Snapshot A 45-year-old woman comes to her primary care physician complaining of pain with urination. She thinks she has a urinary tract infection. She states that this would be the 5th time in the past 3 months. The patient has poorly controlled type II diabetes mellitus. She had a hernia repair as a child. She takes metformin and danagliflozin. Her mother had end stage kidney disease. (Adverse effect of sodium-glucose co-transporter-2 (SGLT-2) inhibitors) Introduction Drugs 10 classes Mechanism of action depends on class Overview of Diabetes Drugs Class Example ↑ Insulin secretion ↑ Insulin utilization ↓ Glucose production Glucose absorption/ excretion Weight Hypoglycemia Insulin Insulin ++ Biguanides Metformin + ++ None Sulfonylureas Glyburide ++ (glucose independent) + + ++ Meglitinides Repaglinide ++ (glucose independent) + Glitazones (thiazolidinediones) Pioglitazone ++ +/- + Glucagon-like peptide-1 (GLP-1) mimetics (incretin mimetics) Exenatide ++ (glucose dependent) + + Gipeptidyl peptidase-4 (DPP-4) inhibitors Sitagliptin ++ (glucose dependent) + Sodium-glucose co-transporter-2 (SGLT-2) inhibitors Dapagliflozin ↑ Excretion None None α-glucosidase inhibitors Acarbose ↓ Absorption None None Amylin analog Pramlintide + + + Adverse effects contraindicated during pregnancy and breastfeeding except insulin except metformin in some cases hypoglycemia combination therapy increases risk increased risk when used peri-operatively due to irregular food intake and fasting Insulin Drugs have differing onsets, peaks, and durations of action based on preparation Preparation Onset Peak Duration Lispro, aspart, and glulisine (rapid-acting) ~15 min 30 min-2 hr 3-4 hrs Regular (short-acting) ~30 min-1 hr 2-5 hr 4-12 hr NPH (intermediate) 1-2 hr 6-12 hr 14-24 hr Glargine and detemir (long-acting) 2-4 hr Flat ~24 hr Mechanism of action binds transmembrane insulin receptor activates tyrosine kinase phosphorylate specific substrates in each tissue type liver ↑ glycogenesis converts glucose to glycogen as storage ↓ glycogenolysis ↓ gluconeogenesis muscle ↑ uptake of glucose ↑ glycogen and protein synthesis ↑ K+ uptake adipose tissue ↑ lipid synthesis increase triglyceride storage Clinical use given parenterally (subcutaneous (SQ) or intravenous (IV)) often the easiest to titrate during acute illness or infection, though caution should still be used type I diabetes mellitus (DM) type II DM if weight loss, exercise, and oral antidiabetics are not sufficient if patient has end stage renal disease (ESRD) gestational diabetes life-threatening hyperkalemia increases intracellular K+ steroid-induced hyperglycemia Adverse effects hypoglycemia weight gain hypokalemia early morning hyperglycemia with evening insulin due to negative feedback from nocturnal hypoglycemia (i.e., glucagon stimulation) lipodystrophy at injection site hypersensitivity reaction (very rare) Biguanides Drugs metformin Mechanism of action ↓ gluconeogenesis exact mechanism unknown ↑ intestinal glucose absorption ↓ postprandial glucose levels may also ↑ insulin sensitivity ↑ glycolysis ↓ low-density lipoprotein (LDL) and ↑ high-density lipoprotein (HDL) Clinical use first-line for type II DM Adverse effects no hypoglycemia possible weight loss nausea, vomiting, and gastrointestinal symptoms lactic acidosis high-risk in elderly and renal insufficiency contraindications chronic kidney disease liver failure chronic pancreatitis sepsis Sulfonylureas Drugs first generation second generation glyburide long half-life glimepiride glipizide short half-life Mechanism of action glucose normally triggers insulin release from pancreatic β cells by increasing intracellular ATP → closes K+ channels → depolarization → ↑ Ca2+ influx → insulin release sulfonylureas mimic action of glucose by closing K+ channels in pancreatic β cells → depolarization → ↑ Ca2+ influx → insulin release continued use results in ↓ glucagon release ↓ hepatic gluconeogenesis ↑ insulin sensitivity in muscle and liver Clinical use type II DM stimulate release