Mount Carmel Health Partners Clinical Guidelines Diabetes Type II

Table 4: Properties of available glucose-lowering agents in the U.S. and Europe that may guide individualized treatment choices in patients with type 2 diabetes. Class Compounds (Brand Names) Cellular Mechanisms Primary Physiological Action(s) Advantages Disadvantages Cost Biguanides Metformin (Fortamet, Glucophage, Glucohage XT, Glumetza, Riomet) Activates AMP-kinase ↓Hepatic glucose production • Extensive experience  No hypoglycemia  ↓ASCVD events (UKPDS) ● Weight neutral • Gastrointestinal side effects (diarrhea, abdominal cramping) • Lactic acidosis risk (rare) • Vitamin B₁₂ deficiency • Multiple contraindications: CKD, acidosis, hypoxia, dehydration, etc. Low Sulfonylureas 2nd Generation • Glyburide (DiaBeta, Micronase, Glyron, Glynase PresTab) • Glipizide (Glucotrol) • Glimepiride (Amaryl) Closes K ATP channels on ß-cell plasma membranes ↑Insulin secretion • Extensive experience • ↓Microvascular risk (UKPDS) • Hypoglycemia • ↑Weight • ?Blunts myocardial ischemic preconditioning • Low durability Low Meglitinides (glinides) • Repaglinide (Prandin) • Nateglinide (Starlix) Closes K ATP channels on ß-cell plasma membranes ↑Insulin secretion • ↓Postprandial glucose excursions • Dosing flexibility • Hypoglycemia • ↑Weight • ?Blunts myocardial ischemic preconditioning • Frequent dosing schedule Moderate TZDs • Pioglitazone‡ (Actos) • Rosiglitazone§ (Avandia) Activates the nuclear transcription factor PPAR-ƴ ↑Insulin sensitivity • No hypoglycemia • Durability • ↑HDL-C • ↓Triglycerides • ↓ASCVD events (PROactive, pioglitazone) • ↑Weight • Edema/heart failure • Bone fractures •↑LDL-C (rosiglitazone) • ? ↑MI (meta-analyses, rosiglitazone) Inhibits intesti- nal α-glucosidase Slows intestinal carbohydrate digestion/ absorption  • Generally modest A1C efficacy • Gastrointestinal side effects (flatulence, diarrhea) • Frequent dosing schedule α-Glucosidase • Acarbose (Precose) inhibitors • Miglitol (Glyset)    No hypoglycemia ↓Postprandia glucose excursions ↓ASCVD events (STOP-NIDDM) Nonsystemic Low Moderate DPP-4 inhibitors • Sitagliptin (Januvia) • Saxagliptin (Onglyza) • Linagliptin (Tradjenta) • Alogliptin (Nesina) Inhibits DPP-4 activity, increasing postprandial active incretin (GLP-1, GIP) concentrations • ↑Insulin secretion (glucose-dependent) • ↓Glucagon secretion (glucose-dependent)  No hypoglycemia  Well tolerated  Weight neutral • Angioedema/urticarial and other immune-mediated dermatological effects • ?Acute pancreatitis • ? ↑Heart failure hospitalizations High Bile acid sequestrants Colesevelam (WelChol) Binds bile acids in intestinal tract, increasing hepatic bile acid production • ? ↓Hepatic glucose production • ? ↑Incretin levels • No hypoglycemia • ↓LDL-C • Generally modest A1C efficacy • Constipation • ↑Triglycerides • May ↓absorption of other medications High Dopamine-2 agonists Bromocriptine (quick release)§ (Cycloset, Parlodel) Activates dopaminergic receptors • Modulates hypothalamic regulation of metabolism • ↑Insulin sensitivity • No hypoglycemia • ? ↓CVD events (Cycloset Safety Trial) • Generally modest A1C efficacy • Dizziness/syncope • Nausea • Fatigue • Rhinitis High SGLT2 inhibitors • Canagliflozin (Invokana) • Dapagliflozin‡ (Farxiga) • Empagliflozin (Jardiance) Inhibits SGLT2 in Blocks glucose the proximal reabsorption by the nephron kidney, increasing glucosuria • No hypoglycemia • ↓Weight • ↓Blood pressure • Effective at all stages of T2DM  Reduce mortality in patients with CVD (empagliflozin) • Genitourinary infections • Polyuria • Volume depletion/ hypotension/dizziness • ↑LDL-C  ↑Creatinine (transient)  DKA High GLP-1 receptor agonists • Exenatide (Bydureon, Byetta) • Exenatide Extended release • Liraglutide (Victoza) • Albiglutide (Tanzeum) • Lixisenatide (Adlyxin) • Dulaglutide (Trulicity) Activates GLP-1 receptors • No hypoglycemia • ↓Weight • ↓Postprandial glucose excursions • ↓Some cardiovascular risk factors  Reduce mortality in patients with CVD (liraglutide) • Gastrointestinal side effects (nausea, vomiting, diarrhea) • ↑Heart rate • ?Acute pancreatitis • C-cell hyperplasia/medullary thyroid tumors in animals • Injectable • Training requirements High • ↑Insulin secretion (glucose-dependent) •↓Glucagon secretion (glucose-dependent) • Slows gastric emptying • ↑Satiety (continues next page) Diabetes Type II - 5

Mount Carmel Health Partners Clinical Guidelines Diabetes Type II | Page 5