Diabetes medication/ja: Difference between revisions

[[[Diabetes mellitus type 1/ja|1型糖尿病]]は、インスリンの不足によって引き起こされる病気である。1型ではインスリンを注射しなければならない。

[Thiazolidinedione/ja|チアゾリジンジオン]]類（[[TZD/ja|TZD]]類）は、「グリタゾン」としても知られ、グルコースおよび脂肪代謝を調節する遺伝子の転写に関与する核内制御タンパク質の一種であるペルオキシソーム増殖因子活性化受容体[[Peroxisome proliferator-activated receptor gamma/ja|γ]]、[[Peroxisome proliferator-activated receptor gamma/ja|PPARγ]]に結合する。これらのPPARはペルオキシソーム増殖因子応答性エレメント（PPRE）に作用する。PPREはインスリン感受性遺伝子に影響を与え、インスリン依存性酵素のmRNAの産生を促進する。その結果、細胞によるグルコースの利用が促進される。これらの薬剤はまた、PPAR-α活性を増強し、HDLとLDLのいくつかの大きな成分の上昇をもたらす。

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, 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).

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===Meglitinides===

{{Main|Meglitinide}}

[[Meglitinide]]s 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. By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, thereby enhancing insulin secretion.

Typical reductions in [[glycated hemoglobin]]&nbsp;(A1C) values are 0.5–1.0%.

* [[repaglinide]]

* [[nateglinide]]

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==Alpha-glucosidase inhibitors==

{{Main|Alpha-glucosidase inhibitor}}

[[Alpha-glucosidase inhibitor]]s 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]]&nbsp;(A1C) values are 0.5–1.0%.

* [[miglitol]]

* [[acarbose]]

* [[voglibose]]

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==Peptide analogs==

[[Image:Incretins and DPP 4 inhibitors.svg|thumb|300px|right|Overview of insulin secretion]]

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===Injectable incretin mimetics===

[[Incretin]]s are also insulin [[secretagogue]]s. 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).

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====Injectable glucagon-like peptide analogs and agonists====

Glucagon-like peptide (GLP) agonists bind to a membrane GLP receptor. 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. As of 2019, the [[American Association of Clinical Endocrinologists|AACE]] lists GLP-1 agonists, along with SGLT2 inhibitors, as the most preferred anti-diabetic agents after metformin. [[Liraglutide]] in particular may be considered first-line in diabetic patients with cardiovascular disease, as it has received FDA approval for reduction of risk of major adverse cardiovascular events in patients with type 2 diabetes. In a 2011 [[Cochrane (organisation)|Cochrane]] [[Systematic review|review]], GLP-1 agonists showed approximately a 1% reduction in HbA1c when compared to placebo. GLP-1 agonists also show improvement of [[Beta cell|beta-cell]] function, but this effect does not last after treatment is stopped. Due to shorter duration of studies, this review did not allow for long-term positiver or negative effects to be assessed.

* [[Exenatide]] (also Exendin-4, marketed as Byetta) is the first [[glucagon-like peptide-1|GLP-1]] agonist approved for the treatment of [[type 2 diabetes]]. Exenatide is not an analogue of GLP but rather a GLP agonist. Exenatide has only 53% homology with GLP, which increases its resistance to degradation by DPP-4 and extends its half-life. A 2011 Cochrane review showed a HbA1c reduction of 0.20% more with Exenatide 2&nbsp;mg compared to insulin glargine, exenatide 10&nbsp;µg twice daily, sitagliptin and pioglitazone. Exenatide, together with liraglutide, led to greater weight loss than glucagon-like peptide analogues.

* [[Liraglutide]], a once-daily human analogue (97% homology), has been developed by [[Novo Nordisk]] under the brand name [[Victoza]]. The product was approved by the [[European Medicines Agency]] (EMEA) on July 3, 2009, and by the [[U.S. Food and Drug Administration]] (FDA) on January 25, 2010. A 2011 Cochrane review showed a HbA1c reduction of 0.24% more with liraglutide 1.8&nbsp;mg compared to insulin glargine, 0.33% more than exenatide 10&nbsp;µg twice daily, sitagliptin and rosiglitazone. Liraglutide, together with exenatide, led to greater weight loss than glucagon-like peptide analogues.

