Drugs used in diabetes treat types of diabetes mellitus by decreasing glucose levels in the blood. Most GLP-1 receptor agonists (liraglutide, exenatide, tirzepatide, pramlintide and others) are administered by injection. Other anti-diabetes medications (including semaglutide as Rybelsus) are administered orally and are thus called oral hypoglycemic agents or oral antihyperglycemic agents. (Semaglutide is available both as a pill and as an injection.) There are different classes of hypoglycemic drugs, and selection of the appropriate agent depends on the nature of the diabetes (Type I vs Type II), the age and situation of the person, as well as other patient factors.
Type 1 diabetes is an endocrine disorder characterized by hyperglycemia due to autoimmune destruction of insulin-secreting pancreatic beta cells. Insulin is a hormone needed by cells to take in glucose from the blood. Insufficient levels of insulin due to Type 1 diabetes can lead to chronic hyperglycemia and eventual multiorgan damage, resulting in renal, neurologic, cardiovascular, and other serious complications.Klandorf, Hillar, PhD, and Sharon W. Stark. "Diabetes Mellitus." Salem Press Encyclopedia of Health, 2024. EBSCOhost, search.ebscohost.com/login.aspx?direct=true&AuthType=cookie,ip,shib,uid&db=ers&AN=86194054&site=eds-live&scope=site. The treatment for Type 1 diabetes involves regular insulin injections.
Type 2 diabetes, the most common type of diabetes, occurs when cells exhibit insulin resistance and become unable to properly utilize insulin. Insulin resistance requires the pancreas to compensate by increasing insulin production. Once compensation fails, chronic hyperglycemia can manifest and type 2 diabetes develops.Type 2 Diabetes: What You Need to Know. GovInfo. (2012, July). https://www.govinfo.gov/app/details/GOVPUB-HE20-PURL-gpo50043 Treatments include dietary changes emphasizing low glycemic index food, physical activity to improve insulin sensitivity, and medications that (1) increase the amount of insulin secreted by the pancreas, (2) increase the sensitivity of target organs to insulin, (3) decrease the rate at which glucose is absorbed from the gastrointestinal tract, and (4) increase the loss of glucose through urination.
Several drug classes are indicated for use in type 2 diabetes and are often used in combination. Therapeutic combinations may include several insulin isoforms or varying classes of oral antihyperglycemic agents. As of 2020, 23 unique antihyperglycemic drug combinations were approved by the FDA. The first triple combination of oral anti-diabetics was approved in 2019, consisting of metformin, saxagliptin, and dapagliflozin. Another triple combination approval for metformin, linagliptin, and empagliflozin followed in 2020.
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Mechanisms of action Diabetes medications have four main mechanisms of action: Insulin sensitization: Increased sensitivity of insulin receptors on cells leading to decreased insulin resistance, and higher effects of insulin on blood glucose levels. Stimulation of beta cells: This stimulation increases insulin secretion from beta cells of pancreas. Alpha-glucosidase inhibition: Inhibition of the alpha-glucosidase enzyme, decreases the rate at which glucose is absorbed from the gastrointestinal tract. Alpha-amylase inhibition: Inhibition of the alpha-amylase enzyme, decreasing the digestion of starch. SGLT2 inhibition: Inhibition of sodium-glucose transport protein 2 (SGLT2) decreases glucose reabsorption in the renal tubules of nephrons, thus increasing the amount of glucose excreted in urine.
Insulin
Insulin is usually given subcutaneously, either by injections or by an insulin pump. In acute care settings, insulin may also be given intravenously. Insulins are typically characterized by the rate at which they are metabolized by the body, yielding different peak times and durations of action. Faster-acting insulins peak quickly and are subsequently metabolized, while longer-acting insulins tend to have extended peak times and remain active in the body for more significant periods.
Examples of rapid-acting insulins (peak at ~1 hour) are: Insulin lispro (Humalog) Insulin aspart (Novolog) Insulin glulisine (Apidra)
Examples of short-acting insulins (peak 2–4 hours) are: Regular insulin (Humulin R, Novolin R) Prompt insulin zinc (Semilente)
Examples of intermediate-acting insulins (peak 4–10 hours) are: Isophane insulin, neutral protamine Hagedorn (NPH) (Humulin N, Novolin N) Insulin zinc (Lente)
Examples of long-acting insulins (duration 24 hours, often without peak) are: Extended insulin zinc insulin (Ultralente) Insulin glargine (Lantus) Insulin detemir (Levemir) Insulin degludec (Tresiba)
Insulin degludec is sometimes classed separately as an "ultra-long" acting insulin due to its duration of action of about 42 hours, compared with 24 hours for most other long-acting insulin preparations.
As a systematic review of studies comparing insulin detemir, insulin glargine, insulin degludec and NPH insulin did not show any clear benefits or serious adverse effects for any particular form of insulin for nocturnal hypoglycemia, severe hypoglycemia, glycated hemoglobin A1c, non-fatal myocardial infarction/stroke, health-related quality of life or all-cause mortality. The same review did not find any differences in effects of using these insulin analogues between adults and children. NPH insulin is an older intermediate-acting form of insulin. They both provide coverage to lower blood glucose levels bwtween meals.
Most oral anti-diabetic agents are contraindicated in pregnancy, in which case insulin is preferred.
