Diabetic drugs Flashcards
What are the medications that act on glucose output and uptake?
How much can they decrease HbA1c by?
Metformin, thiazolidinediones
Metformin: 1.5%
Thiazolidinediones: 0.5-1.4%
What are the dosings for metformin immediate release?
What is the max dose per day?
Which strength would you recommend to start on?
Immediate release: 250mg, 500mg, 850mg, 1000mg
Max dose: 2500 - 2550mg per day
Start with 500-850mg OD, ↑ by 500-850mg OD every 1-2w in divided doses
What are the dosings for metformin extended release?
What is the max dose per day?
Which strength would you recommend to start on?
Extended release: 500mg, 750mg, 1000mg
Max dose: 2000mg OD
(Not for children) Start with 500mg OD, ↑ by 500mg weekly
MOA of metformin? (Primary and Secondary)
Primary: ↓ hepatic glucose production
Secondary: ↑ insulin sensitivity → ↑ glucose uptake into tissues & utilisation
ADEs of metformin?
Usually transient. Take with food and start low dose, titrate slowly:
- GI (n/v/d)
- Loss of appetite
- Metallic taste
Others:
- Long term use → ↓ serum B12 conc (consider periodic measurement esp for pts with anaemia/ peripheral neuropathy)
- Lactic acidosis (rare)
What are the contraindications for metformin?
- Severe renal impairment (GFR < 30ml/min)
- Hypoxic states/ risk for hypoxemia (as risk for lactic acidosis ↑)
- AVOID use in acute decompensated HF
DDIs with metformin? (3)
- EtOH (alcohol): ↑ risk for lactic acidosis
- Iodinated contrast material (withhold metformin at least 48h after iodinated contrast administration)
- Inhibitors/ inducers of organic cationic transporters (cimetidine, dolutegravir, ranolazine)
What are the clinical benefits of metformin?
- Negligible weight gain and hypoglycemia
- Possible ↓ in CV events for T2DM pts
- Prevent and delay T2DM
What are the dosings for TZD?
What is the max dose?
Which strength would you recommend to start on?
15mg, 30mg
Max dose: 45mg OD
Start with 15mg or 30mg OD; if inadequate response ↑ dose by 15mg up to max dose
MOA of TZDs?
Does it have any effect on insulin secretion by pancreas?
Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist which promotes glucose uptake into target cells.
Decreases insulin resistance and increases insulin sensitivity
NO effect on insulin secretion
ADEs of TZDs?
Mnemonics: HHIFWB
- Hepatotoxicity*
(LFT monitoring before initiation and periodically → DO NOT initiate/ discontinue if ALT > 3x ULN or as long as s/sx of hepatic dysfunction occurs; if ALT > 1.5x ULN repeat LFTs weekly until normal) - Fluid retention* (cautious use in NYHA Class I or II HF, monitor for s/sx of HF)
- ↑ risk of fracture (more for women)
- Weight gain
- Risk of bladder cancer
- ↑ risk of hypoglycemia w insulin Tx
DDIs of TZDs?
CYP3A4 or CYP2C8 inhibitors or inducers
Contraindications for TZDs?
- Active liver disease
- Symptomatic/ hx of HF
- Active/ history of bladder cancer
- Pregnancy
Clinical benefits of TZDs?
- Beneficial to pts with fatty liver disease
- Potential risk reduction for stroke
- ↑ risk of HF
What are the medications that act on insulin secretion?
How much can they decrease HbA1c by?
Sulfonylureas, DPP-4i
Sulfonylureas: 1.5%
DPP-4i: 0.5-0.8%
Name the 1st gen, 2nd gen and 3rd gen SUs
1st gen- Tolbutamide
2nd gen- Glipizide, Gliclazide
3rd gen- Glimepiride
MOA of SUs? (Primary and Secondary)
What is one IMPORTANT thing to take note with regards to B-cells functioning?
Primary: stimulate insulin secretion by blocking K+ channel of B cells
Secondary: ↓ hepatic glucose output and ↑ insulin sensitivity
NEED functional B-cells to work!
For a renally impaired pt, what type of SUs (and gen) should we recommend. Why?
Recommend Tolbutamide (1st gen) or Glipizide (2nd gen).
They are cleared hepatically unlike the other SUs.
ADEs of SUs?
- Hypoglycemia (esp elderly)
- Weight gain (~2-5kg)
Contraindications for SUs?
