Medication Summary
Oral antidiabetic agents can be classified into functional categories, as follows [50, 74, 75, 76, 77, 78, 79, 80, 81, 82] :
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Secretagogues (eg, sulfonylureas, meglitinides), which stimulate insulin release
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Insulin sensitizers (eg, biguanides, thiazolidinediones), which reduce insulin resistance
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Medications that slow the digestive/absorptive process (eg, alpha-glucosidase inhibitors)
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Incretin-based therapies: Dipeptidyl peptidase 4 (DPP-4) inhibitors (eg, sitagliptin), which inhibit DPP-4, the enzyme that inactivates incretin hormones glucagon-like peptide 1 (GLP-1) and glucose‐dependent insulinotropic polypepide (GIP). [48, 49] More recently, a GLPRA (GLP-1 receptor agonist) has become available as an oral agent.
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Selective sodium-glucose transporter-2 (SGLT2) inhibitors (eg, canagliflozin) block reabsorption of glucose in the kidney
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Centrally acting dopamine agonist (bromocriptine), presumably via increase in central (hypothalamic) dopaminergic tone
Sulfonylureas
Class Summary
Sulfonylureas stimulate insulin release from pancreatic beta cells. These agents include chlorpropamide and tolbutamide (first-generation), as well as glipizide, glyburide, and glimepiride (second-generation), are secretagogues (ie, medications that stimulate insulin secretion).
Glipizide (Glucotrol, Glucotrol XL)
Glipizide is a second-generation sulfonylurea that stimulates the release of insulin from pancreatic beta cells.
Glyburide (Glynase)
Glyburide is a second-generation sulfonylurea and is more potent and exhibits fewer drug interactions than first-generation agents.
Glimepiride (Amaryl)
Glimepiride is a third-generation sulfonylurea that may cause more physiologic insulin release than some of the older agents.
Chlorpropamide (Diabinese, Glucamide)
Chlorpropamide is a first-generation sulfonylurea that stimulates the release of insulin from pancreatic beta cells. It is the longest-acting sulfonylurea, present in blood longer than 24 hour in many patients, and longer in patients with renal insufficiency.
Tolbutamide
First-generation sulfonylurea that stimulates the release of insulin from pancreatic beta cells.
Meglitinide derivatives
Class Summary
These agents stimulate insulin secretion from pancreatic cells, lowering blood glucose levels.
Repaglinide (Prandin)
Repaglinide is a meglitinide analogue, a secretagogue that acts on the pancreas to stimulate the release of insulin.
Nateglinide (Starlix)
Nateglinide is an analogue of D-phenylalanine. It mimics endogenous insulin patterns, restores early insulin secretion, and controls mealtime glucose surges.
Biguanides
Class Summary
These agents improve peripheral glucose uptake and utilization.
Metformin (Glucophage, Glucophage XR, Fortamet, Glumetza, Riomet)
Metformin reduces insulin resistance (ie, metformin is an insulin sensitizer). Hepatic glucose output is decreased; peripheral insulin-stimulated uptake is increased.
Thiazolidinediones
Class Summary
These agents stimulate peripheral use of glucose as stimulated by insulin. Rosiglitazone and pioglitazone are commonly used.
Following the online publication of a meta-analysis, the Food and Drug Administration on May 21, 2007, issued an alert to patients and health care professionals stating that rosiglitazone can potentially cause an increased risk of myocardial infarction and heart-related deaths. Rosiglitazone is an antidiabetic agent (thiazolidinedione derivative) that improves glycemic control by improving insulin sensitivity.
The drug is highly selective and is a potent agonist for peroxisome proliferator-activated receptor gamma (PPAR gamma). Activation of PPAR-gamma receptors regulates insulin-responsive gene transcription involved in glucose production, transport, and utilization, thereby reducing blood glucose concentrations and reducing hyperinsulinemia. Potent PPAR-gamma agonists have been shown to increase the incidence of edema. A large scale phase III trial (RECORD) is underway that is specifically designed to study cardiovascular outcomes of rosiglitazone.
