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Updated: Feb 18 2023

Diabetes Drugs

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  • Overview
    • Goals of diabetes treatment
      • lower serum glucose to physiologic range
      • keep insulin levels in physiologic range
      • eliminate insulin resistance
      • best initial step in management: weight loss, contractile-based exercise
        • weight loss is more important for insulin sensitivity than is a low-carb diet
    • Modalities of diabetes treatment
      • type I DM
        • insulin
        • low-sugar diet
      • type II DM
        • exercise
        • diet
        • insulin
        • 6 classes of drugs shown below
      • Diabetic Drugs
      • Class
      • Example
      • ↑ Insulin secretion
      • ↑ Insulin sensitivity
      • ↓ Glucose production
      • ↓ Glucose absorption
      • Weight
      • Hypoglycemia
      • Insulin
      • Insulin
      • ++
      • Sulfonylureas
      • Glyburide
      • ++
      • +
      • +
      • ++
      • Meglitinides
      • Nateglinide
      • ++
      • +
      • +
      • ++
      • Biguanides
      • Metformin
      • +
      • ++
      • None
      • Glitazones (thiazolidinediones)
      • Pioglitazone
      • ++
      • +/-
      • ↑↓
      • +
      • α-glucosidase inhibitors
      • Acarbose
      • ++
      • None
      • GLP-1 mimetics (incretin mimetics)
      • Exenatide
      • ++
      • +
      • +
      • Amylin analog
      • Pramlintide
      • +
      • +
      • +
  • Insulin
    • Insulin is only given parenterally (subcutaneous or IV)
    • Various preparations have different durations of action
    • Other preparations include aspart (rapid), detemir (long)
      • Preparation
      • Onset (hrs)
      • Peak (hrs)
      • Duration (hrs)
      • Lispro (rapid-acting)
      • 15 min
      • 0.5-1.5
      • 3-4
      • Regular (short-acting)
      • 0.5-1
      • 2-4
      • 5-7
      • NPH (intermediate)
      • 1-2
      • 6-12
      • 18-24
      • Glargine (long-acting)
      • 1
      • None
      • >24
    • Mechanism
      • bind transmembrane insulin receptor
        • activate tyrosine kinase
        • phosphorylate specific substrates in each tissue type
      • liver
        • ↑ glycogenesis
          • store glucose as glycogen
      • muscle
        • ↑ glycogen and protein synthesis
        • ↑ K+ uptake
      • fat
        • increase triglyceride storage
    • Clinical use
      • type I DM
      • type II DM
      • life-threatening hyperkalemia
        • increases intracellular K+
      • stress-induced hyperglycemia
    • Toxicity
      • hypoglycemia
      • hypersensitivity reaction (very rare)
    • Insulin Synthesis
      • first generated as preproinsulin with an A chain and B chain connected by a C peptide.
      • c-peptide is cleaved from proinsulin after packaging into vesicles leaving behind the A and B chains
  • Sulfonylureas
    • Drugs
      • first generation
        • tolbutamide
        • chlorpropamide
      • second generation
        • glyburide
        • glimepiride
        • glipizide
    • Mechanism
      • 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
        • ↑ insulin sensitivity in muscle and liver
    • Clinical use
      • type II DM
        • stimulates release of endogenous insulin
      • cannot be used in type I DM due to complete lack of islet function
    • Toxicity
      • first generation
        • disulfiram-like effects
          • especially chlorpropamide
      • second generation
        • hypoglycemia
      • weight gain
  • Megltinides
    • Drugs
      • nateglinide
      • repaglinide
    • Mechanism
      • binds to K+ channels on β-cells → postprandial insulin release
        • different site than sulfonylureas
    • Clinical use
      • type 2 diabetes mellitus
        • may be used as monotherapy, or in combination with metformin
    • Toxicity
      • ↑ risk of hypoglycemia
        • at even greater risk in those with renal failure
      • weight gain
  • Biguanides
    • Drugs
      • metformin
    • Mechanism
      • ↓ hepatic gluconeogenesis
        • exact mechanism unknown
        • appears to inhibit complex 1 of respiratory chain
      • may also
        • ↑ insulin sensitivity
        • ↑ glycolysis
        • ↓ serum glucose levels
      • ↓ postprandial glucose levels
    • Clinical use
      • first-line therapy in type II DM
    • Toxicity
      • no hypoglycemia
      • no weight gain
      • lactic acidosis is most serious side effect
        • contraindicated in renal failure
  • Glitazones (thiazolidinediones)
    • Thiazolidinediones, also known as the "-glitazones"
    • Drugs
      • pioglitazone
      • rosiglitazone
    • Mechanism
      • bind to nuclear receptors involved in transcription of genes mediating insulin sensitivity
        • peroxisome proliferator-activating receptors (PPARs)
      • ↑ insulin sensitivity in peripheral tissue
      • ↓ gluconeogenesis
      • ↑ insulin receptor numbers
      • ↓ triglycerides
    • Clinical use
      • type II DM
        • as monotherapy or in combination with other agents
        • contraindicated in CHF
          • associated with increased risk of MI (in particular rosiglitazone)
    • Toxicity
      • weight gain
      • edema
        • peripheral edema
        • pulmonary edema
      • hepatotoxicity
      • CV toxicity
      • less risk of hypoglycemia vs. sulfonylureas
  • α-glucosidase inhibitors
    • Drugs
      • acarbose
      • miglitol
    • Mechanism
      • inhibit α-glucosidases in intestinal brush border
        • delayed sugar hydrolysis
        • delayed glucose absorption
        • ↓ postprandial hyperglycemia
        • ↓ insulin demand
    • Clinical use
      • type II DM
        • as monotherapy or in combination with other agents
    • Toxicity
      • no hypoglycemia
      • GI upset
  • Amylin mimetics
    • Drugs
      • pramlintide
    • Mechanism
      • synthetic analogue of human amylin that acts in conjunction with insulin
      • ↓ release of glucagon
      • delays gastric emptying
    • Clinical use
      • type I and II DM
    • Toxicity
      • hypoglycemia
        • if given with insulin
      • nausea
      • diarrhea
  • GLP-1 analogs
    • Drugs
      • exenatide
    • Mechanism
      • GLP-1 is an incretin released from the small intestine that aids glucose-dependent insulin secretion
        • basis for drug mechanism is the observation that more insulin secreted with oral glucose load compared to IV
      • exenatide is a GLP-1 agonist
        • ↑ insulin
        • ↓ glucagon release
      • the class of dipeptidyl peptidase inhibitors ↓ degradation of endogenous GLP-1
        • e.g.) sitagliptin, -gliptins
    • Clinical use
      • type II DM
    • Toxicity
      • nausea, vomiting
      • pancreatitis
      • hypoglycemia
        • if given with sulfonylureas
    • DPP-4 inhibitors
    • Drugs
      • sitagliptin
      • linagliptin
    • Mechanism
      • prevents the peripheral degradation of GLP-1, thereby potentiating glucose-dependent insulin release
    • Clinical use
      • type II DM
    • Toxicity
      • arthralgias
      • heart failure exacerbation
  • SGLT-2 Inhibitors
    • Drugs
      • canagliflozin
      • empagliflozin
    • Mechanism
      • glucose is reabsorbed in the proximal tubule of the nephron by the sodium-glucose cotransporter 2 (SGLT2)
      • SGLT2-inhibitors lower serum glucose by increasing urinary glucose excretion
      • the mechanism of action is independent of insulin secretion or action
    • Clinical use
      • type II DM
    • Toxicity
      • dehydration
      • urinary and genital infections
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