Hypersensitivity to SUs
DDIs of SUs
- BB may mask s/sx of hypoglycemia
- Disulfiram-like reaction with alcohol (1st gen»_space; 2nd gen → recommend Glipizide (2nd gen) to pts who drink regularly)
- CYP2C9 inhibitors (amiodarone, 5-FU, fluoxetine) may ↑ glimepiride, glipizide
What are the clinical effects of SUs?
- NO apparent benefits other than blood glucose lowering effects
- Use with caution in pts with irregular meals
- Cost-effective Tx
What are the different agents used as DPP4-i?
Sitagliptin- 100mg OD
Linagliptin- 5mg OD
Vildagliptin- 50mg BD with metformin/ TZS; 50mg OD with SU
MOA of DPP-4i?
Inhibits DPP-4 enzyme and ↑ concentration of endogenous incretins.
MOA of endogenous incretins (eg GLP-1):
- ↓ gastric emptying
- ↑ glucose-dependent insulin synthesis and secretion
- ↓ glucagon
- Improved B-cell function
- ↓ food intake
ADEs of DPP-4i?
- Severe joint pain (rare)
- Headache
- Acute pancreatitis*
- Hypersensitivity reaction
- Bullous pemphigoid, skin rash
Contraindications for DPP-4i?
- Hypersensitivity
- Current/ hx of pancreatitis
DDI of DPP-4i?
- Sitagliptin ↑ digoxin (minimal)
- Linagliptin CYP3A4 inducer → ↓ Linagliptin
What are advantages of DPP-4i compared to GLP-1 agonists?
- Route of administration (GLP-1 are injectables, but recently not anymore with PO Semaglutide)
- ↓ incidence of GI adverse effects
- Cheaper
What are the disadvantages of DPP-4i compared to GLP-1 agonists?
- Weight neutral
- Smaller HbA1c reduction
- No “big 3” (ASCVD, HF, CKD) benefits
How much can SGLT2i decrease HbA1c by?
0.8-1.0%
MOA of SGLT2i?
Inhibits SGLT2i, ↑ renal glucose excretion → ↓ blood glucose
ADEs of SGLT2i?
- Hypotension, hypoglycemia, renal impairment, ↑ LDL, urinary urgency
- Genital mycotic infection/ UTI
- ↑ risk of DKA (esp euglycemic DKA)
- Fournier’s gangrene
- Canagliflozin (lower limb amputation, hyperkalemia, fractures)
Contraindications of SGLT2i?
- ESCKD/ dialysis
- History of DKA
- Recurrent, severe and difficult to treat genitourinary infections
SGLT2i used just for glycemic control, when do we NOT initiate and discontinue?
DO NOT initiate when eGFR < 45
Discontinue when eGFR persistently < 45
If SGLT2i is used also for its cardiorenal benefits, when do we NOT initiate and discontinue?
DO NOT initiate when eGFR < 25 (Dapa) and eGFR < 20 (Empa 10mg)
Discontinue at the start of dialysis
What are the clinical benefits of SGLT2i?
What are the disadvantages?
Benefits:
- Slight weight loss benefits (urination)
- ASCVD (Cana, Empa), HF (whole class), CKD (whole class)
Disadvantages:
- Expensive
What medication acts on glucose absorption in the GI tract?
α-glucosidase inhibitors
How much can α-glucosidase inhibitors decreases HbA1c by?
0.5-0.8%
When do we use α-glucosidase inhibitors?
Carbohydrate-rich/ heavy diets
*To control PPG
What are the different dosings of α-glucosidase inhibitors?
25mg, 50mg, 100mg
How should we administer α-glucosidase inhibitors and titrate?
- Start with 25mg BD-TDS WITH LARGEST MEAL
- ↑ by 25mg/day every 2-4 weeks to max dose of 150mg/day (60kg and below) or 300mg/day (above 60kg)
MOA of α-glucosidase inhibitors?
- Competitively inhibit brush border α-glucosidase enzymes which break down complex carbohydrates → delay glucose absorption, ↓ PPG
ADEs of α-glucosidase inhibitors?
- GI (flatulence**, abdominal pain, diarrhoea)
- ↑ LFT (specifically acarbose – ↑ risk when dose > 100mg TDS)
Contraindications α-glucosidase inhibitors?
- GI diseases (obstruction, IBD)
- Liver cirrhosis
- Renal impairment (CrCl <25ml/min)
DDIs of α-glucosidase inhibitors?
- Intestinal absorbents
- Digestive enzyme preparations
