Anti-diabetic medication

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Drugs used in diabetes treat diabetes mellitus by lowering glucose levels in the blood. With the exceptions of insulin, exenatide, liraglutide and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of anti-diabetic drugs, and their selection depends on the nature of the diabetes, age and situation of the person, as well as other factors.

Diabetes mellitus type 1 is a disease caused by the lack of insulin. Insulin must be used in Type I, which must be injected.

Diabetes mellitus type 2 is a disease of insulin resistance by cells. Type 2 diabetes mellitus is the most common type of diabetes. Treatments include (1) agents that increase the amount of insulin secreted by the pancreas, (2) agents that increase the sensitivity of target organs to insulin, and (3) agents that decrease the rate at which glucose is absorbed from the gastrointestinal tract.

Several groups of drugs, mostly given by mouth, are effective in Type II, often in combination. The therapeutic combination in Type II may include insulin, not necessarily because oral agents have failed completely, but in search of a desired combination of effects. The great advantage of injected insulin in Type II is that a well-educated patient can adjust the dose, or even take additional doses, when blood glucose levels measured by the patient, usually with a simple meter, as needed by the measured amount of sugar in the blood.

Insulin[edit]

Main article: insulin

Insulin is usually given subcutaneously, either by injections or by an insulin pump. Research of other routes of administration is underway. In acute-care settings, insulin may also be given intravenously. In general, there are three types of insulin, characterized by the rate which they are metabolized by the body. They are rapid acting insulins, intermediate acting insulins and long acting insulins. Examples of rapid acting insulins include

  • Regular insulin (Humulin R, Novolin R)
  • Insulin lispro (Humalog)
  • Insulin aspart (Novolog)
  • Insulin glulisine (Apidra)
  • Prompt insulin zinc (Semilente, Slightly slower acting)

Examples of intermediate acting insulins include

  • Isophane insulin, neutral protamine Hagedorn (NPH) (Humulin N, Novolin N)
  • Insulin zinc (Lente)

Examples of long acting insulins include

  • Extended insulin zinc insulin (Ultralente)
  • Insulin glargine (Lantus)
  • Insulin detemir (Levemir)

Comparison[edit]

The following table compares some common anti-diabetic agents, generalizing classes, although there may be substantial variation in individual drugs of each class. When the table makes a comparison such as "lower risk" or "more convenient" the comparison is with the other drugs on the table.

Comparison of anti-diabetic medication[1][2]
agent[2] mechanism[3] advantages[2] disadvantages[2]
Sulfonylurea (glyburide, glimepiride, glipizide) Stimulating insulin release by pancreatic beta cells by inhibiting the KATP channel
  • causes an average of 5–10 pounds weight gain
  • Increased risk of hypoglycemia
  • Glyburide has increases risk of hypoglycemia slightly more as compared with glimepiride and glipizide
  • Higher risk of death compared with metformin[4]
Metformin Acts on the liver to reduce gluconeogenesis and causes a decrease in insulin resistance via increasing AMPK signalling.
  • not associated with weight gain
  • low risk of hypoglycemia as compared to alternatives
  • Good effect on LDL cholesterol
  • Decreases triglycerides
  • no effect on blood pressure
  • inexpensive
Alpha-glucosidase inhibitor (acarbose, miglitol, voglibose) Reduces glucose absorbance by acting on small intestine to cause decrease in production of enzymes needed to digest carbohydrates
  • slightly decreased risk of hypoglycemia as compared to sulfonylurea
  • not associated with weight gain
  • decreases triglycerides
  • no effect on cholesterol
  • less effective than most other diabetes pills in decreasing glycated hemoglobin
  • increased risk of GI problems than other diabetes pills except metformin
  • inconvenient dosing
  • expensive
Thiazolidinediones (Pioglitazone, Rosiglitazone) Reduce insulin resistance by activating PPAR-γ in fat and muscle
  • Lower risk of hypoglycemia
  • Slight increase in high-density lipoprotein
  • Actos linked to decreased triglycerides
  • Convenient dosing
  • increased risk of heart failure
  • causes an average of 5–10 pounds weight gain
  • associated with higher risk of edema
  • associated with higher risk of anemia
  • increases low-density lipoprotein
  • Avandia linked to increased triglycerides and risk of heart attack
  • Actos linked to increased risk of bladder cancer
  • slower onset of action
  • requires monitoring for hepatoxicity
  • associated with increased risk of limb fractures
  • expensive

Most anti-diabetic agents are contraindicated in pregnancy, in which insulin is preferred.[3]

Sensitizers[edit]

Insulin sensitizers address the core problem in Type II diabetes—insulin resistance.

