Hypoglycemics - Insulin secretagogues Notes

NOTES NOTES HYPOGLYCEMICS: INSULIN SECRETAGOGUES Figure 1.1 Sulfonylureas & meglitinides: mechanism of action. WHAT ARE THEY? Basic information ▪ Drugs used to treat high blood glucose levels in type 2 diabetes mellitus (DM type 2) ▫ Adjunct to diet, exercise levels), ↓ insulin release (↓ glucose levels) → ↓ hypoglycemia risk (compared to sulfonylureas) Key points ▪ Only useful if some beta-cell function is present ▪ GLP-1 agonist effects are glucose dependent → ↑ insulin release (↑ glucose OSMOSIS.ORG 1

CLASSIFICATION SULFONYLUREAS & MEGLITINIDES Sulfonylurea (first generation) ▪ ChlorproPAMIDE (Diabinese): PO ▪ TOLBUTamide (Orinase): PO ▪ TOLAZamide: PO Sulfonylurea (second generation) ▪ Glimepiride (Amaryl): PO ▪ GlipiZIDE (Glucotrol, Glucotrol XL): PO ▪ GlyBURIDE (glibenclamide) (Micronase, Glynase): PO Meglitinides (Glinides) ▪ Nateglinide (Starlix): PO ▪ Repaglinide: PO Mechanism of action ▪ Pancreatic effect (beta cells): close ATPsensitive potassium channels (K-ATP channels) in beta cells → ↑ intracellular K+ → cellular depolarization → voltage-gated Ca2+ channels open → Ca2+ influx → insulin release → ↓ blood glucose levels ▪ Extrapancreatic effects (sulfonylureas): ↓ hepatic gluconeogenesis; ↑ peripheral insulin sensitivity INCRETINS (GLP-1 RECEPTOR AGONISTS) ADVERSE EFFECTS ▪ Hypoglycemia ▫ Incretins/DPP-4 inhibitors: no hypoglycemia risk unless used with other hypoglycemics Drug specific adverse-effects ▪ Sulfonylureas: weight gain; gastrointestinal (GI) upset (e.g. nausea); allergic reactions (e.g. rash), Stevens–Johnson syndrome (rare); disulfiram-like reactions (first generation) ▪ Meglitinides: weight gain ▪ Incretins: weight loss, ↓ appetite, fatigue; GI disturbance (e.g. nausea, vomiting); ↑ risk of pancreatitis ▪ DPP-4 inhibitors: GI disturbance; headache; nasopharyngitis; mild urinary/ respiratory infections DISEASE-RELATED CONCERNS ▪ Hepatic/renal impairment: use with caution ADMINISTRATION Administration issues ▪ Meglitinides: take before meals; do not take if meal is missed (avoids hypoglycemia) ▪ Exenatide (Bydureon): SubQ ▪ Liraglutide (Saxenda, Victoza): SubQ PREGNANCY/BREASTFEEDING IMPLICATIONS Mechanism of action ▪ Incretin (GLP-1) hormone analogs activate GLP-1 receptors → ↑ glucose-dependent insulin secretion; ↓ glucagon secretion; ↓ rate of gastric emptying; ↑ satiety → ↓ blood glucose levels CONTRAINDICATIONS DIPEPTIDYL PEPTIDASE 4 (DPP-4) INHIBITORS ▪ SAXagliptin (Onglyza): PO ▪ SITagliptin (Januvia): PO Mechanism of action ▪ Inhibits GLP-1 degradation by DPP-4 → ↑ GLP-1 levels/effects → ↑ glucosedependent insulin secretion; ↓ glucagon secretion; ↓ rate of gastric emptying; ↑ satiety → ↓ blood glucose levels 2 CLINICAL CONCERNS OSMOSIS.ORG ▪ Pregnancy: insulin secretagogues not recommended ▪ Breastfeeding: insulin secretagogues not recommended ▪ Sulfonylureas: type 1 diabetes mellitus (DM type 1), diabetic ketoacidosis

Endocrine Hypoglycemics: Insulin Secretagogues Figure 1.2 Incretins (GLP-1 receptor agonists): mechanism of action. Figure 1.3 Dipeptidyl peptidase (DPP) inhibitors: mechanism of action. OSMOSIS.ORG 3

Figure 1.4 Hypoglycemics: insulin secretagogues: pharmacodynamic interactions. 4 OSMOSIS.ORG

Endocrine Hypoglycemics: Insulin Secretagogues Figure 1.5 Hypoglycemics: insulin secretagogues: pharmacokinetic interactions. OSMOSIS.ORG 5

Figure 1.6 Hypoglycemics: insulin secretagogues: general adult dosing guidelines. *Dose and dosing interval varies depending on individual patient characteristics 6 OSMOSIS.ORG