Overview

Type 2 diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus

• Caused by: 
  • Peripheral insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance: Cellular insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin receptors do not appropriately respond to insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin.
  • Beta-cell dysfunction: long term ↑ in insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin demand → defective insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin secretion
• Results in hyperglycemia
• Pharmacologic management can target:
  • Insulin release
  • Insulin resistance
  • Glucagon release
  • Gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis
  • Glucose uptake

Classification

Hyperglycemic medications can be classified based on the mechanism of action: 

Insulinotropic drugs (↑ insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin secretion):

• Sulfonylureas
• Meglitinides
• Glucagon-like peptide-1 (GLP-1) agonists
• DPP-4 inhibitors

Non-insulinotropic drugs (do not affect insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin release):

• ↓ Insulin resistance:
  • Biguanides
  • Thiazolidinediones
• ↓ Glucose absorption/reabsorption:
  • Alpha-glucosidase inhibitors
  • Sodium-glucose transport protein 2 (SGLT2) inhibitors
• ↓ Gastric emptying and glucagon secretion: amylin analogs

Sulfonylureas

Medications in the class

• 1st generation:
  • Tolbutamide
  • Chlorpropamide
  • Tolazamide
• 2nd generation:
  • Glyburide
  • Glipizide
  • Glimepiride

Pharmacodynamics

• Binds and inhibits the ATP-sensitive potassium (KATP) channels on pancreatic beta cells
• Cell depolarization → calcium (Ca²⁺) channel opens → Ca²⁺ influx
• Stimulates insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin release 
• Result: ↑ beta-cell responsiveness to glucose

Pharmacokinetics

The following describes the pharmacokinetics for 2nd-generation sulfonylureas:

• Absorption: well-absorbed orally
• Distribution: extensively protein-bound
• Metabolism:
  • Hepatic via cytochrome P450 system (CYP2C9)
  • Metabolites have low hypoglycemic activity
• Excretion:
  • Primarily in urine
  • Some excretion through feces

Indications

Sulfonylureas are used in the treatment of type 2 diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus:

• Generally used in combination with other medications
• May be considered as a 1st-line agent with:
  • Contraindications to metformin
  • Severe hyperglycemia without ketonuria (if contraindications to insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin or GLP-1 analogs)
• Not often used due to the side effects

Adverse effects

• Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
• Weight gain
• Nausea
• Photosensitivity
• Hepatitis
• Hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia
• Disulfiram-like reactions 
• Hypersensitivity reactions:
  • Rash
  • Pruritus

Contraindications

• Hypersensitivity to sulfonamides
• Hepatic impairment: drugs undergo metabolism in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver (can lead to hypoglycemia)
• Renal insufficiency: excreted by the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys (can lead to hypoglycemia)
• Type 1 diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
• Diabetic ketoacidosis

Drug interactions

• Disulfiram-like reaction: ethanol
• ↑ Hypoglycemic effect:
  • Other antidiabetic medications
  • Amiodarone
  • Androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens
  • Beta blockers
  • Chloramphenicol Chloramphenicol Chloramphenicol, the only clinically relevant drug in the amphenicol class, is a potent inhibitor of bacterial protein synthesis by binding to the 50S ribosomal subunit and preventing peptide bond formation. Chloramphenicol is a broad-spectrum antibiotic with wide distribution; however, due to its toxicity, its use is limited to severe infections. Chloramphenicol
  • Antidepressants
  • Sulfa antibiotics

Meglitinides

Medications in the class

• Repaglinide
• Nateglinide

Pharmacodynamics

• Structurally different, but act similarly to sulfonylureas
• Affect KATP channels on pancreatic beta cells
• ↑ Insulin release

Pharmacokinetics

• Absorption:
  • Rapid
  • Quicker onset of action than sulfonylureas
• Distribution:
  • Extensively protein-bound
  • Shorter duration of action than sulfonylureas
• Metabolism:
  • Hepatic 
  • Via cytochrome P450 system: 
    • CYP3A4
    • CYP2C8
• Excretion: 
  • Repaglinide: primarily feces
  • Nateglinide: primarily urine

Indications

Meglitinides treat type 2 diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus:

• In combination with other drugs
• In place of a sulfonylurea in individuals with an allergy
• To control postprandial hyperglycemia

Adverse effects

• Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
• Weight gain
• Respiratory tract infections
• Headache