Biguanides[edit]

Main article: Biguanide

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,[5] 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.[6]
  • Buformin also was withdrawn due to lactic acidosis risk.[7]

Metformin is usually the first-line medication used for treatment of type 2 diabetes. In general, it is prescribed at initial diagnosis in conjunction with exercise and weight loss, as opposed to in 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 GI side-effects. It is also available in combination with other oral diabetic medications.

Thiazolidinediones[edit]

Main article: Thiazolidinedione

Thiazolidinediones (TZDs), also known as "glitazones," bind to PPARγ, a type of nuclear regulatory protein involved in transcription of genes regulating glucose and fat metabolism. These PPARs act on peroxysome proliferator responsive elements (PPRE).[8] 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.

Typical reductions in glycated hemoglobin (A1C) values are 1.5–2.0%. Some examples are:

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,[11] as did the DREAM trial.[12]

Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in the New England Journal of Medicine.[13] There have been a significant number of publications since then, and a Food and Drug Administration panel[14] 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.[15] 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.[16]

Secretagogues[edit]

Secretagogues are drugs that increase insulin output from the pancreas.

Sulfonylureas[edit]

Main article: Sulfonylurea

Sulfonylureas were the first widely used oral anti-hyperglycaemic 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" drugs are now more commonly used. They are more effective than first-generation drugs and have fewer side-effects. All may cause weight gain. A 2012 study found sulfonylureas raise the risk of death compared with metformin.[4]

Sulfonylureas bind strongly to plasma proteins. Sulfonylureas are useful only in Type II diabetes, as they work by stimulating endogenous release of insulin. They work best with patients over 40 years old who have had diabetes mellitus for under ten years. They cannot be used with type I diabetes, or diabetes of pregnancy. They can be safely used with metformin or -glitazones. The primary side-effect is hypoglycemia.

Typical reductions in glycated hemoglobin (A1C) values for second-generation sulfonylureas are 1.0–2.0%.

Nonsulfonylurea secretagogues[edit]

Meglitinides[edit]

Main article: Meglitinide

Meglitinides help the pancreas produce insulin and are often called "short-acting secretagogues." They act on the same potassium channels as sulfonylureas, but at a different binding site.[17] By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, thereby enhancing insulin secretion.[18]

They are taken with or shortly before meals to boost the insulin response to each meal. If a meal is skipped, the medication is also skipped.

Typical reductions in glycated hemoglobin (A1C) values are 0.5–1.0%.

Adverse reactions include weight gain and hypoglycemia.

Alpha-glucosidase inhibitors[edit]

Alpha-glucosidase inhibitors are "diabetes pills" but not technically hypoglycemic agents because they do not have a direct effect on insulin secretion or sensitivity. These agents slow the digestion of starch in the small intestine, so that glucose from the starch of a meal enters the bloodstream more slowly, and can be matched more effectively by an impaired insulin response or sensitivity. These agents are effective by themselves only in the earliest stages of impaired glucose tolerance, but can be helpful in combination with other agents in type 2 diabetes.

Typical reductions in glycated hemoglobin (A1C) values are 0.5–1.0%.

These medications are rarely used in the United States because of the severity of their side-effects (flatulence and bloating). They are more commonly prescribed in Europe. They do have the potential to cause weight loss by lowering the amount of sugar metabolized.

Research has shown that the culinary mushroom maitake (Grifola frondosa) has a hypoglycemic effect,[19][20][21][22][23][24] possibly due to the mushroom acting as a natural alpha glucosidase inhibitor.[25]

Peptide analogs[edit]

Overview of insulin secretion

Injectable Incretin mimetics[edit]

Incretins are insulin secretagogues. The two main candidate molecules that fulfill criteria for being an incretin are glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (glucose-dependent insulinotropic peptide, GIP). Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).

