Endocrinology

Question 1

Metformin

Answer 1

• MOA - sensitises tissues to insulin + inhibits hepatic gluconeogenesis (incompletely understood)
• 1.0-2.0% decrease in HbA1C
• contraindicated CrCl <30
• benefits: weight neutral/weight loss
• AE: GI side effects, risk of lactic acidosis

Question 2

Sulfonylureas

Answer 2

• glimepiride, gliclazide, glibenclamide and glipizide
• MOA - @betaislet cells - bind to and close KATP channels -> depolarisation -> open voltage gated Ca channels and Ca influx -> more insulin fuses to cell membrane and is secreted
• 1.0-2.0% decrease in HbA1C
• benefits: rapidly effective
• AE: weight gain, sig risk of hypo

Question 3

Thiazolidinediones

Answer 3

• pioglitazone and rosiglitazone
• MOA - activate peroxisome proliferator-activated gamma receptors (PPARGs) leading to changes in gene expression -> increased insulin sensitivity,
• 0.5-1.4% decrease in HbA1C
• benefits: improved lipid profile
• AE: weight gain, risk of MI/CCF/fractures/bladder cancer

Question 4

Dipeptidyl peptidase 4 (DPP-4) inhibitors

Answer 4

• linagliptin, saxagliptin, sitagliptin, vildagliptin and alogliptin
• boost levels of incretins (GLP-1 and GIP) which stimulate insulin release and inhibit glucagon release by inhibiting DPP-4 which normally degrades incretins
• 0.5-0.8% decrease in HbA1C
• benefits: weight neutral
• AE: expensive

Question 5

Sodium-glucose co-transporter 2 (SGLT2) inhibitors

Answer 5

• dapagliflozin, canagliflozin and empagliflozin
• MOA - inhibit glucose reabsorption in the PCT leading to renal wasting of glucose
• 0.5-0.7% decrease in HbA1C
• benefits: weight loss, improved BP, reduced cardiovascular mortality in established CVD, renoprotective in patients with CKD
• AE: euglycaemic DKA, UTI/candida, fractures, AKI

Question 6

Glucagon-like-peptide-1 (GLP-1) analogue

Answer 6

• exenatide
• MOA - directly stimulate GLP1 receptor leading to increased insulin secretion and decreased glucagon secretion
• 0.5-1.0% decrease in HbA1C
• benefits: weight loss, reduced cardiovascular mortality in established CVD
• AE: requires injection, GI side effects, expensive

Question 7

Oral bisphosphonates

Answer 7

• alendronate, risendronate, ibandronate
• antiresorptive agent
• MOA - incorporated into osteoclasts then disrupt their intracellular enzymatic functions thereby inhibiting bone resorption
• generally initial therapy
• instructions: take on empty stomach first thing in AM, no food drink/other meds and stay upright for 30 min post
• adverse effects: oesophagitis, ONJ, hypocalcaemia, atypical femoral fractures
• contraindications: oesophageal disorders, prev bariatric surgery, inability to stay upright for at least 30 minutes, CKD with eGFR <30mL/min

Question 8

IV bisphosphonates

Answer 8

• zoledronic acid, ibandronate
• antiresorptive agent
• MOA - incorporated into osteoclasts then disrupt their intracellular enzymatic functions thereby inhibiting bone resorption
• generally initial therapy as alternative if oral bisphosphonates contraindicated/poorly tolerated
• adverse effects: ONJ, hypocalcaemia, infusion reaction (flu like symptoms), atypical femoral fractures
• contraindications: CKD with eGFR <30mL/min

Question 9

RANK ligand inhibitor

Answer 9

• denosumab
• antiresorptive agent
• MOA - RANKL (nuclear factor-kappa ligand) inhibitor - RANKL is secreted by osteoblasts and normally activates osteoclast precursors and subsequent osteolysis
• initial therapy if bisphosphonates contraindicated
• adverse effects - musculoskeletal pains, high risk of vertebral fracture after discontinuation, hypocalcaemia

Question 10

SERM

Answer 10

• raloxifene
• antiresorptive agent
• MOA - mixed agonist-antagonist of estrogen receptor - estrogenic effect in bone (leading to increased BMD) - antiestrogenic effect in breasts and uterus
• generally bisphosphonates preferred as therapy, selected patients for serm
• adverse effects - increased risk of VTE, hot flushes
• reduces risk of breast and endometrial cancer

Question 11

Sclerostin Inhibitor

Answer 11

• romosozumab
• anabolic agent
• MAB against sclerostin - sclerostin is normally produced by osteocytes and inhibits bone formation through Wnt/Beta-catenin signaling pathway
• used in selected patients
• adverse effect: headache, arthralfia, injection site pain ?increased MACE (MI + stroke),

Question 12

Parathyroid Hormone and Parathryoid Hormone-Related Protein Analogue

Answer 12

• teriparatide/abaloparatide
• anabolic agent
• mechanism of action: intermittent use stimulates osteoblasts more than osteoclasts leading to overall anabolic effect
• used in patients with progressive loss of BMD despite antiresorptive therapy, can be considered for severe disease with T score