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Updated: Dec 21 2019

Diabetes Drugs

  • 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
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