Injectable Glucagon-like peptide analogs and agonists[edit]

Glucagon-like peptide (GLP) agonists bind to a membrane GLP receptor.[18] As a consequence, insulin release from the pancreatic beta cells is increased. Endogenous GLP has a half-life of only a few minutes, thus an analogue of GLP would not be practical.

These agents may also cause a decrease in gastric motility, responsible for the common side-effect of nausea, and is probably the mechanism by which weight loss occurs.

Gastric inhibitory peptide analogs[edit]

  • None are FDA approved

Dipeptidyl Peptidase-4 Inhibitors[edit]

GLP-1 analogs resulted in weight loss and had more gastrointestinal side-effects, while in general DPP-4 inhibitors were weight-neutral and increased risk for infection and headache, but both classes appear to present an alternative to other antidiabetic drugs. However, weight gain and/or hypoglycaemia have been observed when DPP-4 inhibitors were used with sulfonylureas; effect on long-term health and morbidity rates are still unknown.[35]

Dipeptidyl peptidase-4 (DPP-4) inhibitors increase blood concentration of the incretin GLP-1 by inhibiting its degradation by dipeptidyl peptidase-4.

Examples are:

DPP-4 inhibitors lowered hemoglobin A1C values by 0.74%, comparable to other antidiabetic drugs.[36]

A result in one RCT comprising 206 patients aged 65 or older (mean baseline HgbA1c of 7.8%) receiving either 50 or 100 mg/d of Sitagliptin was shown to reduce HbA1c by 0.7% (combined result of both doses).[37] A combined result of 5 RCTs enlisting a total of 279 patients aged 65 or older (mean baseline HbA1c of 8%) receiving 5 mg/d of Saxagliptin was shown to reduce HbA1c by 0.73%.[38] A combined result of 5 RCTs enlisting a total of 238 patients aged 65 or older (mean baseline HbA1c of 8.6%) receiving 100 mg/d of Vildagliptin was shown to reduce HbA1c by 1.2%.[39] Another set of 6 combined RCTs involving Alogliptin (not yet approved, might be released in 2012) was shown to reduce HbA1c by 0.73% in 455 patients aged 65 or older who received 12.5 or 25 mg/d of the medication.[40]

Injectable Amylin analogues[edit]

Amylin agonist analogues slow gastric emptying and suppress glucagon. They have all the incretins actions except stimulation of insulin secretion. As of 2007, pramlintide is the only clinically available amylin analogue. Like insulin, it is administered by subcutaneous injection. The most frequent and severe adverse effect of pramlintide is nausea, which occurs mostly at the beginning of treatment and gradually reduces. Typical reductions in A1C values are 0.5–1.0%.

Glycosurics[edit]

SGLT-2 inhibitors block the re-uptake of glucose in the renal tubules, promoting loss of glucose in the urine. This causes both mild weight loss, and a mild reduction in blood sugar levels with little risk of hypoglycaemia.[41] Urinary tract infection is a common side effect. Examples of SGLT-2 inhibitors include:

Natural substances[edit]

Plants[edit]

A number of medicinal plants have been studied for the treatment of diabetes, however there is insufficient evidence to determine their effectiveness.[42] Cinnamon has blood sugar-lowering properties, however whether or not it is useful for treating diabetes is unknown.[43] Researchers from Australia's Swinburne University have found extracts from Australian Sandalwood and Indian Kino tree slows down two key enzymes in carbohydrate metabolism.[44] Bioassay-directed fractionation techniques led to isolation of isoorientin as the main hypoglycemic component in Gentiana olivieri.[45]

Elements[edit]

While chromium supplements have no beneficial effect on healthy people, there might be an improvement in glucose metabolism in individuals with diabetes, although the evidence for this effect remains weak.[46] Vanadyl sulfate, a salt of vanadium, is still in preliminary studies.[47] There is tentative research that thiamine may prevent some diabetic complications however more research is needed.[48]

Generic[edit]

Many anti-diabetes drugs are available as generics. These include:[49]

No generics are available for dipeptidyl peptidase-4 inhibitors (Januvia, Onglyza) and other combinations.

References[edit]

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Further reading[edit]