PharmacologyTier 1Medical Sciences concept

Mechanisms of hypoglycaemia risk by diabetic drug class

Core concept

The dividing question: does the drug raise insulin independently of the ambient glucose?
- Yes -> hypoglycaemia. No -> effectively none as monotherapy

Glucose-INdependent secretagogues - high risk

Sulfonylureas close the beta-cell K-ATP channel via SUR1 regardless of glucose -> insulin released at any blood sugar
Meglitinides - same channel, shorter action, lower risk
Insulin - no glucose sensing at all

Glucose-DEPENDENT - low risk

GLP-1 RA and DPP-4i - incretin effect requires beta-cell glucose sensing; insulinotropic effect switches off below ~4 mmol/L, and glucagon suppression is also glucose-dependent

Insulin-independent - no intrinsic risk

Metformin (dec hepatic gluconeogenesis), SGLT2i (glycosuria), TZDs (inc sensitivity), acarbose

Class	Hypo risk alone	Risk when added to insulin/SU
Sulfonylurea	High	-
Insulin	High	-
Meglitinide	Moderate	-
GLP-1 RA, DPP-4i	Minimal	Increased
Metformin, SGLT2i, TZD, acarbose	Minimal	Increased

Sulfonylurea hypoglycaemia is prolonged, recurrent and dangerous
- Long half-life plus active metabolites; glibenclamide the worst (avoid in the elderly), gliclazide preferred
- Renal impairment prolongs it further - metabolites accumulate
- Admit for at least 24 h; a single glucose bolus is not enough
- Refractory -> octreotide 50-100 mcg SC (suppresses the ongoing insulin release that dextrose itself provokes)
Amplifiers of risk in any patient: age, CKD, hepatic impairment, missed meals/fasting, alcohol (blocks gluconeogenesis), exercise, weight loss, hypoadrenalism, beta-blockers (mask warning symptoms), sepsis
Acarbose complicates rescue - blocks disaccharide breakdown, so treat with glucose (dextrose), not sucrose
Hypoglycaemia unawareness develops with recurrent episodes - loss of the counter-regulatory adrenergic warning; reversible by strict avoidance for weeks
Metformin does not cause hypoglycaemia - its concern is lactic acidosis

In an older patient with CKD presenting with recurrent hypoglycaemia, the sulfonylurea is the answer until proven otherwise - and de-escalating it is the treatment
Deprescribe as HbA1c targets relax with age and frailty (target 7-8.5% in frail elderly) - overtreatment is the modifiable cause
On starting a GLP-1 RA or SGLT2 inhibitor in a patient already on insulin or a sulfonylurea, reduce the insulin/SU dose pre-emptively
Ramadan, procedures and fasting for surgery - withhold sulfonylureas and short-acting insulin, halve basal
Hypoglycaemia in a patient not on a hypoglycaemic drug -> exclude insulinoma, sulfonylurea ingestion (check C-peptide and a sulfonylurea screen), adrenal insufficiency, liver failure, sepsis
- Exogenous insulin: high insulin, LOW C-peptide. Sulfonylurea: high insulin, HIGH C-peptide - the drug screen separates it from insulinoma

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