Type 2 Diabetes Mellitus MOA/Characteristics -Decrease hepatic glucose Biguanides production -Increased insulin sensitivity Drugs Metformin Indications -1st line DMT2 -PCOS AEs -GI -> N/D, indigestion, abd cramps/bloating -Impaired B12 absorption Contraindications/BBW BBW: -Lactic acidosis -> esp w/ sepsis, MI, HF -Renal failure (GFR <30 mL/min) Characteristics -Weight neutral/loss -Hypoglycemia uncommon SHORT ACTING: -Glipizide (#1) (Glucotrol) -DMT2 -> for pts on budget -Administer w/caution in hepatic or renal insufficiency -Weight gain -Hypoglycemia -Cheap LONG ACTING: -Glimepiride (Amaryl) -Glipizide XR -Glyburide (DiaBeta) -Glyburide micronized *titrate up -Coma (hypoglycemia) -N/V, cholestatic jaundice, agranulocytosis, anemias, HST rxns -Flushing -Active hepatic dz -Weight gain -HF (hepatic & peripheral muscle tissue) Sulfonylureas -g…ide / glucose uptake -> via AMPK activation -Increased insulin secretion via pancreatic beta cells -Only 2nd generation available -Short t½ (3-5 hr) BUT hypoglycemic effects evident for 12-24 hrs (bind to albumin) -Administer 1x/d -Benefit w/chronic administration -> circulating insulin levels decline to those prior to tx but reduced plasma glucose levels are maintained Drug-Drug -> worsen hypoglycemia: -Androgens -Anticoagulants -Azoles -H2 antagonists -Mg salts -Methyldopa -MAO-I, TCAs Drug-Drug -> diminished effects: -B-blockers, CCBs -Thiazide diuretics -Nicotinic acid -Phenothiazines -Estrogens TZDs -Increased insulin sensitivity (Thiazolidinediones) (hepatic & peripheral muscle tissue) -zone -Reduces plasma levels of fatty acids -Slow onset -> max glucose homeostasis ~1-3 months -Rosiglitazone (Avandia) -Pioglitazone (Actos) -DMT2 *Ok in pts w/renal insufficiency -Lower transaminases -Edema, weight gain -Macular edema -Bone fx (women) Drug-Drug: -Rifampin -> decreases plasma concentrations -Gemfibrozil -> increases plasma levels 2x -Insulin + TZD -> 2x more edema, weight gain BBW: -Cause/exacerbate HF DPP-4Inhibitors -Increased insulin secretion from beta cells (Dipeptidyl Peptidase-4 Inhibitors) (glucose-dependent) -gliptin SGLT2Inhibitors (sodium-glucose cotransporter 2 inhibitors) -Decreased glucagon secretion from alpha cells (glucosedependent) *Inhibition of DPP-4 = less breakdown of GLP1 -Blocks glucose reabsorption by kidneys -> increases renal excretion of glucose -flozin *glucose flo(zin) out of the kidneys GLP-1Receptor Agonists (Glucagon-like peptide1 receptor agonists) -tide -Increased insulin secretion (glucose-dependent) -Decreased glucagon secretion (glucose-dependent) -Slowed gastric emptying -Increased satiety -Sitagliptin (Januvia) -Alogliptin (Nesina) -Linagliptin (Tradjenta) -Saxagliptin (Onglyza) -DMT2 -Canagliflozin* (Invokana) -Dapagliflozin (Farxiga) -Empagliflozin* (Jardiance) -Ertugliflozin (Steglatro) -Exenatide (2x/d or 1x/wk) -DMT2 -*CV risk reduction (Byetta, Bydureor) -Dulaglutide* (1x/wk) (Trulicity) -Liraglutide* (daily) (Victoza) -GLP1 -> incretin released by endocrine cells, target pancreatic beta cells to secrete insulin -Lixisenatide Rare: -Pancreatitis, HF, arthralgias, SJS (Ozempic) -Albiglutide* -Lower UTI, yeast infections -Mild diuresis -> HoTN *Preferred if HF or CKD