Anti-diabetic medication

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Drugs used in diabetes treat diabetes mellitus by altering the glucose level 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.

Contents

Diabetes mellitus type 1 is a disease caused by the lack of insulin. Insulin must be used in type 1, 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 agents 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 loss of glucose through urination.

Several groups of drugs, mostly given by mouth, are effective in type 2, often in combination. The therapeutic combination in type 2 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 2 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

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. Insulins are typically characterized by the rate at which they are metabolized by the body, yielding different peak times and durations of action. [1] 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. [2]

Examples of rapid-acting insulins (peak at ~1 hour) are:

Examples of short-acting insulins (peak 2–4 hours) are:

Examples of intermediate-acting insulins (peak 4–10 hours) are:

Examples of long-acting insulins (duration ~24 hours, often without peak) are:

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. [2]

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

Vanadium

Most studies involving vanadium compounds have employed vanadium salts, mainly vanadyl sulfate, and dose-limiting side effects were reported at therapeutic doses. One organic vanadium compound, bis(ethylmaltolato)oxovanadium(IV), had improved efficacy compared to the vanadyl sulfate and was selected for Phase 1 and 2 clinical trials. [4]

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 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 gastrointestinal side-effects. It is also available in combination with other oral diabetic medications.

Thiazolidinediones

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, [12] as did the DREAM trial. [13] 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). [14]

Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in the New England Journal of Medicine. [15] There have been a significant number of publications since then, and a Food and Drug Administration panel [16] 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. [17] 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. [18]

Lyn kinase activators

The LYN kinase activator tolimidone has been reported to potentiate insulin signaling in a manner that is distinct from the glitazones. [19] The compound has demonstrated positive results in a Phase 2a clinical study involving 130 diabetic subjects. [20]

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" drugs 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, TZDs (glitazones), and DPP-4 inhibitors (gliptins). [14] 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.

Sulfonylureas bind strongly to plasma proteins. Sulfonylureas are useful only in type 2 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 1 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

Meglitinides

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. [21] By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, thereby enhancing insulin secretion. [22]

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

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.

Peptide analogs

Overview of insulin secretion Incretins and DPP 4 inhibitors.svg
Overview of insulin secretion

Injectable incretin mimetics

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

Glucagon-like peptide (GLP) agonists bind to a membrane GLP receptor. [22] 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 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. [14] [23]

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

Dipeptidyl peptidase-4 inhibitors

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 hypoglycemia have been observed when DPP-4 inhibitors were used with sulfonylureas; effect on long-term health and morbidity rates are still unknown. [33]

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. [34]

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). [35] 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%. [36] 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%. [37] 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 mg/d of the medication. [38]

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%.

Glycosurics

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 hypoglycemia. [39] Oral preparations may be available alone or in combination with other agents. [40] 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. [14] Because they are taken by mouth, rather than injected (like GLP-1 agonists), patients who are 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. [41] Because they are not available as generic medications, however, cost may limit their feasibility for many patients.

Examples include:

The side effects of SGLT-2 inhibitors are derived directly from their mechanism of action; these include an increased risk of: ketoacidosis, urinary tract infections, candidal vulvovaginitis, and hypoglycemia. [42]

Comparison

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 [43] [44]
Drug class [44] Mechanism of action [3] Advantages [44] Disadvantages [44]
Sulfonylureas (glyburide, glimepiride, glipizide)Stimulating insulin release by pancreatic beta cells by inhibiting the KATP channel
  • Cause an average of 5–10 pounds 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
Alpha-glucosidase inhibitors (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 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 5–10 pounds 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 hepatoxicity
  • Expensive
SGLT2 inhibitors

Generic

Many anti-diabetes drugs are available as generics. These include: [45]

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

Related Research Articles

Type 2 diabetes Type of diabetes mellitus with high blood sugar and insulin resistance

Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, and unexplained weight loss. Symptoms may also include increased hunger, feeling tired, and sores that do not heal. Often symptoms come on slowly. Long-term complications from high blood sugar include heart disease, strokes, diabetic retinopathy which can result in blindness, kidney failure, and poor blood flow in the limbs which may lead to amputations. The sudden onset of hyperosmolar hyperglycemic state may occur; however, ketoacidosis is uncommon.

Metformin Medication

Metformin, marketed under the trade name Glucophage among others, is the first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. It is not associated with weight gain. It is taken by mouth.

Rosiglitazone Chemical compound

Rosiglitazone is an antidiabetic drug in the thiazolidinedione class. It works as an insulin sensitizer, by binding to the PPAR in fat cells and making the cells more responsive to insulin. It is marketed by the pharmaceutical company GlaxoSmithKline (GSK) as a stand-alone drug or for use in combination with metformin or with glimepiride. First released in 1999, annual sales peaked at approximately $2.5-billion in 2006; however, following a meta-analysis in 2007 that linked the drug's use to an increased risk of heart attack, sales plummeted to just $9.5-million in 2012. The drug's patent expired in 2012.

Pioglitazone Chemical compound

Pioglitazone, sold under the brand name Actos among others, is an anti-diabetic medication used to treat type 2 diabetes. It may be used with metformin, a sulfonylurea, or insulin. Use is recommended together with exercise and diet. It is not recommended in type 1 diabetes. It is taken by mouth.

Sulfonylureas are a class of organic compounds used in medicine and agriculture, for example as antidiabetic drugs widely used in the management of diabetes mellitus type 2. They act by increasing insulin release from the beta cells in the pancreas. A number of sulfonylureas are also used as herbicides, because they can interfere with plant biosynthesis of certain amino acids. Sulfonylureas are also used experimentally to inhibit interleukin 1 beta release from the NALP3 inflammasome.

