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Charis & Ellie vs Endocrine > Type 2 Diabetes Drugs > Flashcards

Type 2 Diabetes Drugs Flashcards

1
Q

which drug is first line?

A

metformin

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2
Q

how does metformin work?

A

a weak cellular poison - inhibits complex 1 of the mitochondrial respiratory chain
Reduces efficiency of mitochondrial respiration and causes fall in cellular ATP
fall in ATP
- rise in AMP:ATP
- activation of AMPK
- reduction in gluconeogenesis

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3
Q

how is metformin taken up?

A

highly hydrophilic so isn’t readily taken up by cells

only really gets into the intestine, liver and kidney because they have organic cation transporters (OTCs) to take it up

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4
Q

how is metformin excreted?

A

unchanged in the urine

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5
Q

what are the main effects of metformin on the body?

A

lowers hepatic glucose production (in patients with poorly controlled diabetes)
increases gut glucose utilization and metabolism
increases intestinal GLP-1 secretion
altered gut microbiome
decreased lipogenesis
reduced inflammation

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6
Q

how does metformin help diabetes?

A

lowers glucose production and increases glucose utilization
‘similar’ to insulin, but does it in an insulin independent way
sometimes metformin is incorrectly termed an ‘insulin sensitizer’ - doesn’t increase tissue sensitivity to insulin

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7
Q

what is the dose of metformin?

A

usual dose 500mg bd

max dose 1g bd

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8
Q

GI side effects of metformin

A

20% have GI intolerance
1/20 need to stop because of it
symptoms: diarrhoea, bloating, abdominal pain, dyspepsia, metallic taste in mouth
most likely reflective of the high conc. of metformin in the intestine
reduce side effects: introduce metformin slowly, 500mg od 1 week and increase by 500mg od per week or use a modified release formulatoin: metformin M/R 1g od or 2g od

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9
Q

metformin associated lactic acidosis (MALA)

A

metformin increases lactate production esp. in the liver and gut
lactate is normally cleared by the liver and kidneys
in AKI - often in the context of sepsis, when other sources of lactate too an impaired liver clearance - metformin is associated with greater risk of lactic acidosis

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10
Q

renal function and metformin

A

dose should be decreased as renal function falls
max dose 1g daily if eGFR <45ml/min
contraindicated if eGFR <30ml/min

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11
Q

metformin and weight

A

weight neutral or weight losing - important due to link between T2DM and obesity

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12
Q

what is the target of Sulphonylureas?

A

they work on the pancreatic B cells

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13
Q

how do sulphonylureas work?

A

bind to extracellular SUR1, causes the closure of ATP sensitive K channels (how K leaves the cell) this causes a rise in membrane potential which triggers the voltage gated calcium channel - calcium influx causes insulin exocytosis

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14
Q

how are sulphonylureas classed?

A

as insulin secretagogues
- cause pancreatic B cells to release insulin even when there is no increase in glucose, they act independently of glucose concentration because they are glucose independent they can result in hypoglycaemia

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15
Q

what is sulphonylureas affect on weight?

A

they increase weight because of increased insulin

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16
Q

what is the most common sulphonylurea in the UK?

A

Gliclazide

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17
Q

what is the dose for sulphonylureas?

A

gliclazide

start 40-80mg od - little benefit by increasing over 80mg bd although max dose 160mg bd

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18
Q

what are the side effects of sulphonylureas?

A

hypoglycaemia
- don’t over treat
- careful in the elderly - esp. long acting SUs that are renally cleared
- caution if hypoglycaemia would be risk e.g. driving, working up ladders
- risk 5 x lower than insulin treated T2DM
weight gain
- insulin concentrations are increased. Insulin is anabolic - increased carbohydrate storage. Insulin increases appetite
CV risk
- some think increases CV risk
- some potentially are
- not so much a risk with Gliclazide because it’s pancreatic specific
- recent trials also don’t show increased risk

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19
Q

how do TZDs (thiazolidinediones) work?

A

act as ligands and bind to and activate PPARy (a transcription factor)
this then forms a complex with a co-activator
increased transcriptional activation of PPARy of target genes - 100s of these target genes some beneficial and some are adverse

20
Q

what is the classification of TZDs?

A

only true insulin sensitizers used to treat T2DM

21
Q

how do TZDs affect weight?

A

increase

22
Q

how do TZDs affect BP?

A

reduce

23
Q

what group is contraindicated for TZDs?

A

over 65s because fracture risk and HF risk

24
Q

what is the physiological mechanism of TZDs on adipocytes?

A

increase differentiation from pre-adipocytes to adipocytes
increase fat mass - subcutaneous, the better place to store fat
‘lipid steal’ - FFA uptake removes fat from liver and muscle - reduces lipotoxicity
increases adiponectin which acts on the liver to increase insulin sensitivity
net-result - increased insulin sensitivity

25
Q

what is the dose for TZDs?

A

particularly potent in obese women
Pioglitazone - only available TZD
Pioglitazone 15-30mg od

26
Q

what are the side effects of TZDs?

A

Weight gain
Fluid retention – resulting in peripheral oedema and doubling of risk of hospitalization for cardiac failure. – But absolute risk in younger patients without HF is very low. Big issue for people with heart failure though
Fracture risk – fat accumulation in bone marrow and reduction in bone density. Up to doubling of fracture risk esp in the elderly.
CV risk – pioglitazone probably reduces CV risk

27
Q

what are incretin?

