Pharmacology: Diabetes Treatments Flashcards
Metformin
Lowers glucose production and increases glucose utilisation
First line therapy for T2DM
It is a biguanide
Metformin molecular mechanism
Weak cellular poison
- Inhibition of complex 1 of the mitochondrial respiratory train
- Fall in cellular ATP (rise in ADP/ ATP ratio)
- Many consequences
- Rise in AMP: ATP ratio
- Activation of AMPK
- Reduction in gluconeogenesi
Metformin Site of action
Hydrophilic- not readily taken up by cells.
Requires active transport by Organic Cation Transporters (OCT)
- Present in intestines, liver and kidney
Excreted unchanged in the urine (metformin is NOT metabolised)
Metformin physiological mechanisms (6)
Lowers hepatic glucose production
Increases gut glucose utilisation and metabolism
Increases intestinal GLP-1 secretion
Altered gut microbiome
Decrease lipogenesis
Reduced inflammation
Metformin clinical use
Potent glucose lowering (HbA1c ~18mmol/L)
Weight neutral or negative
Usual dose 500mg bd
Cheap
Metformin side effects
GI Intolerance
- Diarrhoea, bloating, abode pain, metallic taste, dyspepsia
- To reduce side effects initiate slowly or use modified release formulation
Metformin Associated Lactic Acidosis (MALA)
Metformin Associated Lactic Acidosis
Metformin increases lactate production (especially by gut and liver)
Lactate is normally cleared by liver and kidneys
In Acute Kidney Injury, metformin is associated with greater risk of lactic acidosis.
metformin dose should be decreased as renal function falls
- Max dose 1g daily if eGFR <45ml/min
- Contraindicated if eGFr <30ml/min
Sulphonylureas
Act directly on pancreatic beta-cells to increase insulin secretion
–> insulin secretagogues
Sulphonylurea Generation Examples
1st Generation (very limited use)
- Tolbutamide
- Chloropropamide
2nd Generation
- Gliclazide
- Glipizide
- Glimepiride
- Glibenclamide
Sulphonylurea Stimulated insulin secretion (4)
Glucose independent insulin secretion
- SUs bind to SUR1
- Closure of Katp
- Rise in membrane potential triggers voltage gated calcium channel
- Calcium influx leads to insulin exocytosis
Sulphonylurea Clinical use
Potent glucose lowering (HbA1c ~18mmol/L)
increase weight (1-2kg on average)
Risk of hypoglycaemia
Cheap
Sulphonylurea Hypoglycaemia risk
Risk of hypoglycaemia increased with:
- Increased age
- diabetes duration
- creatinine
- lower HbA1c (esp <50mmol/L)
Sulphonylurea Side Effects
Hypoglycaemia
Weight gain
Thiazolidinediones (TZDs)
PPAR(gamma) agonists
Net effect is to increase fat mass in subcutaneous depots and to ‘suck out’ fat from viscera (liver and pancreas) and muscle.
Also increased adiponectin and reduced inflammatory cytokines like TNF-alpha and IL-6
Work to increase fat mass and increase beneficial/ reduce harmful cytokines
TZDs molecular mechanism
PPAR(gamma) ligands
Ligand binding results in formation of a complex with a co-activator
increased transcriptional activation of PPAR(gamma) target genes
TZDs physiological mechanism (4)
Main effect is on adipocytes
- Increased differentiation from pre-adipoctyes to adipocytes
- Increase fat mass (subcutaneous)
- ‘lipid steal’- FFA uptake removes fat from liver and muscle which reduces lipotoxicity.
