T2DM Therapeutics Flashcards
Oral anti-hyperglycaemic agents?
Biguanides:
• Metformin
Sulphonylureas:
• Glicazide
• Glibenclamide
• Glimeparide
Thiazolidinediones:
• Pioglitazone
GLP-1 receptor agonists: • Exenatide • Exendin • Liraglutide • Lixisenatide
DPP-4 inhibitors (AKA gliptins) • Vildagliptin • Sitagliptin • Saxagliptin • Linagliptin
SGLT2 inhibitors:
• Dapagliflozin
• Canagliflozin
• Empagliflozin
Brief mechanism of action of metformin?
Increases sensitivity to insulin
Dosages available for metformin?
500, 850 and 1000mg tablets
Most start on 500mg OD/BD and this is increased slowly, however there is little evidence for a dose >1g BD
Liquid formulation has 500mg in 5ml
Effects of metformin?
Hyperglycaemic Mx - reduced HbA1c by 15-20 mmol/L (lowers insulin resistance)
Hypoglycaemia - does not cause these when used as a monotherapy
Weight - overall, it is weight neutral but it can sometimes reduce weight
Prevents micro and macrovascular complications
Additional effects of Metformin
Reduced triglycerides and LDL
Effective in PCOS and NAFLD
Metformin in pregnancy?
Safe to use in both gestational DM and pregnancy with pre-existing T2DM
Adverse effects of metformin?
GI side effects (anorexia, nausea, vomiting, diarrhoea, abdominal pain, taste disturbance)
Interference with vitamin B12 and folic acid absorption (anaemia is rare though)
Lactic acidosis (most likely in existing severe renal, cardiac or liver failure, due to tissue hypoxia)
Liver failure
Rash
Occurrence of lactic acidosis with metformin use?
Rarely occurs de novo but patients at risk should be cautioned: • ACUTE heart failure • Sepsis • Acute MI • Respiratory failure • Hypotension of any cause
Metformin use when renal toxicity is a concern?
Avoid or stop if eGFR <30ml/min or serum creatinine >150μmol/l
Half dose if eGFR 30-45 ml/min
Temporarily withhold if IV contrast being used, e.g: angiography, CT scan
Metformin use when liver toxicity is a concern?
Discontinue if advanced cirrhosis/liver failure
Discontinue if risk of lactic acidosis, e.g: encephalopathy, alcohol excess
May be beneficial in NAFLD
What is the 1st line agent for T2DM?
Metformin
Generations of sulphonylureas?
1st generation (rarely used now):
• Chlorpropramide
• Tolbutamide
2nd generation (shorter-acting): • Glicazide 40mg OD - 160mg BD • Glipizide 2.5 mg – 15 mg • Glibenclamide/glyburide 5 mg - 15 mg OD • Glimepiride 1 mg - 6 mg OD
Brief mechanism of action of sulphonylureas?
Insulin secretagogues that binds to SUR receptors and allow closure of the KATP channel
Causes depolarisation of the cell (as K+ accumulates) and this opens Ca+ channel and allows insulin secretion
Effects of sulphonylureas?
Hyperglycaemic Mx:
• Reduces HbA1c by 15-20 mmol/mol by increasing insulin secretion
• Results in more rapid reduction in hyperglycaemia than insulin sensitizers
• Concern re-acceleration of beta cell demise
Prevent microvascular complications but NOT macrovascular complications
Uses of sulphonylureas?
Only used 1st line in underweight T2DM or 2nd line, as add on to metformin, or in those intolerant to metformin
Adverse affects of sulphonylureas?
Hypoglycaemia (more so in older agents); particular care must be taken in elderly-frail patients and those with alcohol excess and liver disease
Weight gain (only used 1st line in underweight patients)
GI upset and headache
Rarely, hypersensitivity, blood dyscrasias and liver dysfunction
In whom should sulphonylureas be avoided?
Severe renal or hepatic failure
Brief mechanism of action of Thiazolidinediones (TZDs)?
