出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/10/02 16:32:44」(JST)
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 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.[1]
Examples of rapid acting insulins include
Examples of intermediate acting insulins include
Examples of long acting insulins include
Most anti-diabetic agents are contraindicated in pregnancy, in which insulin is preferred.[2]
Insulin sensitizers address the core problem in Type II diabetes—insulin resistance.
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 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 (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).[6] 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,[9] as did the DREAM trial.[10]
Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in the New England Journal of Medicine.[11] There have been a significant number of publications since then, and a Food and Drug Administration panel[12] 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.[13] 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.[14]
Secretagogues are drugs that increase insulin output from the pancreas.
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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.
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%.
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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.[15] By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, thereby enhancing insulin secretion.[16]
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.
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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.
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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).
Glucagon-like peptide (GLP) agonists bind to a membrane GLP receptor.[16] 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.
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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.[26]
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.[27]
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).[28] 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%.[29] 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%.[30] 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.[31]
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Amylin agonist analogues slow gastric emptying and suppress glucagon. They have all the incretins actions except stimulation of insulin secretion. As of 2007[update], 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%.
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.[32]
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[33][34] | |||
|---|---|---|---|
| agent[34] | mechanism[2] | advantages[34] | disadvantages[34] |
| Sulfonylurea (glyburide, glimepiride, glipizide) | Stimulating insulin release by pancreatic beta cells by inhibiting the KATP channel |
|
|
| Metformin | Acts on the liver to reduce gluconeogenesis and causes a decrease in insulin resistance via increasing AMPK signalling. |
|
|
| 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 |
|
|
| Thiazolidinediones (Pioglitazone, Rosiglitazone) | Reduce insulin resistance by activating PPAR-γ in fat and muscle |
|
|
Many anti-diabetes drugs are available as generics. These include:[35]
No generics are available for dipeptidyl peptidase-4 inhibitors (Januvia, Onglyza) and other combinations.
Oral anti-diabetic drugs, insulins and insulin analogs, and other drugs used in diabetes (A10)
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| Insulin |
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| Other |
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Pharmacology: major drug groups
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| Gastrointestinal tract/ metabolism (A) |
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| Blood and blood forming organs (B) |
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| Cardiovascular system (C) |
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| Skin (D) |
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| Genitourinary system (G) |
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| Endocrine system (H) |
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| Infections and infestations (J, P, QI) |
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| Malignant disease (L01-L02) |
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| Immune disease (L03-L04) |
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| Muscles, bones, and joints (M) |
|
| Brain and nervous system (N) |
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| Respiratory system (R) |
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| Sensory organs (S) |
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| Other ATC (V) |
|
Diabetes (E10–E14, 250)
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|---|---|
| Types |
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| Blood tests |
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| Management |
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| Complications |
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| Other |
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| リンク元 | 「経口血糖降下薬」「経口糖尿病治療薬」「経口糖尿病薬」 |
| 関連記事 | 「antidiabetics」「antidiabetic」「oral」 |
| 名称 | 一般名 | 主な特徴 | 適応 | 副作用 | 空腹時 血糖改善 |
食後 過血糖改善 |
低血糖の 少なさ |
肥満者に 使いやすい |
他の リスク ファクター 改善 |
膵β細胞を 疲弊させない | |
| インスリン分泌促進薬 | スルホニル尿素薬 (SU薬) |
グリベンクラミド グリクラジド グリメピリド |
・インスリン追加分泌・基礎分泌上昇 ・食後血糖の選択的低下は期待できない |
・空腹時高血糖が顕著 ・非肥満がよい適応 (肥満にはグリメピリド) |
・低血糖 ・肝障害 ・腎障害 ・白血球減少 ・貧血 |
＋＋ | － | － | － | － | － |
| フェニルアラニン誘導体 (速効型インスリン分泌促進薬) |
ナテグリニド メチグリニド |
・食後のインスリン追加分泌上昇 ・インスリン分泌パターンの改善 ・SU薬に比べ低血糖を来しにくい |
・食後高血糖が顕著 (軽症2型糖尿病) |
－～＋ | ＋＋ | ＋ | －～＋ | － | －～＋ | ||
| インスリン抵抗性改善薬 | チアゾリジン誘導体 | ピオグリタゾン | ・脂肪細胞のインスリン抵抗性惹起物質分泌を抑制 ・その他 ・肝臓・筋のインスリン抵抗性改善 ・肝臓の糖新生抑制 |
・インスリン抵抗性を呈す (肥満2型糖尿病) |
・肝機能障害 ・浮腫 ・心不全 ・貧血 |
＋～＋＋ | － | ＋ | ＋＋ | ＋＋ | ＋ |
| ビグアナイド薬 (BG薬) |
メトホルミン ブホルミン |
・肝臓：糖新生抑制による糖放出率抑制 ・小腸：糖吸収抑制 ・筋・脂肪組織：糖取り込み増加・インスリン抵抗性改善 |
・乳酸アシドーシス (嫌気性解糖の亢進による) |
＋ | － | ＋ | ＋＋ | ＋ | ＋ | ||
| 糖吸収調節薬 | α-グルコシダーゼ阻害薬 (α-GI) |
アカルボース ボグリボース |
・食後の急激な血糖上昇を抑制 (高血糖刺激によるインスリン分泌も抑制) |
・食後高血糖 | ・消化器症状(腹部膨満・放屁・下痢など) ・低血糖 ・肝機能障害 |
－～＋ | ＋ | ＋ | ＋＋ | ＋ | ＋ |