* [[Taspoglutide]] is presently in Phase III clinical trials with [[Hoffman-La Roche]].

* Lixisenatide (Lyxumia) Sanofi Aventis

* [[Semaglutide]] (Ozempic) (oral version is Rybelsus)

* [[Dulaglutide]] ([[Trulicity]]) - once weekly

* [[Albiglutide]] (Tanzeum) - once weekly

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====Gastric inhibitory peptide analogs====

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====Dipeptidyl peptidase-4 inhibitors====

{{Main|Dipeptidyl peptidase-4 inhibitor}}

GLP-1 analogs resulted in weight loss and had more gastrointestinal side-effects, while in general [[dipeptidyl peptidase-4]] (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 hypoglycemia have been observed when [[dipeptidyl peptidase-4 inhibitor]]s were used with sulfonylureas; effects on long-term health and morbidity rates are still unknown.

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DPP-4 inhibitors increase blood concentration of the [[incretin]] GLP-1 by inhibiting its degradation by DPP-4.

* [[vildagliptin]] (Galvus) EU Approved 2008

* [[sitagliptin]] (Januvia) FDA approved Oct 2006

* [[saxagliptin]] (Onglyza) FDA Approved July 2009

* [[linagliptin]] (Tradjenta) FDA Approved May 2, 2011

* [[alogliptin]]

* [[septagliptin]]

* [[teneligliptin]]

* [[gemigliptin]] (Zemiglo)

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

A result in one RCT comprising 206 patients aged 65 or older (mean baseline HgbA1c of 7.8%) receiving either 50 or 100&nbsp;mg/d of [[sitagliptin]] was shown to reduce HbA1c by 0.7% (combined result of both doses). A combined result of 5 RCTs enlisting a total of 279 patients aged 65 or older (mean baseline HbA1c of 8%) receiving 5&nbsp;mg/d of [[saxagliptin]] was shown to reduce HbA1c by 0.73%. A combined result of 5 RCTs enlisting a total of 238 patients aged 65 or older (mean baseline HbA1c of 8.6%) receiving 100&nbsp;mg/d of [[vildagliptin]] was shown to reduce HbA1c by 1.2%. Another set of 6 combined RCTs involving [[alogliptin]] (approved by FDA in 2013) was shown to reduce HbA1c by 0.73% in 455 patients aged 65 or older who received 12.5 or 25&nbsp;mg/d of the medication.

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===Injectable amylin analogues===

[[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%.

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==SGLT2 inhibitors==

{{Main|Gliflozin}}

[[SGLT2 inhibitor]]s block the sodium-glucose linked transporter 2 proteins in [[renal tubule]]s of [[nephron]]s in kidneys, reabsorption of glucose in into the renal tubules, promoting excretion of glucose in the urine. This causes both mild weight loss, and a mild reduction in blood sugar levels with little risk of hypoglycemia. Oral preparations may be available alone or in combination with other agents. Along with GLP-1 agonists, they are considered preferred second or third agents for type 2 diabetics sub-optimally controlled with metformin alone, according to most recent clinical practice guidelines. Because they are taken by mouth, rather than injected (like GLP-1 agonists), patients who are [[Fear of needles|injection-averse]] may prefer these agents over the former. They may be considered first line in diabetic patients with cardiovascular disease, especially [[heart failure]], as these medications have been shown to reduce the risk of hospitalization in patients with such comorbidities. Because they are not available as generic medications, however, cost may limit their feasibility for many patients. Furthermore, there has been growing evidence that the effectiveness and safety of this drug class could depend on genetic variability of the patients.

* [[Dapagliflozin]]

* [[Canagliflozin]]

* [[Empagliflozin]]

* [[Remogliflozin]]

The side effects of SGLT2 inhibitors are derived directly from their mechanism of action; these include an increased risk of: [[ketoacidosis]], [[urinary tract infection]]s, [[Vaginal yeast infection|candidal vulvovaginitis]], and [[hypoglycemia]].