As of September 2010, the FDA is requiring a restricted access program to be developed for rosiglitazone under a risk evaluation and mitigation strategy (REMS). Patients currently taking rosiglitazone and benefiting from the drug will be able to continue if they choose to do so. Rosiglitazone will only be available to new patients if they are unable to achieve glucose control on other medications and are unable to take pioglitazone, the only other thiazolidinedione.
For more information, see FDA’s Safety Alert on Avandia. The meta-analysis published online, entitled "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes" can be viewed at The New England Journal of Medicine. Additionally, responses to the controversy can be viewed at the Heartwire news (theheart.org from WebMD), including the following articles: Rosiglitazone increases MI and CV death in meta-analysis and The rosiglitazone aftermath: legitimate concerns or hype?
Rosiglitazone (Avandia)
Available only through a restricted access program. Rosiglitazone sensitizes target cells' response to insulin and has an effect on the stimulation of glucose uptake in skeletal muscle and adipose tissue.
Pioglitazone (Actos)
Pioglitazone improves target cell response to insulin and increases insulin-dependent glucose use in skeletal muscle and adipose tissue.
Alpha-glucosidase inhibitors
Class Summary
These agents include acarbose and miglitol, medications that slow the digestive and absorptive process, preventing postprandial glucose surges.
Acarbose (Precose)
Acarbose slows digestive and absorptive processes. It delays hydrolysis of ingested complex carbohydrates and disaccharides and absorption of glucose. Acarbose inhibits the metabolism of sucrose to glucose and fructose.
Miglitol (Glyset)
Miglitol delays glucose absorption in the small intestine and lowers postprandial hyperglycemia.
Rapid-acting insulins
Class Summary
Rapid-acting insulins have a short duration of action and are appropriate before meals or when blood glucose levels exceed target levels and correction doses are needed. These agents are associated with less hypoglycemia than regular insulin.
Insulin aspart (NovoLog)
Insulin aspart has a short onset of action of 5-15 minutes and a short duration of action of 3-5 hours. The peak effect occurs within 30-90 minutes. Insulin aspart is FDA approved for use in insulin pumps.
Insulin glulisine (Apidra)
Insulin glulisine has a rapid onset of action of 5-15 minutes and a short duration of action of 3-5 hours. The peak effect occurs within 30-90 minutes. Insulin glulisine is FDA approved for use in insulin pumps.
Insulin lispro (Humalog)
Insulin lispro has a rapid onset of action of 5-15 minutes and a short duration of action of 4 hours.
Insulin inhaled (Afrezza)
Inhaled human insulin is identical, in structure, to that of native human insulin. It is absorbed into carrier particles which dissolve within the lungs after inhalation. This leads to rapid absorption of insulin in the systemic circulation. Inhaled insulin is an ultra-rapid acting insulin.
Short-acting insulins
Class Summary
Short-acting insulins are commonly used when a slower onset of action or greater duration of action is desired.
Regular insulin (Humulin R, Novolin R)
Regular insulin has a rapid onset of action of 0.5-1 hours and duration of action of 4-6 hours. The peak effects are seen within 2-4 hours. Preparations that contain a mixture of 70% neutral protamine Hagedorn (NPH) and 30% regular human insulin (ie, Novolin 70/30, Humulin 70/30) are also available.
Intermediate-acting insulins
Class Summary
Intermediate-acting insulins have a slow onset of action and a longer duration of action. These agents are commonly combined with faster-acting insulins to maximize the benefits of a single injection.
Insulin NPH (Humulin N, Novolin N)
Insulin NPH has an onset of action of 3-4 hours and duration of action of 16-24 hours. The peak effect of insulin NPH occurs within 8-14 hours.
Long-acting insulins
Class Summary
These insulins provide a longer duration of action, and, when combined with rapid- or short-acting insulins, they provide better glucose control.
Insulin detemir (Levemir)
Insulin detemir is indicated for once- or twice-daily dosing for patients with type 1 or 2 diabetes mellitus. The duration of action is up to 24 hours, resulting from slow systemic absorption of detemir from the injection site.
Insulin Glargine (Lantus)
Insulin glargine has an onset of action of 4-8 hours and duration of action of 24 hours. Peak effects occur within 16-18 hours.
