Miscellaneous hypoglycemics Notes

NOTES NOTES MISCELLANEOUS HYPOGLYCEMICS Figure 1.1 Biguanides: mechanism of action. WHAT ARE THEY? CLASSIFICATION Basic information ▪ Drugs used to lower blood glucose levels via mechanisms other than ↑ insulin secretion (e.g. ↑ insulin sensitivity, ↓ glucose production/absorption, ↑ glucose excretion, etc) BIGUANIDES Key points ▪ Used alone/in combination with other antidiabetic agents Mechanism of action ▪ ↑ hepatic AMP-dependent protein kinase activity → inhibits genes that promote gluconeogenesis (e.g. phosphoenolpyruvate carboxykinase, glucose-6-phosphatase) → ↓ gluconeogenesis → ↓ blood glucose ▪ MetFORMIN (Glucophage, Glucophage XR, Glumetza): PO ▫ ↓ fasting, postprandial glucose levels ▫ Not associated with hypoglycemia/ weight gain OSMOSIS.ORG 1

▪ ↑ adipose/muscle GLUT4 translocation → ↑ peripheral insulin sensitivity → ↑ peripheral glucose uptake → ↓ blood glucose ▪ ↓ intestinal glucose absorption → ↓ blood glucose ▪ ↓ plasma glucagon levels THIAZOLIDINEDIONES (GLITAZONES) ▪ Pioglitazone (Actos): PO ▪ Rosiglitazone (Avandia): PO ▫ Slow onset of action (several weeks) ▫ ↓ fasting, postprandial glucose levels Mechanism of action ▪ Agonists at peroxisome proliferator activated receptor-gamma (PPAR-y) → binds retinoid X receptor → transcription of genes involved in glucose, lipid metabolism ▫ ↑ insulin sensitivity in liver, adipose, skeletal muscle tissues → ↓ blood glucose ▫ ↑ adiponectin levels → ↓ hepatic gluconeogenesis; ↑ glucose uptake by skeletal muscles → ↓ blood glucose ▫ ↓ triglycerides, ↑ HDL, ↑ LDL ALPHA-GLUCOSIDASE INHIBITORS ▪ Acarbose (Precose): PO ▪ Miglitol (Glyset): PO ▫ Helpful for overweight people with type II diabetes ▫ Lack an effect on fasting glucose Mechanism of action ▪ Inhibits intestinal brush border α-glucosidases → delay breakdown of oligosaccharide/disaccharides to absorbable monosaccharides → ↓ glucose absorption → ↓ postprandial blood glucose SYNTHETICS AMYLIN ANALOGUE, AMYLINOMIMETIC ▪ Pramlintide (SymlinPen 120, SymlinPen 60): SubQ ▫ Synthetic amylin analog Mechanism of action ▪ Prolongs gastric emptying ▪ ↓ glucagon secretion 2 OSMOSIS.ORG ▪ ↑ satiety/appetite suppression SGLT2 INHIBITORS ▪ ▪ ▪ ▪ Canagliflozin (Invokana): PO Dapagliflozin (Farxiga): PO Empagliflozin (Jardiance): PO Ertugliflozin (Steglatro): PO Mechanism of action ▪ Inhibit sodium-glucose cotransporter 2 (SGLT2) in proximal renal tubules → ↓ reabsorption of filtered glucose → glycosuria → ↓ blood glucose Common indications ▪ Type 2 diabetes mellitus, gestational diabetes ▫ MetFORMIN: First-line therapy for type 2 diabetes; polycystic ovarian syndrome; antipsychotic-induced weight gain ▫ Pramlintide: also used in type I diabetes CLINICAL CONCERNS ADVERSE EFFECTS ▪ Hypoglycemia (except MetFORMIN ) Drug specific effects ▪ Biguanides ▫ Gastrointestinal (GI) disturbances (diarrhea, nausea, vomiting, abdominal cramping) ▫ Weight loss ▫ Vitamin B12 deficiency (long-term use) ▪ Thiazolidinediones ▫ Hypoglycemia (rare as monotherapy) ▫ Fluid retention, edema → ↑ risk of heart failure ▫ Weight gain ▫ Osteopenia, ↑ risk of fractures ▫ Hepatitis, liver failure (monitor liver enzymes) ▫ Rosiglitazone: ↑ risk of myocardial infarction, stroke ▫ Pioglitazone: ↑ risk of bladder cancer ▪ Alpha-glucosidase inhibitors ▫ GI disturbances → ↑ amount of carbohydrates in colon → ↑ bacterial fermentation