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==Comparison==

! colspan="5" style="background-color: #CCEEEE;" | Comparison of anti-diabetic medication

! Drug class

! Mechanism of action

! Advantages

! Disadvantages

| [[Sulfonylurea]]s ([[glyburide]], [[glimepiride]], [[glipizide]])

| Stimulating insulin release by pancreatic [[beta cell]]s by inhibiting the [[ATP-sensitive potassium channel|K_ATP channel]]

* Inexpensive

* Fast onset of action

* No effect on [[blood pressure]]

* No detrimental effect on [[low-density lipoprotein]]

* Lower risk of [[Human gastrointestinal tract|gastrointestinal]] side effects than metformin

* Convenient dosing

* Cause an average of 2–5&nbsp;kg [[weight gain]]

* Increase the risk of hypoglycemia

* Glyburide increases risk of [[hypoglycemia]] slightly more compared to glimepiride and glipizide

| [[Metformin]]

| Acts on the liver to reduce gluconeogenesis and causes a decrease in [[insulin resistance]] via increasing [[AMPK]] signalling.

* Associated with weight loss

* Lower risk of hypoglycemia compared to other antidiabetics

* Decreases [[low-density lipoprotein]]

* Decreases [[triglycerides]]

* No effect on blood pressure

* Lowered all-cause mortality in diabetics

* Inexpensive

* Higher risk of [[Human gastrointestinal tract|gastrointestinal]] side effects

* Due to the risk of potentially fatal [[lactic acidosis]], contraindicated in people with [[shock (circulatory)|shock]]; with acute or chronic, moderate or severe [[kidney disease]] or at risk for impaired kidney function from [[Radiocontrast agent|intravenous dye]]; and with acute or chronic [[metabolic acidosis]]

* Risk of lactic acidosis also is increased for people with unstable or acute [[heart failure]], [[liver disease]], or [[alcoholism]], or who are recovering from major [[surgery]]

* Increased risk of [[vitamin B12 deficiency]]

* [[Metallic taste]]

| [[Alpha-glucosidase inhibitor]]s ([[acarbose]], [[miglitol]], [[voglibose]])

| Inhibit carbohydrate digestion in the small intestine by inhibiting enzymes that break down polysaccharides

* Slightly lower risk of hypoglycemia compared to sulfonylureas

* Associated with modest weight loss

* Decreases triglycerides

* No detrimental effect on cholesterol

* Less effective than most other diabetes pills in lowering [[glycated hemoglobin]]

* Increased risk of GI side effects than other diabetes pills except metformin

* Inconvenient dosing

| [[Thiazolidinediones]] ([[Pioglitazone]], [[Rosiglitazone]])

| Reduce insulin resistance by activating [[Peroxisome proliferator-activated receptor gamma|PPAR-γ]] in fat and muscle

* Lower the risk of hypoglycemia

* May slightly increase [[high-density lipoprotein]]

* Rosiglitazone linked to decreased triglycerides

* Convenient dosing

* Increase the risk of [[heart failure]]

* Cause an average of 2–5&nbsp;kg [[weight gain]]

* Are associated with a higher risk of edema, anemia and bone fractures

* Can increase low-density lipoprotein

* Rosiglitazone has been linked to increased triglycerides and an increased risk of a heart attack

* Pioglitazone has been linked to an increased risk of bladder cancer

* Have a slower onset of action

* Require monitoring for [[hepatotoxicity]]

* Expensive

|[[SGLT2 inhibitors]]

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==Generic==

* [[Sulfonylureas]] – glimepiride, glipizide, glyburide

* [[Biguanides]] – metformin

* [[Thiazolidinediones]] (Tzd) – pioglitazone, Actos generic

* [[Alpha-glucosidase inhibitor]]s – Acarbose

* [[Meglitinide]]s – nateglinide

* Combination of sulfonylureas plus metformin – known by generic names of the two drugs

No generics are available for [[dipeptidyl peptidase-4 inhibitor]]s (Onglyza), the glifozins, the incretins and various combinations. Sitagliptin patent expired in July 2022, leading to launch of generic sitagliptin brands . This lowered the cost of therapy for type 2 diabetes using sitagliptin .

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== Alternative Medicine ==

The effect of [[Ayurveda|Ayurvedic]] treatments has been researched, however due to methodological flaws of relevant studies and research, it has not been possible to draw conclusions regarding efficacy of these treatments and there is insufficient evidence to recommend them.

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== Further reading ==

{{Oral hypoglycemics}}

{{Major Drug Groups}}

{{Diabetes}}