W7 Pharmacotherapy of T2DM (SM) Flashcards
What are the Goals of Treatment/Management (T1DM & T2DM)? (4)
- Maintain Glycaemia
- Alleviate symptoms
- Prevent complications (long-term/secondary)
–microvascular
–macrovascular - Improve the quality of life
What does pharmacotherapy mean?
Pharmacological drug treatment
Using drugs as medication
Glycaemic control: Diet & Lifestyle
What should patients do to control this?
What is the benefit of maintaining glycaemic control?
- Regular meals, don’t skip meals
- A healthy diet (seek dietician support)
- low fat/sugar/ salt
- high in fibre / complex CHOs (low G.I.)
- Lots of fruit & veg (5 portions/day)
- Beware “high glycaemic/diabetic” foods
- Alcohol awareness (<21 units (M), <14 units (F), avoid drinking empty stomach)
- Smoking cessation
- Active lifestyle
- Regular exercise
- Promote insulin sensitivity/glucose utilisation
- Promote weight loss
Maintain glycaemic control
=Decrease/delay the onset of long-term secondary complications
Glycaemic control: Antidiabetic drugs
What are the examples? (drug classes)
- Insulin sensitisers (T2DM)
* Biguanides
* Thiazolidinediones - Insulin secretagogues (T2DM)
* Sulfonylureas
* Meglitinides
* Incretin analogues
* Gliptins - Miscellaneous (T2DM)
* Gliflozins
* Acarbose
Biguanides, Metformin
What is the MOA of metformin?
Other effects?
- First-line choice of drug for patients with T2DM and overweight
- Metformin promotes insulin action
Pharmacological MOA is unclear.
* Stimulate AMP-kinase (an enzyme involved in insulin signalling and hepatic glucose production)
* Reduce hepatic glucose production/gluconeogenesis
Other effects
* Increase glucose uptake into adipose and muscle (by increasing GLUT4 translocation)
* Reduce glucose absorption from the GI tract
* Reduce fatty acid activation
* Lowers LDL and VLDL in the circulation
* Several other emerging (anticancer)
* No hypoglycaemia and weight gain
What are the Adverse effects of Metformin?
Caution in which patients?
Lactic acidosis (metformin increases plasma lactate level)
GI discomfort
Vitamin B12 deficiency (long-term use)
* Cautioned/contra-indicated in patients with impaired liver and renal function
Thiazolidinediones: Pioglitazone
What is the MOA?
- Pioglitazone is the only glitazone used in the UK (rosiglitazone and troglitazone were withdrawn due to associated cardiac and hepatic toxicity)
- Pioglitazone is structurally similar to fibrates (recollect CVS lecture 4, MOA of fibrates)
Pioglitazone activates a class of nuclear (steroid) receptors/transcription factor, PPARγ, to upregulate the genes encoding proteins involved in fat metabolism in adipose tissue (also in liver and muscle?), including lipoprotein lipase, fatty acid transporter
protein and insulin-responsive GLUT4.
- Reduce hepatic glucose production.
- Reduce TGL, free fatty acids (in the circulation)
- Reduces peripheral insulin resistance
- Sensitise insulin action (adipokines mediated)
Doesn’t cause hypoglycaemia but leads to weight gain (usually prescribed along with metformin/sulfonylureas/insulin)
What are the adverse effects of Thiazolidinediones, pioglitazone?
Contraindicated in which patients?
- Sodium and water retention, Oedema
(Pioglit. act on the Na+ channel in DCT) - Contraindicated in patients with heart failure and bladder cancer
Insulin Secretagogues: Sulfonylureas
Pharmacological MOA?
What are 1st and 2nd gen examples?
- Augment insulin secretion
- 1st Gen: tolbutamide, chlorpropamide; 2nd Gen: gliclazide, glimepiride, glipizide
Sulfonylureas binds to ATP-dependent K+ channels in the pancreatic β-cells and block the K+ efflux. This leads to membrane depolarisation-opening of calcium channels-
intracellular Ca2+ rise- insulin exocytosis.
- SUs stimulate insulin release continuously.
- SU-mediated insulin release is independent of the presence of glucose (but require some residual functioning of β-cells; ineffective at
the later stage of DM or complete loss of β-cells function) - Increase sensitivity of the insulin (minimal)
- Preferred for long-term use (cardiovascular benefit)
- Slow onset of action (ineffective in managing post-prandial hyperglycaemia)
- Increase appetite and leads to weight gain
Adverse effects of Sulfonylureas?
Contraindicated/cautioned in?
Hypoglycaemia, Weight gain, Haemolysis, eu-DKA
Contraindicated/cautioned in acute porphyria, pregnancy & breastfeeding, elderly, overweight, G6PD, and ketosis.
What is Euglycaemic-Diabetic Ketoacidosis (eu-DKA)?
- Euglycemic diabetic ketoacidosis (eu-DKA) presents as a clinical triad characterised by an elevated anion gap metabolic acidosis, ketones in the blood or urine, and maintaining normal blood glucose levels below 200 mg/dL.
- While the precise mechanism behind eu-DKA remains partially understood, it has been linked to factors such as incomplete diabetes treatment, restricted carbohydrate intake, alcohol consumption, and the inhibition of gluconeogenesis.
- eu-DKA can be triggered by certain medications, including sodium-glucose cotransporter 2 (SGLT-2) inhibitors and sulfonylureas.
- Diagnosing this condition can be challenging due to the deceptive euglycemia masking the underlying DKA
Meglitinides (prandial glucose regulators):
- Augment insulin secretion (rapid onset)
- Repaglinide (& nateglinide)
Meglitinides binds to ATP-dependent K+ channels in the pancreatic β-cells and block the K+ efflux. This leads to membrane depolarisation-opening of calcium channels-
intracellular Ca2+ rise- insulin exocytosis (same as sulfonylureas)
- Stimulate insulin release continuously and irrespective of the glucose level
- Increase sensitivity of the insulin (minimal)
- Rapid onset of action (effective in managing post-prandial hyperglycaemia, offer flexibility with patient’s mealtime)
- Rapid elimination (half-life~ 1 hr; reduced risk of hypoglycaemia and weight gain)
- Used either as monotherapy or in combination with metformin (when metformin alone inadequate)
Meglitinides
Adverse effect?
C/I in..?
Adverse effects: Hypoglycaemia
Contraindicated/cautioned in ketosis, pregnancy & breast feeding, elderly
Incretin analogues (Glucagon-like peptide 1 receptor agonist):
What is exenatide
What is their MOA?
- Exenatide is a synthetic form of exendin-4
o isolated from the saliva of the Gila monster lizard
o over 50% structural similarity with
GLP-1
- Exenatide is a synthetic form of exendin-4
- Mimic GLP-1 hormone and potentiate
glucose-induced insulin secretion, also
known as incretin mimetics/GLP-1 agonists
What are 2nd gen GLP-1 receptor antagonists?
Liraglutide, dulaglutide, lixisenatide, semaglutide