PPARγ agonists; PPARγ is a receptor mostly found in adipose tissue, and also in skeletal muscle and liver, so these drugs target fat cells
Genes activated inc. those than encode:
• Lipoprotein lipase (hydrolysis of lipids found in lipoproteins)
• Fatty acid transport protein and fatty acid CoA synthase (allow lipogenesis and adipocyte differentiation)
• GLUT4 (increases glucose uptake and utilisation)
Effects of TZDs?
Hyperglycaemia management:
• Reduces HbA1c by 15-20 mmol/mol, by increasing insulin sensitivity
Hypoglycaemia (not if used without an SU)
Weight GAIN due to increase in subcutaneous, not visceral, fat and fluid retention
Heart failure (due to fluid retention)
Prevents MACROvascular complications but not microvascular
Complications of Glitazone drugs?
Increase risk of hip fractures (not recommended in those >65 years)
Which classes of drugs act on the incretin pathways?
GLP-1 receptor agonists
DPP-4 inhibitors
These are both insulin secretagogues
Describe the incretin effect
Amplification of insulin secretion observed when glucose is taken orally as opposed to infused IV, to provide identical plasma glucose conc.
Intestinal secretion of insulin:
• GIP from K cells
• GLP-1 from L cells
These have a very short 1/2-life and are changed into inactive metabolites by DPP-4; they are cleared by the kidneys
Administration of Exenatide?
Levels increase 4-6 hours after dose
Given twice daily as a subcutaneous injection
Administration of Exendin LAR?
Administered once weekly
Administration of Liraglutide?
Most commonly used in this class; it is a GLP-1 analogue that is DPP-4 resistant, so it has a long half-life (10-14 hours)
Given as a once daily injection
Administration of Lixisenatide?
A GLP-1 analogue
Given once daily
Benefits of GLP-1 receptor agonists?
- Promote insulin secretion from pancreas without hypoglycaemia
- Suppress glucagon (which is increased in T2DM)
- Decrease gastric emptying to allow early satiety
- Act on hypothalamus to reduce appetite, resulting weight loss (~3kg)
Disadvantages of GLP-1 receptor agonists?
- Nausea (usually resolves in most by 6-8 weeks)
- Injectable
- Pancreatitis (due to increased β-cell growth) and potential for pancreatic cancer
Benefits of DPP-4 inhibitors?
Promote insulin secretion from pancreas without hypoglycaemia
Suppress glucagon (which is increased in T2DM)
Weight neutral
Disadvantages of DPP-4 inhibitors?
Very limited side effects
Not that potent
No weight loss (but there is no weight gain either)
Pancreatitis and potential risk of pancreatic cancer
Brief mechanism of action of SGLT2 inhibitors?
Decrease uptake of sugar by ~1/4; this is excreted in the urine
They also REDUCE CV MORTALITY
Disadvantages of SGLT2 inhibitors?
Sugar in the urine increases thrush incidence and there is a possible increase in urine infections
Difference between the use of insulin in T2DM and T1DM?
In T2DM:
• Less use of the basal bolus (it may be used)
• More use of basal insulin
Use of insulin in T2DM?
Usually, once people fail on non-insulin therapies:
• Once daily NPH (isophane) insulin is added to metformin (+/- SU)
If this is ineffective, change to BD NPH insulin OR mixed insulin (Humulin M3)
Summarise SUs?
Potent
Weight gain
Hypo episodes
Summarise TZDs?
Potent
Weight gain
Heart failure and fractures
Summarise DPP-4 inhibitors?
Weight neutral
No hypo episodes
Concern with pancreatitis and pancreatic cancer
Summarise SGLT2 inhibitors?
Weight loss
No hypos
Thrush/UTIs
CV benefit
Summarise GLP-RA (e.g: liraglutide/exenatide/lixisenatide)?
Injectable
Weight loss
Concern with pancreatisis and pancreatic cancer
Non-drug therapies for T2DM?
Weight loss
Bariatric surgery, e.g: gastric banding, recommended for BMI >35; remission rates are higher than with conventional treatment and dietary advice but there are many other problems assoc. with surgery