A

incretins are the substances released by the gut when glucose is ingested - leading to more insulin release and incretin is one of the 1st things to be lost in the development of T2DM

28
Q

what are the 2 types of incretin?

A

GIP form K cells and GLP-1 from L cells

29
Q

what doe GLP and GIP do?

A

amplifies insulin release, acting via the G protein coupled receptors but only after the production of insulin has been triggered already
GLP-1 also reduces the production of glucagon, can act on the hypothalamus suppressing appetite, can act on the stomach to reduce emptying, can act on the heart and increase heart rate.

30
Q

what are DDP4 inhibitors

A

incretin drugs
they are known as gliptins
There are different classes of DDP4 inhibitors which inhibit the DDP4 molecules in different ways – binding to different subunits
DDP4 inactivates peptides including GLP-1 and GIP which then means there will be a lesser effect. The action of DDP4 inhibitors therefore causes less inhibition of these peptides so there is more GLP-1 and GIP in circulation and there is an increased incretin effect

31
Q

different types of DDP4 inhibitors?

A

Sitagliptin,
Alogliptin,
Saxagliptin
– commonly used in the UK

32
Q

what dose of DDP4 is used?

A

not massively potent
weight neutral
Sitagliptin usual dose - 100mg od

33
Q

what are the side effects of DDP4 inhibitors?

A

Generally very well tolerated
Possible increased risk of pancreatitis
CV risk – mixed. Some signal for increase heart failure hospitalization

34
Q

what are GLP-1 receptor antagonists?

A

the GLP-1 molecule is modified to avoid DDP4 breakdown - there have been different modifications done to give a longer half-life by putting them in little capsules
GLP-1 like molecules modified to avoid breakdown by DPP4. Act directly on the GLP-1 Receptor. Pharmacological levels – far greater than seen with DPP4i.

35
Q

what do GLP-1 receptor antagonists do?

A

act to promote insulin secretion (insulin secretagogues) in a glucose dependent mechanism (better than SUs)
lower glucagon which is increased in T2DM

36
Q

what does do GLP-1 antagonists need?

A

potent drugs
liraglutide usual does is 1.2mg daily subcutaneously
semaglutide 0.5mg weekly subcutaneous

37
Q

what is the effect of GLP-1 antagonists on blood pressure and weight?

A

cause 2-3kg weight loss

BP 2-5mmHg reduction in systolic BP and increase in HR 3-10bpm

38
Q

what are the side effects of GLP-1 antagonists?

A

Nausea and vomiting – improves after roughly 6 weeks but can be hard to deal with. Maybe because of early satiety and reduced gastric emptying
Gall stones – small increase
Sustained increase in pancreatic lipase and amylase – probably not increased risk in pancreatitis
CV risk – reduces CV mortality mostly
Evidence they improve renal disease

39
Q

what are SGLT2 inhibitors?

A

sugar is filtered by the glomerulus into the renal tubules - glucose transporters are in a renal tubules called SGLT2 which reabsorb the glucose from the urine - shouldn’t be glucose in most people’s urine
need to be specific to SGLT2 because SGLT1 is the main glucose transporter in the gut so is very necessary

40
Q

effect of SGLT2 inhibitors on the body?

A

makes you pee out sugar, good for glucose control and pees out a lot of calories causing weight loss

41
Q

what are the other effects of SGLT2 inhibitors?

A

Inhibiting a Na glucose transporter so less reabsorption of sodium. Glucose loss also causes osmotic diuresis. – both have diuretic effect and could explain some of the reduction in heart failure
Urate excretion is increased – reduction in plasma urate concentrations
Increased sodium delivery to distal convoluted tubule = increased Na uptake by Na/K/Cl transporter at macula densa = Increase in adenosine secretion = reduction in renal afferent vasodilation = reduced filtration pressure = renal protection
Glucose reduction – Reduction in insulin and increase in glucagon = Increase in lipolysis – Increase in FFA results in increase Ketone body production = FFA and Ketones are a fuel to cardiac myocytes – improves cardiac bioenergetics. Cardiac benefit = But this can increase Ketosis and risk of ketoacidosis

42
Q

what is the dose of SGLT-2 inhibitors?

A

moderate efficacy, if renal function is impaired then there is less benefit
Blood pressure – 3-6mmHg SBP and 2-3mmHg DBP reduction
Lipids – slight increase in LDL and HDL cholesterol
Dapagliflozin, Canaglifozin and Empagliflozin – common ones in use
Empagliflozin – 10mg od

43
Q

what are the potential side effects of SGLT2 inhibitors?

A

Genital mycotic infection (thrush) – secondary to glycosuria
o 10% of women and 4% of men
o Usually mild and readily treatable
o For some – intractable so they have to stop
Fournier Gangrene
o Rare but severe. 15/100,000 person years with SGLT2i vs ~10/100,000 person years with DPP4i
Hypovolemia and hypotension
o Due to diuretic effect
o Caution in patients on other diuretics or with low blood pressure
Diabetic Ketoacidosis
o ~double risk of DKA compared to DPP4i. Can occur despite normal glucose (Euglycaemic Ketoacidosis)
o Due to increased ketone body production (low insulin, increase glucagon)

44
Q

effect of SGLT2i on CV risk?

A

massive benefit
38% reduction in CV death
35% reduction in HF hospitalisation

45
Q

effect of SGLT2i on renal outcomes?

A

very good for most renal outcomes

Charis & Ellie vs Endocrine (79 decks)

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