Diabetes Drugs

Overview

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

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

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