Antihyperglycemic Agents
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Authored by: Rlweber 08:48, 29 March 2007 (PDT)
Diabetes Mellitus
Diabetes mellitus is defined as a group of metabolic disorders involving hyperglycemia and abnormalities in fat, protein and carbohydrate metabolism.[1] Diabetes mellitus can be caused by defects in insulin sensitivity, defects in insulin secretion, or both.[1] Diabetes mellitus type II is more prevalent, accounting for approximately 90% of cases.[1] It is characterized by insulin resistance and insulin deficiency, where diabetes mellitus type I is characterized by pancreatic beta-cell death and an absolute insulin deficiency.[1] Diabetes mellitus type I most often occurs in childhood or early adulthood, whereas diabetes mellitus type II occurs in adulthood.[1] Patients with diabetes mellitus type I are often insulin-dependant, and patients with diabetes mellitus type II are often non-insulin dependant.[1] Complications of diabetes mellitus include microvascular (retinopathy, neuropathy, and nephropathy), macrovascular (stroke, peripheral vascular disease and coronary heart disease) and neuropathic complications.[1] Physical activity, smoking cessation, nutrition therapy, and alcohol abstinence are examples of non-pharmacological therapy used as treatment of diabetes mellitus. Pharmacological treatment includes insulin, sulfonylureas,meglitinides, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, incretin mimetics and dipeptidyl-peptidase-IV (DPP-IV) inhibitors.
Description of Insulin
Insulin is a hormone secreted by the pancreatic beta-cells.[1] It is formed from proinsulin, and is responsible for glucose homeostasis and glucose metbaolism.[1] There are many different insulin types, each with different onsets of action, time to peak, and duration of action. Insulin is used to treat type I and type II diabetes mellitus. Patients with type II diabetes often use an oral agent in conjunction with insulin for proper glucose control.
Human insulins include: regular insulin, isophane insulin, lente insulin and ultralente insulin.
Insulin analogues include: aspart, lispro, glargine and pramlintide
- Rapid-acting insulins include insulin aspart (Novolog) and insulin lispro (Humalog). These insulin types were created by alterations of the human insulin molecule.[1] They are rapidly absorbed and have a short duration of effect.[1] They are most often administered just prior to meals.[1]
- Short-acting insulins include regular insulin (Humulin-R and Novolin-R). These types of insulin have a slow onset of action, and are often given at least half-hour prior to meals.[1] Regular insulin can be given intravenously or subcutaneously, but subcutaneously administration results in longer onset of action, time to maximum effect and duration of action.[1]
- Intermediate-acting insulins include [[isophane insulin]] (Humulin-N and Novolin-N), and lente insulin (Humulin-L and Novolin-L). The onset of action of lente insulin is 1-4 hours, with a mean duration of action of 12-24 hours.[2] The onset of action of isophane insulin is 1-4 hours, with a duration of action of approximately 10-24 hours.[2].
- Long-acting insulins include ultralente insulin (Humulin-U) and insulin glargine (Lantus). Insulin glargine does not have a peak, and if given once daily, with a duration of action of 24 hours.[2][1]. Ultralente insulin’s onset of action is 2-4 hours, and its duration of action is approximately 18—36 hours.[2][1].
Description of Sulfonylureas
Sulfonylureas were the first oral agents available for diabetes mellitus, and are indicated for diabetes mellitus type II.[1]. They are broken up into two classes: first-generation and second-generation.
First Generation: Acetohexamide (Dymelor), Chlorpropamide (Diabinese), Tolazamide (Tolinase) and Tolbutamide (Orinase).
Second-Generation: Glimepiride (Amaryl), Glipizide (Glucotrol, Glucotrol XL), Glyburide (DiaBeta, Micronase, Glynase)
These drugs work by stimulating insulin release from beta-cells and by decreasing the hepatic clearance of insulin.[1]. Use of these drugs will result in a 1.5-2% decrease in the hemoglobin A1C.[1]. .
The most common side effects are hypoglycemia, rash and weight gain.[1]. Sulfonylureas are classified as pregnancy category C.[2]
Description of Meglitinides
Meglitinides work very similar to sulfonylureas. They stimulate the release of insulin from the pancreatic beta-cells, but insulin release is glucose dependant.[1]. Meglitinides are indicated for diabetes mellitus type II.[1].
Meglitinides include Repaglinide (Prandin) and Nateglinide (Starlix).
The average hemoglobin A1C reduction is 0.6%-1%.[1].
Although hypoglycemia and weight gain are still a concern with meglitinides, the incidence is less when compared to sulfonylureas.[1]. Other common side effects include gastrointestinal upset.[1].
Description of Biguanides
Currently metformin is the only biguanide agent available. It is an oral anti-hyperglycemic agent used in type II diabetes mellitus. It is similar to phenformin- a biguanide medication that was taken off the market in 1977 due to its ability to induce lactic acidosis.[3] Full Text Here[4] Full Text Here
The only FDA-approved indication for metformin is diabetes mellitus type II, although it can be used for polycystic ovary syndrome (PCOS), infertility and precocious puberty.[2] It received its FDA approval on December 30, 1994.[2] It acts to lower fasting and postprandial hyperglycemia, and is used in conjunction with insulin, sulfonylureas or alpha-glucosidase inhibitors.[5] [1] Its mechanism of action includes decreasing glucose output from the liver, increasing peripheral glucose uptake, and decreasing intestinal glucose abosrption. It lowers fasting plasma glucose by approximately 25-30%.[2]
The most common side effects include vomiting, diarrhea, nausea and a metallic taste (which often goes away with continued use and slow dose titration).[1].