Premixed Insulins
Class Summary
Premixed insulins are used in the treatment of type 1 or 2 diabetes mellitus. These combinations combine rapid- and long-acting insulins.
Insulin aspart protamine/insulin aspart (NovoLog 50/50, NovoLog 70/30)
The insulin aspart protamine/insulin aspart combination includes a rapid-onset insulin, insulin aspart, and intermediate-acting insulin, insulin aspart protamine. Insulin aspart is absorbed more rapidly than regular human insulin, and insulin aspart protamine has a prolonged absorption profile after injection.
Insulin lispro protamine/insulin lispro (Humalog 50/50, Humalog 75/25)
The insulin lispro protamine/insulin lispro combination includes a rapid-onset insulin, insulin lispro, and insulin lispro protamine, which has a prolonged duration of action.
Glucagon-like Peptide-1 (glp-1) Receptor Agonists
Class Summary
This new class broadens the armamentarium of antidiabetic medications. Exenatide and liraglutide are dipeptidyl peptidase 4 (DPP-4)–resistant glucagonlike peptide-1 (GLP-1) receptor agonists or analogues. As incretin mimetics, they enhance insulin secretion, suppress glucagon secretion, and slow gastric emptying. Exenatide has been approved by the FDA as adjunctive therapy in patients who have not achieved adequate control with metformin or sulfonylurea; exenatide has been available since June 2005, and a new, long-acting, once-weekly subcutaneous injection (Bydureon) was approved by the FDA in January 2012. Liraglutide was approved by the FDA in January 2010. This agent is administered daily.
In the DURATION-5 (Diabetes therapy Utilization: Researching changes in A1C, weight and other factors Through Intervention with exenatide ONce weekly) study, the exenatide once-weekly formulation was found to provide significantly greater improvement in glycemic control than the twice-daily preparation. Additionally, less nausea was observed with the once-weekly exenatide formulation compared with the twice-daily preparation. [83]
There are currently other weekly injectable GLPRA (GLP-1 receptor agonists) (eg, dulaglutide, semaglutide). Semaglutide is available as an oral formulation (Rybelsus), approved by the FDA in 2019, the first in the class that does not need to be injected.
Lixisenatide is another injectable GLPRA. It is administered daily.
Recommendations for the use of GLPRAs have been strengthened by increasing evidence of their efficacy and cardiovascular outcome.
Exenatide injectable solution/suspension (Byetta, Bydureon)
Exenatide is a 39-amino acid incretin mimetic peptide derived from Gila monster hormone exendin-4. It is structurally similar to glucagonlike peptide-1 (GLP-1). It enhances glucose-mediated insulin secretion in the beta cell, decreases the pathologic hypersecretion of glucagon in the alpha cell, slows gastric emptying, and induces satiety. It also improves postprandial hyperglycemia without a significant risk of hypoglycemia, producing moderate weight loss. Improvement in islet cell function has been demonstrated by increased proinsulin-to-insulin ratio.
The suspension form of exenatide allows once-weekly dosing by SC administration. Clinical trials observed a statistically significant improvement in HBA1c levels and fasting plasma glucose levels with the long-acting exenatide once-weekly SC injection compared with the twice-daily SC injection. The suspension is supplied as a pre-filled disposable single-dose autoinjector or cartons of four single-dose trays (includes one vial containing 2mg exenatide, one prefilled syringe containing diluent, one vial connector, and two custom needles specific to this delivery system).
Liraglutide (Victoza, Saxenda)
Liraglutide is an incretin mimetic agent that elicits glucagonlike peptide-1 (GLP-1) receptor agonist activity. It activates GLP-1 receptor by stimulating G-protein in pancreatic beta cells. It also increases intracellular cyclic AMP, leading to insulin release in the presence of elevated glucose concentrations.
Liraglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It has not been studied in combination with insulin.
