500mg once daily but can go up to 1g

Question 7

what are the main side effects of metformin?

Answer 7

GI intolerance - diarrhoea, bloating, abdominal pain, dyspepsia, metallic taste in mouth

metformin associated lactic acidosis (MALA) as it increases lactate production, in impaired kidney function lactate cannot be cleared. usually will not happen if there is no kidney injury

Question 8

what is the main benefit of metformin instead of other diabetes drugs?

Answer 8

large decrease in risk of cardiovascular mortality

Question 9

what is the first line treatment of type 2 diabetes?

Answer 9

metformin and lifestyle changes

Question 10

what is the prefix for sulphonylurea drugs?

Answer 10

gli- (e.g. gliclazide)

Question 11

what is the mechanism of action of suphonylureas?

Answer 11

glucose stimulated insulin secretion

glucose metabolism –> rise in intracellular ATP –>
closure of K channels –> change in membrane potential triggers CA channel –> calcium influx causes insulin exocytosis

Question 12

basic summary of suphonylureas

Answer 12

Act directly on pancreatic beta-cells to increase insulin secretion – as such are termed “Insulin secretagogues”

Are glucose independent i.e. insulin secretion even when not needed (when glucose is low or normal). This results in HYPOGLYCAEMIA.

Question 13

what is sulphonylureas clinical use?

Answer 13

potent glucose lowering
increase weight
risk of hypoglycaemia
gliclazide most common
normal dose 40-80mg, max dose 160mg

Question 14

what is the mechanism of action of thiazolidinediones?

Answer 14

TZDs are PPARg agonists

Ligand binding results in formation of a complex with a co-activator

Increased transcriptional activation of PPARg target genes

Question 15

what type of cells do TZDs mainly act on?

Answer 15

adipocytes

Question 16

how do TZDs work on adipocytes?

Answer 16

Increase differentiation from pre-adipocytes to adipocytes
Increases fat mass (subcutaneous)
‘lipid steal’ – FFA uptake removes fat from liver and muscle. Reduces lipotoxicity.
Increases adiponectin which acts on liver to increase insulin sensitivity

this all results in increased insulin sensitivity

Question 17

what effects do TZDs have?

Answer 17

increase in weight
reduction in blood pressure
fluid retention
fracture risk due to fat accumulation in bone marrow

Question 18

what is the only TZD available?

Answer 18

pioglitazone

Question 19

what are the 2 incretin peptides?

Answer 19

GIP from K cells
GLP-1 from L cells

Question 20

what is the mechanism of action of incretin drugs?

Answer 20

they act via the amplifying pathway

at the GLP-1/GIP receptor (G protein coupled)
increase in cAMP works in many ways
net result is augmentation of insulin secretion only when the pathway is triggered
no hypoglycaemia

Question 21

what are the 2 main types of incretin drugs?

Answer 21

DPP4 inhibitors (aka gliptins)
GLP-1 receptor agonists

Question 22

what is the clinical use of DPP4 inhibitors?

Answer 22

they inhibit breakdwon of GLP-1 and GIP
insulin secretagogues- weak glucose lowering
weight neutral

Question 23

what are the benefits of DPP4 inhibitors over other drugs?

Answer 23

well tolerated by patients- little proven side effects

Question 24

how do GLP-1 receptor agonists work?

Answer 24

insulin secretagogues in a glucose dependant mechanism
act on other tissues especially hypothalamus to reduce appetite and intestines to reduce gastric emptying

Question 25

what is the GLP-1RA clinical use?

Answer 25

potent HbA1c reduction
2-3kg weight loss
liraglutide 1.2mg daily , semaglutide 0.5mg weekly
expensive
CV benefit and some renal benefit

Question 26

what are the GLP-1RA side effects?

Answer 26

nausea and vomiting (should improve after 6 weeks)
gallstones (small increased risk)

Question 27

how do SGLT2 inhibitors work?

Answer 27

decrease uptake of sugar by 1/4- resulting in glucose reduction and weight loss - effect eventually plateaus so should be no dangerous weight loss

Question 28

what is the SGLT2i clinical use?

Answer 28

moderate efficacy- mid range on potency of other drugs
lower glucose
lower bp
most common in tayside is empagliflozin- 10mg od
large CV benefit

Question 29

what are the side effects of SGLT2 inhibitors?

Answer 29

thrush (genital mycotic infection)
fournier gangrene (rare)
hypovolaemia and hypotension
diabetic ketoacidosis

Question 30

what is do you do if diabetes patient is showing signs of nephropathy?

Answer 30

stop metformin/ reduce dose
assess albumin to creatinine ratio (ACR)
start SGLT2i to protect renal function