Insulin is not administered by other routes, although this has been studied. An inhaled form was briefly licensed but was subsequently withdrawn.
Sensitizers Insulin sensitizers address the core problem in type 2 diabetes – insulin resistance.
Biguanides
Biguanides reduce hepatic glucose output and increase uptake of glucose by the periphery, including skeletal muscle. Although it must be used with caution in patients with impaired liver or kidney function, Metformin, a biguanide, has become the most commonly used agent for type 2 diabetes in children and teenagers. Among common diabetic drugs, Metformin is the only widely used oral drug that does not cause weight gain.
Typical reduction in glycated hemoglobin (A1C) values for Metformin is 1.5–2.0% Metformin (Glucophage) may be the best choice for patients who also have heart failure, but it should be temporarily discontinued before any radiographic procedure involving intravenous iodinated contrast, as patients are at an increased risk of lactic acidosis. Phenformin (DBI) was used from 1960s through 1980s, but was withdrawn due to lactic acidosis risk. Buformin also was withdrawn due to lactic acidosis risk.
Metformin is a first-line medication used for treatment of type 2 diabetes. It is generally prescribed at initial diagnosis in conjunction with exercise and weight loss, as opposed to the past, where it was prescribed after diet and exercise had failed. There is an immediate-release as well as an extended-release formulation, typically reserved for patients experiencing gastrointestinal side-effects. It is also available in combination with other oral diabetic medications.
Thiazolidinediones
Thiazolidinediones (TZDs), also known as "glitazones," bind to PPARγ, peroxisome proliferator activated receptor γ, a type of nuclear regulatory protein involved in the transcription of genes that regulate glucose and fat metabolism. These PPARs act on peroxisome proliferator responsive elements (PPRE). The PPREs influence insulin-sensitive genes, which enhance production of mRNAs of insulin-dependent enzymes. The final result is better use of glucose by the cells. These drugs also enhance PPAR-α activity and hence lead to a rise in HDL and some larger components of LDL.
Typical reductions in glycated hemoglobin (A1C) values are 1.5–2.0%. Some examples are: Rosiglitazone (Avandia): the European Medicines Agency recommended in September 2010 that it be suspended from the EU market due to elevated cardiovascular risks.European Medicines Agency, "European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim" , EMA, 23 September 2009 Pioglitazone (Actos): remains on the market but has also been associated with increased cardiovascular risks. Troglitazone (Rezulin): used in 1990s, withdrawn due to hepatitis and liver damage risk.
Multiple retrospective studies have resulted in a concern about rosiglitazone's safety, although it is established that the group, as a whole, has beneficial effects on diabetes. The greatest concern is an increase in the number of severe cardiac events in patients taking it. The ADOPT study showed that initial therapy with drugs of this type may prevent the progression of disease, as did the DREAM trial. The American Association of Clinical Endocrinologists (AACE), which provides clinical practice guidelines for management of diabetes, retains thiazolidinediones as recommended first, second, or third line agents for type 2 diabetes mellitus, as of their 2019 executive summary, over sulfonylureas and α-glucosidase inhibitors. However, they are less preferred than GLP-1 agonists or SGLT2 inhibitors, especially in patients with cardiovascular disease (which liraglutide, empagliflozin, and canagliflozin are all FDA approved to treat).
Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in the New England Journal of Medicine. There have been a significant number of publications since then, and a Food and Drug Administration panel voted, with some controversy, 20:3 that available studies "supported a signal of harm", but voted 22:1 to keep the drug on the market. The meta-analysis was not supported by an interim analysis of the trial designed to evaluate the issue, and several other reports have failed to conclude the controversy. This weak evidence for adverse effects has reduced the use of rosiglitazone, despite its important and sustained effects on glycemic control. Safety studies are continuing.
In contrast, at least one large prospective study, PROactive 05, has shown that pioglitazone may decrease the overall incidence of cardiac events in people with type 2 diabetes who have already had a heart attack.
LYN Kinase Activators The LYN kinase activator Tolimidone has been reported to potentiate insulin signaling in a manner that is distinct from the glitazones. The compound has demonstrated positive results in a Phase 2a clinical study involving 130 diabetic subjects.
Secretagogues Secretagogues are drugs that increase output from a gland, in the case of insulin from the pancreas.
Sulfonylureas
Sulfonylureas were the first widely used oral anti-hyperglycemic medications. They are insulin secretagogues, triggering insulin release by inhibiting the KATP channel of the pancreatic beta cells. Eight types of these pills have been marketed in North America, but not all remain available. The "second-generation" sulfonylureas are now more commonly used. They are more effective than first-generation drugs and have fewer side-effects. All may cause weight gain.
Current clinical practice guidelines from the AACE rate sulfonylureas (as well as glinides) below all other classes of antidiabetic drugs in terms of suggested use as first, second, or third line agents - this includes Bromocriptine, the bile acid sequestrant Colesevelam, α-glucosidase inhibitors, Thiazolidinediones (glitazones), and DPP-4 inhibitors (gliptins). The low cost of most sulfonylureas, however, especially when considering their significant efficacy in blood glucose reduction, tends to keep them as a more feasible option in many patients - neither SGLT2 inhibitors nor GLP-1 agonists, the classes most favored by the AACE guidelines after metformin, are currently available as generics.