Contraindications

• Renal insufficiency
• Hepatic insufficiency 
• Type 1 diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus 
• Diabetic ketoacidosis

Drug interactions

An increased hypoglycemic effect may be seen with:

• Other antidiabetic medications
• Androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens
• Direct-acting antiviral agents
• Gemfibrozil
• Statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins
• Clopidogrel
• Antidepressants

Glucagon-like peptide-1 (GLP-1) Agonists

Medications in the class

• Exenatide (derived from the venom of the Gila monster)
• Liraglutide
• Dulaglutide
• Semaglutide

Pharmacodynamics

• Incretin mimetics (GLP-1 agonists) → bind to GLP-1 receptors:
  • Beta cells → ↑ glucose-dependent insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin secretion
  • Alpha cells → ↓ glucagon secretion
• Additional effects:
  • Slowed gastric emptying
  • ↓ Appetite
  • Weight loss

Pharmacokinetics

• Absorption: given as subcutaneous injections
• Distribution: highly protein-bound
• Excretion: urine and feces

Indications

• Treatment of type 2 diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus:
  • Not an initial therapy for most individuals
  • Usually used in combination with other medications
  • Associated with a reduction in cardiovascular events
• Weight management

Adverse effects

• Nausea and vomiting
• Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea 
• Pancreatitis
• Thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
• Acute kidney injury Acute Kidney Injury Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury
• Hypersensitive reactions:
  • Angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema
  • Anaphylaxis
  • Injection site reactions

Contraindications

• Personal or family history of medullary thyroid carcinoma (MTC) (animal studies show potential thyroid cancer Thyroid cancer Thyroid cancer is a malignancy arising from the thyroid gland cells: thyroid follicular cells (papillary, follicular, and anaplastic carcinomas) and calcitonin-producing C cells (medullary carcinomas). Rare cancers are derived from the lymphocytes (lymphoma) and/or stromal and vascular elements (sarcoma). Thyroid Cancer association)
• GI motility disorders due to decreased GI emptying
• History of pancreatitis 
• Renal failure

Drug interactions

• ↑ Hypoglycemic effect:
  • Other antidiabetic medications
  • Androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens
  • Direct-acting antiviral agents
  • Antidepressants
• Combination therapy with DPP-4 inhibitors does not provide additional benefits.

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

Medications in the class

• Sitagliptin
• Saxagliptin
• Linagliptin
• Alogliptin

Pharmacodynamics

• Inhibits the DPP-4 enzyme, which normally breaks down GLP-1 
• ↑ Incretin effects:
  • ↑ Glucose-dependent insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin secretion
  • ↓ Glucagon levels

Pharmacokinetics

• Absorption: absorbed orally
• Distribution:
  • Extensive
  • Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables protein-binding
• Metabolism:
  • Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables
  • Hepatic
  • Some by the cytochrome P450 system
• Excretion:
  • Mainly through urine
  • Exception: Linagliptin is primarily excreted through feces.

Indications

DPP-4 inhibitors treat type 2 diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus:

• Not an initial therapy for most individuals
• Used as adjunctive therapy

Adverse effects

• Nasopharyngitis and upper respiratory tract infections
• Headache 
• Arthralgia and myalgia
• Acute pancreatitis Acute pancreatitis Acute pancreatitis is an inflammatory disease of the pancreas due to autodigestion. Common etiologies include gallstones and excessive alcohol use. Patients typically present with epigastric pain radiating to the back. Acute Pancreatitis 
• Hepatic dysfunction
• Bullous pemphigoid Bullous pemphigoid Bullous pemphigoid and pemphigus vulgaris are two different blistering autoimmune diseases. In bullous pemphigoid, autoantibodies attack the hemidesmosomes, which connect epidermal keratinocytes to the basement membrane. This attack results in large, tense subepidermal blisters. Bullous Pemphigoid and Pemphigus Vulgaris
• Hypersensitivity reactions:
  • Angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema
  • Anaphylaxis
  • Urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives)

Contraindications

• Renal failure
• Liver failure
• Type 1 diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
• Diabetic ketoacidosis

Drug interactions

• ↑ Hypoglycemic effect:
  • Other antidiabetic medications
  • Androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens
  • Direct-acting antiviral agents
  • Antidepressants
• ↑ Toxicity of:
  • ACE inhibitors
  • Digoxin
• Combination therapy with GLP-1 agonists does not provide additional benefit.