- Increases adiponectin which acts on insulin to increase insulin sensitivity.
net Result: increased insulin sensitivity
TZDs clinical use
Good efficacy (HbA1c reduction. 15-20mmol/l) - Especially potent in obese women
increase in weight
- Increase in fat mass and fluid retention
Reduction in blood pressure
- SBP: Reduced by 4.7
- DBP: Reduced by 3.8
TZDs side effects
Weight gain
Fluid retention
- resulting in peripheral oedema
- doubles risk of hospitalisation for cardiac failure
Fracture risk
- fat accumulation in bone marrow
- reduction in bone density
TZDs uses
Due to side effects they are normally used only in
obese, young, insulin resistant patients
TZD example
Pioglitazone
Incretin Drug Types (2)
DPP4 Inhibitors
GLP-1 Receptor Agonists
Incretins
Intestinal secretion of insulin
Secreted in response to nutrient stimuli
GIP from K cells
GLP-1 from L cells
Incretin MOA
Act via amplifying pathway (of beta cells)
Act via GLP-1/ GIP receptor. G-protein coupled.
Results in increase cAMP
- Closes Katy channel
- Modulate calcium currents
- Directly acts on insulin secretory mechanism
net Result: Augmentation of insulin secretion when the pathway is triggered (by glucose or sulphonylurea)
DPP4 inhibitor examples
Dipeptidyl Peptidase 4 Inhibitors
Commonly used DPP4i
- Sitagliptin
- Alogliptin
- Saxagliptin
DPP4 inhibitors mechanism
Inhibit breakdown of GLP-1 and GIP
Augments insulin secretion
Incretin action is glucose dependent and therefore does NOT cause hypoglycaemia
DPP4 inhibitors clinical use
Weak glucose lower (HbA1c reduction ~5-8mmol/L)
Weight neutral
DPP4 inhibitor side effects
Minimal
Possible increased risk of pancreatitis
GLP-1 Receptor Agonists
Potent injectable treatments that promote incretin mediated insulin secretion
GLP-1 Receptor Agonist mechanism
GLP-1 molecule modified to avoid breakdown by DPP4.
Different modifications or attachment alter half life
Act-directly on GLP-1 receptor
Act to promote insulin secretion in a glucose dependent mechanism
Also lower glucagon
GLP-1 receptor agonist action in other tissues (2)
Act in the hypothalamus to reduce hunger
Act in the intestines to reduce gastric emptying
GLP-1 receptor agonist clinical use
Potent(HbA1c reduction ~11-15mmol/L)
Weight loss (2-3 kg on average)
Blood Pressure
- SBP: 2-5mmHg reduction
Heart rate increase by 3-10bpm
GLP-1 Receptor agonist examples
Liraglutide
Semaglutide
GLP-1 Receptor Agonists Side Effects
nausea and vomiting
- often improves after ~6 weeks
Gallstones (small increase)
CV and renal benefit
SGLT2 Inhibitors
Specific inhibitors of renal sodium glucose transporter 2
Increased renal glucose losses results in lowering of blood glucose and loss of calories
–> results in weight looss
SGLT2 Inhibitors Physiology Direct Effects
Glucose loss results in osmotic diuresis.
Inhibition of SGLT2 reduces Na reabsorption
– Mild diuretic action
urate excretion is increased
- reduction in plasma urate concentration
SGLT2 Inhibitors Renal Protection (4)
- 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
SGLT2 Inhibitors Indirect Effect
Glucose Reduction
- Reduction in insulin
- Increased in glucagon
Increase in lipolyisis
- Increase in FFA results in increased ketone body production
FFA and ketones are a fuel to cardiac monocytes
–> Cardiac benefit
SGLT2 Inhibitor Clinical Use
moderate Efficacy (HbA1c ~11mmol/L)
Glucose lowering relies on renal glucose filtration
- No glucose benefit if eGFR <45ml/min
Blood Pressure
- SBP reduction by 3-6 mmHg
- DBP reduction by 2-3mmHg
Lipids: Slight increase in LDL and HDL cholesterol
SGLT 2 Inhibitor Examples
Empagliflozin
Dapagliflozin
Canagliflozin
SGLT2 Inhibitor Side Effects
Genetic mycotic infections (thrush)
- secondary to glycosuria
- usually mild and readily treatable
Fournier Gangrene
-rare but severe
Hypovolaemia and hypotension
-due to diuretic effect
Diabetic ketooacidosis
- due to increased ketone body production
SGLT2 Inhibitor contraindications
Prolonged fasting
Acute Illness