Description of Thiazolidinediones
Thiazolidinediones work by decreasing peripheral insulin resistance and decreasing hepatic gluconeogenesis.[1]. They activate a nuclear transcription factor (PPARγ), which is responsible for fatty acid metabolism and cell differentiation.[1]. Insulin must also be present for these actions to take place.[1]. Thiazolidinediones are indicted for diabetes mellitus type II.[1].
The two agents available include: Rosiglitazone (Avandia) and Pioglitazone (Actos).
The average reduction in hemoglobin A1C is 1%-2%.[1].
The most common side effects include weight gain and edema, and it may take 3-4 months before their full effect is seen.[6].[1]. These agents also have a favorable effect on triglycerides, low-density lipoproteins and high-density lipoproteins.[1].
Description of Alpha-glucosidase Inhibitors
Alpha-glucosidase Inhibitors decrease the breakdown of sucrose and complex carbohydrates in the small intestine, allowing for prolonged absorption of carbohydrates and a reduction in the rate of glucose absorption.[1] The end result is a reduction in the postprandial glucose with unchanged fasting glucose levels.[1] They are indicated for diabetes mellitus type I (when insulin is not enough to control blood sugar) and for diabetes mellitus type II.[1][6]
The two available agents include: Acarbose (Precose) and Miglitol (Glyset).
The average reduction in hemoglobin A1C is 0.3%-1%.[1]
The most common adverse effects include flatulence, dyspepsia and diarrhea.[1][6]
Description of Incretin Mimetics
The only available incretin mimetic is exenatide (Byetta). It was FDA-approved in April 2005, and is indicated for use in diabetes mellitus type II.[2] Exenatide was isolated from the salivary gland venom of the lizard Heloderma suspectum.[2] Incretin is an endogenous compound. It works by mimicking the enhancement of glucose-dependent insulin secretion and other anti-hyperglycemic actions.[7] It suppresses glucagon secretions, promotes beta-cell proliferation, decreases gastric emptying and reduces food intake.[7] Exenatide reduces fasting and postprandial glucose levels and causes insulin release only in the presence of elevated glucose levels.[7]
Exenatide reduces the hemoglobin A1C by 0.4—0.9%.[7]
The major side effects of exenatide include hypoglycemia, nausea and vomiting.[7]
Description of Dipeptidyl-peptidase-IV (DPP-IV) Inhibitors
Sitagliptin (Januvia) is the first member of the dipeptidyl-peptidase-IV (DPP-IV) inhibitor drug family.[8] It was FDA-approved in October 2006 for diabetes mellitus type II, either as monotherapy or in conjunction with metformin or a thiazolidinedione.[2] DPP-IV is an enzyme that inactivates incretin hormones.[8] Sitagliptin works to slow the inactivation of these incretin hormones and allows for their prolongation and increased action.[8] Incretin hormones are involved in glucose homeostasis, and during times of glucose homeostasis or elevated glucose levels, these hormones increase insulin synthesis and release from beta-cells.[8] Sitagliptin also increases insulin release and decreases glucagon levels.[8]
The average reduction in hemoglobin A1C was 0.6—1.05% (when sitagliptin was used as monotherapy).[8]
The average reduction in hemoglobin A1C was 0.65%-0.7% (when used in conjunction with metformin or pioglitazone).[8]
Common side effects include: nausea, vomiting, diarrhea, headache, and abdominal pain.[8]
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 1.29 1.30 1.31 1.32 1.33 1.34 1.35 1.36 1.37 1.38 Wells, Dipiro, Schwinghammer, et al. Pharmacotherapy Handbook Fifth Edition. Pages 170-183.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 Insulin Monograph.Clinical Pharmacology (database on the internet) Available at www.clinicalpharmacolgy.com.
- ↑ Enia G, Garozzo M, Zoccali C (1997). "Lactic acidosis induced by phenformin is still a public health problem in Italy.". BMJ 315 (7120): 1466-7.
- ↑ Rosand J, Friedberg J, Yang J (1997). "Fatal phenformin-associated lactic acidosis.". Ann Intern Med 127 (2): 170.
- ↑ Gucophage® (metformin hydrochloride) package insert. Livonia, MI; Major Pharmaceuticals Inc; 1994 December.
- ↑ 6.0 6.1 6.2 Lexi-Comp (2003). Drug Information Handbook. 11th Edition., APhA
- ↑ 7.0 7.1 7.2 7.3 7.4 Byetta™(exenatide) package insert. San Diego, CA: Amylin Pharmaceuticals, Inc.; 2007 Feb
- ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 Januvia™(sitagliptin phosphate) package insert. Whitehouse Station, NJ: Merck& Co.,, Inc.; 2006 Oct.