Diabetic nephropathy Chronic loss of kidney function

Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is one of the leading causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally. Protein loss in the urine due to damage to the glomeruli may become massive, and cause a low serum albumin with resulting generalized body swelling (edema) and result in the nephrotic syndrome. Likewise, the estimated glomerular filtration rate (eGFR) may progressively fall from a normal of over 90 ml/min/1.73m2 to less than 15, at which point the patient is said to have end-stage renal disease. It usually is slowly progressive over years.

Exenatide

Exenatide, sold under the brand name Byetta and Bydureon among others, is a medication used to treat diabetes mellitus type 2. It is used together with diet, exercise, and potentially other antidiabetic medication. It is a treatment option after metformin and sulfonylureas. It is given by injection under the skin within an hour before the first and last meal of the day. A once-weekly injection version is also available.

Sitagliptin Diabetes medication

Sitagliptin, sold under the brand name Januvia among others, is an anti-diabetic medication used to treat type 2 diabetes. In the United Kingdom it is listed as less preferred than metformin or a sulfonylurea. It is taken by mouth. It is also available in the fixed-dose combination medication sitagliptin/metformin.

Saxagliptin Chemical compound

Saxagliptin, sold under the brand name Onglyza, is an oral hypoglycemic of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. Early development was solely by Bristol-Myers Squibb; in 2007 AstraZeneca joined with Bristol-Myers Squibb to co-develop the final compound and collaborate on the marketing of the drug.

Dapagliflozin Diabetes medication

Dapagliflozin, sold under the brand name Farxiga among others, is a medication used to treat type 2 diabetes and, with certain restrictions, type 1 diabetes. It is also used to treat adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure.

Liraglutide

Liraglutide, sold under the brand name Victoza among others, is a medication used to treat diabetes mellitus type 2 and obesity. In diabetes it is a less preferred agent compared to metformin. Its effects on long-term health outcomes like heart disease and life expectancy are unclear. It is given by injection under the skin.

Albiglutide is a glucagon-like peptide-1 agonist drug marketed by GlaxoSmithKline (GSK) for treatment of type 2 diabetes. As of 2017 it is unclear if it affects a person's risk of death. GSK has announced that it intends to withdraw the drug from the worldwide market by July 2018 for economic reasons.

Glucagon-like peptide-1 receptor agonists, also known as GLP-1 receptor agonists or incretin mimetics, are agonists of the GLP-1 receptor. This class of medications is used for the treatment of type 2 diabetes. One of their advantages over older insulin secretagogues, such as sulfonylureas or meglitinides, is that they have a lower risk of causing hypoglycemia. GLP-1 has a short duration of action, so to overcome this limitation several modifications either in the drug or the formulations are being developed.

Canagliflozin

Canagliflozin, sold under the brand name Invokana among others, is a medication used to treat type 2 diabetes. It is a third-line medication to metformin. It is used together with exercise and diet. It is not recommended in type 1 diabetes. It is taken by mouth.

Andrej Janež is a Slovenian diabetologist and diabetes researcher. Janež is the Head of Department of Endocrinology, Diabetes and Metabolic Disease at University Medical Centre Ljubljana, Assistant Professor for Internal Medicine at the Medical University Ljubljana, Chairman of the Advances in Diabetes and Insulin Therapy conference, member of the advisory board for peroral antidiabetic therapy in Servier Pharma, member for Slovenia in the Diabetes Education Study Group at European Association for the Study of Diabetes, and member of the European advisory board for continuous glucose monitoring system in development for Lifescan.

Empagliflozin, sold under the brand name Jardiance among others, is a medication used together with diet and exercise to treat type 2 diabetes. It can be prescribed instead of metformin and has benefits over sulfonylureas. It may be used together with other medications such as metformin or insulin. It is not recommended for type 1 diabetes. It is taken by mouth. In view of recent trial evidence, it is expected to soon receive licence to be used for patients with heart failure, irrespective of diabetic status.

Dulaglutide, sold under the brand name Trulicity among others, is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. It is also approved in the United States for the reduction of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors. It can be used once weekly.

Gliflozins are a class of drugs in the treatment of type 2 diabetes (T2D). They act by inhibiting sodium/glucose cotransporter 2 (SGLT-2), and are therefore also called SGLT-2 inhibitors. The efficacy of the drug is dependent on renal excretion and prevents glucose from going into blood circulation by promoting glucosuria. The mechanism of action is insulin independent.

SGLT2 inhibitors, also called gliflozins, are a class of medications that alter essential physiology of the nephron; unlike SGLT1 inhibitors that modulate sodium/glucose channels in the intestinal mucosa. All of these advances are within the influence of the #SLC5A gene family. The foremost metabolic effect appears to show that this pharmaceutical class inhibits reabsorption of glucose in the kidney and therefore lower blood sugar. They act by inhibiting sodium-glucose transport protein 2 (SGLT2). SGLT2 inhibitors are used in the treatment of type II diabetes mellitus (T2DM). Apart from blood sugar control, gliflozins have been shown to provide significant cardiovascular benefit in T2DM patients. Several medications of this class have been approved or are currently under development. In studies on canagliflozin, a member of this class, the medication was found to enhance blood sugar control as well as reduce body weight and systolic and diastolic blood pressure.

Ipragliflozin

Ipragliflozin is a pharmaceutical drug for treatment of type 2 diabetes. Ipragliflozin, jointly developed by Astellas Pharma and Kotobuki Pharmaceutical, was approved in Japan on January 17, 2014, and in Russia on May 22, 2019.

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