Endocrine Miscellaneous Hypoglycemics Figure 1.2 Thiazolidinediones: mechanism of action. Figure 1.3 Alpha-glucosidase inhibitors: mechanism of action. OSMOSIS.ORG 3

▫ Hypoglycemia: rare, treat with dextrose (absorption not inhibited) ▪ Synthetic amylin analogue/amylinomimetics ▫ GI disturbances ▪ SGLT2 inhibitors ▫ Weight loss ▫ Polyuria → dehydration, ↓ intravascular volume → hypotension ▫ Hyperkalemia, ketoacidosis, acute kidney injury ▫ ↑ risk of genitourinary infections (e.g. vulvovaginal candidiasis, urinary tract infections) Boxed warnings ▪ Biguanides ▫ Lactic acidosis ▪ Thiazolidinediones ▫ May cause/exacerbate heart failure; rosiglitazone → may ↑ risk of myocardial infarction ▪ Synthetic amylin analogue/amylinomimetics ▫ Severe hypoglycemia when used with insulin, dose ↓ required ▪ SGLT2 inhibitors (canagliflozin) ▫ ↑ risk of lower limb amputations for people with type 2 diabetes + cardiovascular disease (CVD)/↑ risk for CVD DISEASE-RELATED CONCERNS ▪ Renal impairment ▫ Dosage reduction (metFORMIN, alphaglucosidase inhibitors, SGLT2 inhibitors) ▪ Hepatic impairment ▫ Thiazolidinediones: dosage reduction, perform baseline liver function tests ▫ Alpha-glucosidase inhibitors, SGLT inhibitors: not recommended ▪ Heart failure ▫ Thiazolidinediones: may exacerbate symptoms of heart failure ▪ Ischemic heart disease ▫ Rosiglitazone: ↑ risk of cardiovascular complications ADMINISTRATION ▪ MetFORMIN: administer with a meal (↓ GI upset) ▪ Thiazolidinediones: monitor liver enzymes ▪ Pramlintide: can be used in combination with insulin ▪ Alpha-glucosidase inhibitors: take immediately before meal ▪ SGLT2 inhibitors: monitor serum creatinine before, after initiating therapy Dietary ▪ Maitake: mushroom → ↑ hypoglycemic effect of antidiabetic drugs Figure 1.4 Synthetic amylin analogue: mechanism of action. 4 OSMOSIS.ORG

Endocrine Miscellaneous Hypoglycemics ▪ MetFORMIN: Consider vitamin B12 supplementation ▪ Alpha-glucosidase inhibitors: ↑ dietary sucrose → ↑ GI disturbances PREGNANCY/BREASTFEEDING IMPLICATIONS ▪ MetFORMIN may be used for gestational diabetes (alternative agent) CONTRAINDICATIONS ▪ MetFORMIN: renal, liver impairment, ▪ ▪ ▪ ▪ alcoholism, chronic cardiopulmonary dysfunction, administration of IV iodinated contrast medium → ↑ risk of lactic acidosis Thiazolidinediones: NYHA Class III/IV heart failure Alpha-glucosidase inhibitors: intestinal conditions (e.g. inflammatory bowel disease) Pramlintide: gastroparesis → exacerbate GI disturbances/transit time SGLT2 inhibitors: severe renal impairment; recurrent UTIs (e.g. urinary tract anomalies) Figure 1.5 SGLT2 inhibitors: mechanism of action. Figure 1.6 Miscellaneous hypoglycemics: pharmacokinetic interactions. OSMOSIS.ORG 5

Figure 1.7 Miscellaneous hypoglycemics: common drug-drug interactions. 6 OSMOSIS.ORG

Endocrine Miscellaneous Hypoglycemics Figure 1.8 Miscellaneous hypoglycemics: general adult dosing guidelines. *Dose and dosing interval varies depending on individual characteristics OSMOSIS.ORG 7