of endogenous insulin cannot be used in type I DM due to complete lack of islet function Adverse effects disulfiram-like effects/alcohol intolerance hypoglycemia weight gain granulocytopenia and hemolytic anemia contraindicated kidney failure liver failure sulfonamide allergy severe cardiovascular disease Meglitinides (Sulfonylurea Analogs) Drugs repaglinide nateglinide Mechanism of action similar to sulfonylureas increase insulin secretion Clinical use consider repaglinide in chronic kidney disease Adverse effects hypoglycemia more short-acting than sulfonylureas, so less risk weight gain hepatotoxicity contraindications liver failure severe renal failure don’t use with sulfonylureas Glitazones (Thiazolidinediones) Drugs pioglitazone rosiglitazone Mechanism bind and activate to nuclear receptors involved in transcription of genes mediating insulin sensitivity peroxisome proliferator-activating receptors (PPARs) increase transcription of genes involving glucose and lipid metabolism ↑ insulin sensitivity in peripheral tissue ↓ gluconeogenesis ↑ insulin receptor numbers ↓ triglycerides Clinical use consider in severe renal failure Adverse effects less risk of hypoglycemia weight gain edema cardiotoxicity osteoporosis contraindications liver failure severe congestive heart failure history of bladder cancer/active bladder cancer for pioglitazone GLP-1 Analogs Drugs exenatide liraglutide albiglutide Mechanism of action GLP-1 agonist GLP-1 is an incretin normally released from the small intestine that aids glucose-dependent insulin secretion ↑ insulin ↓ glucagon release slow gastric emptying increase satiety GLP-1 normally degraded by DPP-4, but incretin mimetics are resistant to degradation Clinical use type II DM patients requiring 2 drugs and looking to lose weight e.g., metformin and exenatide Adverse effects weight loss no risk of hypoglycemia gastrointestinal complaints pancreatitis and pancreatic cancer contraindications higher risk of hypoglycemia if given with sulfonylureas gastrointestinal motility disorders gastroparesis DPP-4 Inhibitors (-gliptins) Drugs sitagliptin saxagliptin Mechanism of action inhibit DPP-4, which normally breaks down GLP-1 indirectly increases endogenous incretin ↑ insulin ↓ glucagon release slow gastric emptying increase satiety Adverse effects gastrointestinal complaints arthralgia increased risk of pancreatitis contraindications severe renal failure liver failure SGLT-2 Inhibitors (-gliflozins) Drugs canagliflozin dapagliflozin empagliflozin Mechanism of action inhibits sodium-dependent glucose co-transporter in proximal tubule of kidney ↓ glucose reabsorption in kidney ↑ glycosuria Clinical use consider in young males less risk of urinary tract infections Adverse effects weight loss reduces blood pressure urinary tract infections genital infections (i.e., yeast infection) polyuria dehydration severe diabetic ketoacidosis contraindications chronic kidney disease anatomical or functional urinary tract anomalies α-Glucosidase Inhibitors Drugs acarbose miglitol Mechanism of action inhibits α-glucosidases in intestinal brush border delayed sugar hydrolysis delayed intestinal glucose absorption ↓ postprandial hyperglycemia ↓ insulin demand Clinical use type II DM as monotherapy or in combination with other agents Adverse effects no hypoglycemia gastrointestinal upset undigested carbohydrates ends up in colon degraded by intestinal bacteria results in increase in flatulence and diarrhea contraindications inflammatory bowel disease other malabsorption disorders severe renal failure Amylin Mimetics Drugs pramlintide Mechanism of action synthetic analogue of human amylin that acts in conjunction with insulin basis for drug mechanism is the observation that more insulin is secreted with oral glucose load compared to intravenous ↓ release of glucagon delay gastric emptying increase satiety Clinical use type I and II DM Adverse effects hypoglycemia especially if given with insulin gastrointestinal complaints contraindications gastroparesis