Amylinomimetic agents
Class Summary
Pramlintide is an amylinomimetic agent that modulates gastric emptying, prevents postprandial increases in plasma glucagon, and promotes satiety, leading to decreased caloric intake and potential weight loss. [52, 53, 54, 55, 56, 84]
Although naturally occurring human amylin is unsuitable for clinical use because of several physicochemical properties (eg, poor solubility; self-aggregation; formation of b-pleated sheets, amyloid fibrils, amyloid plaques), the selective substitution of the amino acid proline for Ala25, Ser28, and Ser29 addresses the suboptimal physicochemical properties of human amylin while preserving the important metabolic actions. Pramlintide acetate injection, which contains this amylin analogue, is a sterile, clear, colorless, aqueous solution that also contains mannitol for isotonicity and the preservative m-cresol.
Pramlintide (SymlinPen)
Pramlintide is a synthetic analogue of human amylin, a naturally occurring hormone made in pancreas beta cells. Pramlintide slows gastric emptying, suppresses postprandial glucagon secretion, and regulates food intake through centrally mediated appetite modulation. It is indicated to treat type 1 or type 2 diabetes in combination with insulin.
Pramlintide is administered before meals in patients who have not achieved desired glucose control despite optimal insulin therapy. The drug helps to achieve lower blood glucose levels after meals, less fluctuation of blood glucose levels during the day, and improvement of long-term control of glucose levels (ie, HbA1c levels) compared with insulin alone. Reductions in insulin use and body weight are also observed.
Dipeptidyl Peptidase-IV Inhibitors
Class Summary
The DPP-4 inhibitors are oral agents that inactivate the major enzyme responsible for degrading incretin hormones in vivo.
Sitagliptin (Januvia)
Sitagliptin blocks the enzyme DPP-4, which is known to degrade incretin hormones. Sitagliptin increases concentrations of active intact incretin hormones (GLP-1 and GIP). The hormones stimulate insulin release in response to increased blood glucose levels following meals. This action enhances glycemic control. Sitagliptin is indicated for diabetes type 2 as monotherapy or in combination with metformin or with a peroxisome proliferator-activated receptor gamma agonist (eg, thiazolidinediones).
Saxagliptin (Onglyza)
Saxagliptin blocks the enzyme DPP-4, which is known to degrade incretin hormones. It increases concentrations of active intact incretin hormones (GLP-1 and GIP). The hormones stimulate insulin release in response to increased blood glucose levels following meals. This action enhances glycemic control. Saxagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Sodium-glucose Cotransporter 2 Inhibitors
Class Summary
SGLT2 inhibitors block the reabsorption of glucose in the kidney through an increased glucose excretion by lowering the renal threshold.
Canagliflozin (Invokana)
Canagliflozin reduces plasma glucose concentrations by increasing urinary excretion of glucose.
Dopamine Agonists
Class Summary
The exact mechanism is unclear. The dopamine receptor agonist is considered to increase CNS dopamine receptor activity to positively affect neuroendocrine metabolic control.
Bromocriptine (Cycloset)
Bromocriptine quick-release formulation (Cycloset) is the only bromocriptine product indicated for type 2 diabetes as an adjunct to diet and exercise to improve glycemic control. It is thought to increase dopamine receptor activity in the central nervous system, thereby positively affecting neuroendocrine metabolic control.
Antidiabetics, Glucagon-like Peptide-1 Agonists
Semaglutide (Rybelsus, Ozempic)
Semaglutide is a GLP-1 receptor agonist that is available in an oral form (Rybelsus) and as an injectable (Ozempic). It is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes.
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Glucose intolerance. Etiologic types and stages of the major disorders of glucose tolerance are displayed.
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- Overview
- Presentation
- DDx
- Workup
- Treatment
- Guidelines
- Medication
- Medication Summary
- Sulfonylureas
- Meglitinide derivatives
- Biguanides
- Thiazolidinediones
- Alpha-glucosidase inhibitors
- Rapid-acting insulins
- Short-acting insulins
- Intermediate-acting insulins
- Long-acting insulins
- Premixed Insulins
- Glucagon-like Peptide-1 (glp-1) Receptor Agonists
- Amylinomimetic agents
- Dipeptidyl Peptidase-IV Inhibitors
- Sodium-glucose Cotransporter 2 Inhibitors
- Dopamine Agonists
- Antidiabetics, Glucagon-like Peptide-1 Agonists
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- Questions & Answers
- References
