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M301 > W7 Pharmacotherapy of T2DM (SM) > Flashcards

W7 Pharmacotherapy of T2DM (SM) Flashcards

1
Q

What are the Goals of Treatment/Management (T1DM & T2DM)? (4)

A
  • Maintain Glycaemia
  • Alleviate symptoms
  • Prevent complications (long-term/secondary)
    –microvascular
    –macrovascular
  • Improve the quality of life
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2
Q

What does pharmacotherapy mean?

A

Pharmacological drug treatment
Using drugs as medication

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3
Q

Glycaemic control: Diet & Lifestyle
What should patients do to control this?
What is the benefit of maintaining glycaemic control?

A
  • 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

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4
Q

Glycaemic control: Antidiabetic drugs
What are the examples? (drug classes)

A
  1. Insulin sensitisers (T2DM)
    * Biguanides
    * Thiazolidinediones
  2. Insulin secretagogues (T2DM)
    * Sulfonylureas
    * Meglitinides
    * Incretin analogues
    * Gliptins
  3. Miscellaneous (T2DM)
    * Gliflozins
    * Acarbose
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5
Q

Biguanides, Metformin
What is the MOA of metformin?
Other effects?

A
  • 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

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6
Q

What are the Adverse effects of Metformin?
Caution in which patients?

A

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

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7
Q

Thiazolidinediones: Pioglitazone
What is the MOA?

A
  • 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)

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8
Q

What are the adverse effects of Thiazolidinediones, pioglitazone?

Contraindicated in which patients?

A
  • Sodium and water retention, Oedema
    (Pioglit. act on the Na+ channel in DCT)
  • Contraindicated in patients with heart failure and bladder cancer
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9
Q

Insulin Secretagogues: Sulfonylureas
Pharmacological MOA?
What are 1st and 2nd gen examples?

A
  • 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
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10
Q

Adverse effects of Sulfonylureas?
Contraindicated/cautioned in?

A

Hypoglycaemia, Weight gain, Haemolysis, eu-DKA

Contraindicated/cautioned in acute porphyria, pregnancy & breastfeeding, elderly, overweight, G6PD, and ketosis.

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11
Q

What is Euglycaemic-Diabetic Ketoacidosis (eu-DKA)?

A
  • 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
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12
Q

Meglitinides (prandial glucose regulators):

A
  • 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)
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13
Q

Meglitinides
Adverse effect?
C/I in..?

A

Adverse effects: Hypoglycaemia
Contraindicated/cautioned in ketosis, pregnancy & breast feeding, elderly

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14
Q

Incretin analogues (Glucagon-like peptide 1 receptor agonist):
What is exenatide
What is their MOA?

A
    • 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
  • Mimic GLP-1 hormone and potentiate
    glucose-induced insulin secretion, also
    known as incretin mimetics/GLP-1 agonists
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15
Q

What are 2nd gen GLP-1 receptor antagonists?

A

Liraglutide, dulaglutide, lixisenatide, semaglutide

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16
Q

What is the Incretin effect?

A

60% post-meal insulin secretion due to effects of incretins, INCRETIN effect, (glucose only produces 40% of insuliin secretion)
- but it is impaired in T2DM

17
Q

What is the pharmacological MOA of GLP-1 receptor agonists?

A
  • Incretin mimetics (exenatide and analogues)
    potentiate glucose-induced insulin secretion
  • Incretin mimetics (exenatide and analogues)
    suppress glucagon release
18
Q

Incretin analogues
(Glucagon-like peptide 1 receptor agonist)
MOA in depth:

A
  • Incretin mimetics/GLP-1 agonists are resistant to degradation by di-peptidyl peptidase-4 (DPP-4 is an enzyme responsible for the degradation of incretins in the circulation) *
  • Longer half-life than GLP-1, thus effective in
    managing post-prandial glycaemic rise
  • Promotes proliferation of B-cell
  • Delays gastric emptying (decrease food intake, benefit for overweight patients, may affect the absorption of certain drugs, e.g. antibiotics)
  • Promote satiety (direct action on the appetite centres in the hypothalamus)
  • Sensitise insulin action in adipose and
    skeletal muscle

*DPP enzymes break down GLP-1. If this enzyme is blocked, insulin secretion increases.

  • Given subcutaneous injection (daily/weekly)
  • Combined with metformin/sulfonylurea
  • Hypoglycaemia is uncommon
  • Gastrointestinal discomfort incidences
    (more than 50 % of patients, resolves with time)
19
Q

Gliptins (DPP-4 inhibitors)
MOA?

A
  • Prolong the bioavailability and action of endogenous incretins
  • Aloegliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin

DPP-4 (di-peptidyl peptidase-4) is an enzyme responsible for the degradation of incretins (GLP-1 & GIP-1) in the circulation
Gliptins are competitive inhibitors of DPP-4 and thereby prolong the incretin effect
Similar to GLP-1 agonists, DPP-4 inhibitors promote insulin release, reduce glucagon secretion, reduce gastric emptying, promote satiety, reduce hepatic glucose production.
Mostly given together with either sulfonyl urea or metformin (by mouth)
No apparent weight gain (long term safety data are emerging)

  1. Gliptins prevent DPP-4 breakdown of insulin
  2. So no Incretin is released (GLP-1 and GIP-1)
  3. So glucose-induced insulin and supression of glucagon secretion
20
Q

Gliflozin (SGLT-2 Inhibitor)
Pharmacological MOA?
Adverse effects?

A
  • Increase glucose excretion in the urine
  • Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin
  • Reversibly inhibit SGLT-2 in renal PCT to reduce glucose reabsorption
  • Increase urinary glucose excretion
  • Glucose excreted is directly proportional to the amount of glucose in the plasma
  • Lower plasma volume (reduce blood pressure)
  • Adverse effects: Hypoglycaemia, Hypotension,
    Diabetic ketoacidosis and urinary infections
21
Q

Acarbose (alpha-glucosidase inhibitor)
Pharmacological MOA?
Adverse effects?

A

Delays glucose absorption

  • Alpha-glucosidase is an enzyme that catalyses the breakdown of monosaccharides from disaccharides
  • Acarbose competitively reversibly binds to the alpha-glucosidase and inhibits its catalytic function.
    – Delayed glucose absorption (& lipid absorption)
    – Small but significant reduction in blood glucose
    – Effective in managing post-prandial glycaemia
  • Adverse effects: GI discomfort (bloating and
    flatulence); Diarrhoea

Mostly combined with other medications in T2DM

=Acarbose delays glucose absorption in small intestine (blocks) by acting on Alpha glucodinase

22
Q

Pharmacotherapy - Limitations

A

Antidiabetic drugs are not a CURE:
– augment the effects of a healthy diet and lifestyle (exercise)
– Many patients do not reach the target
– Long-term use – loss of efficacy
– Need for combination therapy (multiple drugs)
– Side-effects & interactions
(E.g. Hypoglycaemia, weight gain and other

23
Q

Management of secondary complications:
Reasonable glycaemic control is critical
in preventing/ delaying the onset of
acute and long-term (secondary)
complications.

A
  • Glycaemic control
  • Blood pressure
  • Lipid profile
  • Cardiovascular functions
  • Renal functions
24
Q

Summary: T2DM pharmacotherapy strategies

A
  1. Diet/lifestyle interventions
  2. Metformin or SGLT-1 inhibitors -monotherapy
  3. Metformin + SGLT1i (or other anti diabetics) -dual therapy
  4. Metformin + SGLT1i + other -triple therapy
    • Insulin (dual or triple)
  6. Intensify insulin regimen

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