predominates (alt: GLP-1 RA) -DMT2 -> adjunct for known CVD*, @risk of CKD *All subq except for semaglutide tablets (Adlyxin) -Semaglutide *minimal -> none consistent *Preferred if CVD predominates (alt: SGLT2-I) -Lower dose for renal function (sitagliptin, saxagliptin) -Saxagliptin metabolized by CYP3A4 -Weight neutral -No hypoglycemia -Less effective in renal impairment (stage 3 kidney dz, GFR 60-30) -Weight loss -No hypoglycemia BBW (Canagliflozin): -2x ^risk leg/foot amputation if established CV dz -GI (N/V) -> goes away over time Drug-Drug: -Exenatide or Liraglutide + sulfonylurea -> ^^rate hypoglycemia -May alter kinetics of drugs requiring rapid GI absorption (OCPs, abx) Exenatide: -Do not give w/ mod-severe renal failure (CrCl <30 mL/min) (d/t renal clearance) -Pts w/hx pancreatitis BBW: -Thyroid C-cell tumor risk -> do not administer if personal/family hx MEN2/3 -Weight loss, appetite suppression -Significant reduction in CV events*, reduce risk of CKD -$$$$ (Tanzeum) AlphaGlucosidase Inhibitor -Decreased glucose absorption -Increased release of GLP-1 Oral: -Semaglutide* (Rybelsus) -Acarbose (Precose) -Miglitol (Glyset) -DMT2 -Malabsorption, flatulence, diarrhea, abd bloating -^LFTs -Take before meals, TID Drug-Drug: -Acarbose -> decreased absorption of digoxin -Miglitol -> decreased absorption of propranolol, ranitidine -Stage 4 renal failure -Cheap Meglitinides -inide Amylin Mimetics -Increased insulin release -Similar to sulfonylureas except -> different beta-cell receptor -Rapid onset, short duration -Rapaglinide (Prandin) -Nateglinide (Starlix) -Take 15-30 min before meals -Decreased glucagon secretion -> via amylin receptor activation (glucose-dependent) -Slowed gastric emptying -Increased satiety -Decreased insulin needs -DMT2 -Hypoglycemia (esp repaglinide) -Decline in efficacy after initial improvement in glycemic control *Good for pts allergic to sulfa -Weight gain -Hypoglycemia -Cheap (but more expensive than sulfonylureas) -DMT1 & 2, adjunct for pts who take insulin w/meals -Subcutaneous injection prior to meals Tirzepatide (Mounjaro) -Activates GIP & GLP-1 receptors -Increased insulin secretion -Decreased glucagon secretion -Increased insulin sensitivity -Slowed gastric emptying -DMT2 -GI -Decreased appetite -Tachycardia -Weekly injection Other Bile Acid Sequestrants Dopamine Agonists -Binds bile acids in intestine -> unknown how this impacts glucose levels -Unknown -> improved hepatic insulin sensitivity, decreased hepatic glucose output Colsevelam (Welchol) Bromocriptine BBW: -Thyroid C-cell tumor risk -> do not administer if personal/family hx MEN2/3 -Most significant weight loss Managing Other Conditions w/DM MOA/Characteristics Glucagon -Induces liver glycogen breakdown & glucose release -Relaxes GI smooth muscle -IV, IM, subq -Inject & repeat q15-20 min PRN ACE-I, ARB Statins Indications AEs -Severe hypoglycemia -Beta-blocker/CCB induced myocardial depression -N/V -Hyperglycemia -Rash -Tachycardia -Necrolytic migratory erythema -DM + HTN + albuminuria DM + <40 y/o, no risk CVD-> none DM + >40 y/o -> statin* *Established CVD -> high intensity *None established -> moderate intensity (malignant tumor of pancreas alpha cells – rare)