Category Archive: Diabetes drugs
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Diabetes drugs protect against heart disease
The medication rosiglitazone (Avandia) controls diabetics’ blood sugar by binding to the PPAR gamma receptor in fat cells, doctors have known. Now new research shows that these receptors also exist in arteries, where they may help protect against heart disease, Dr. Ronald E. Law and colleagues at the University of California at Los Angeles School of Medicine report in the March 21, 2000, Circulation. The study was a preclinical in vitro study using both human and rat tissue.
Previous studies had “been divided as to [the receptor's] presence in the artery wall,” although they did show that it existed in other types of tissue, Dr. Law said.
By binding to the artery receptors, the medication may lower diabetics’ risk of clogged arteries, including restenosis (when an artery is blocked again after angioplasty), the team reports. Rosiglitazone treats type 2 diabetes, which begins in adulthood, and not type 1, which usually begins in childhood.
If an artery is damaged even slightly, such as from atherosclerosis or after angioplasty, the tissue increases production of growth factors that cause cells in the area to multiply and migrate. Such cell activity is dangerous, because it can lead to artery walls getting thicker. However, when the researchers exposed artery smooth muscle cells to the diabetes medication, the cells failed to multiply or migrate, the team reports. The drugs may slow the build-up of fatty substances along the artery wall.
What the PPAR gamma receptor normally does other than bind with diabetes drugs is unclear, Dr. Law told Mediconsult. “We don’t really understand what normally turns these receptors on, or what their role is in tissue other than…to make more fat cells, he said.
The team also tested another diabetes drug, troglitazone (Rezulin), but it was taken off the market in March 2000, because of possible dangerous side effects. Both drugs are part of the thiazolidinedione (TZD) class of drugs that control blood sugar levels in people with type 2 diabetes.
Commenting on the study, Dr. Andrew P. Levy, M.D., Ph.D, at the Technion Faculty of Medicine, and Medical Advisor for HeartInfo, says that, “The new TZD drugs described above will help patients with type 2 control their glucose levels. The precise mechanism as to how these drugs achieve their effect is not entirely clear. More research is required to fully understand their mode of action, but their efficacy is indisputable.”
Dose of Actos (Pioglitazone) as an Add-on to Insulin
Dose Comparison of Pioglitazone (Actos) (30 mg and 45 mg) as an Add-on to Insulin
Study Design
This was a multicentre, randomised, double-blind study of the safety and efficacy of a combination of 30 or 45 mg of pioglitazone (Actos) and insulin when given to patients with type 2 diabetes mellitus whose glucose levels were poorly controlled by their current insulin therapy. Patients who participated in this study were at least 18 years of age, had an HbA1c value greater than or equal to 8.0%, and were on a stable, fixed dose (at least 30 units/day) of insulin for at least 30 days before the study.
The primary efficacy variable was HbA1c. The secondary efficacy variables were HbA1c responder rate defined as a percentage of patients meeting a clinically relevant target value, fasting plasma glucose (FPG), FPG responder rate, and serum lipids (ie, triglycerides, total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, and very low density lipoprotein (VLDL) cholesterol, and free fatty acids (FFA). A total of 345 patients were randomly assigned to each treatment arm, for a total of 690 patients in the intent-to-treat (ITT) population. The mean age for patients was 56.5 years, and mean BMI was 33.19 kg/m2. Approximately two thirds (63.3%) of the patients were Caucasian, and slightly more than half (54.6%) were male. The mean insulin dose (all forms) at Baseline for ITT patients was 69.2 units/day, and 27.1% of the patients reported use of antidiabetes therapy in addition to insulin. There were no major differences between the treatment groups with regard to any of the baseline variables.
Results
The improvements in glycaemic control observed in this study occurred in concert with overall reductions in insulin use by both treatment groups. Statistically significant difference from Baseline in insulin use were first observed at Week 4 for the 45 mg treatment group and at Week 8 for the 30 mg treatment group. The reductions were maintained throughout the remainder of the study, and there was a 4.5 and 7.3 U/d reduction with 30 mg and 45 mg of pioglitazone (Actos), respectively, at Endpoint. The reduction in insulin dose was statistically significantly greater in the 45 mg treatment group at all time points.
Actos: Insulin-Sensitizing Agent for Type 2 Diabetes
Brand Name: Actos
Active Ingredient: pioglitazone HCl
Indication: To improve glycemic control in patients with type 2 diabetes, in conjunction with diet and exercise
Company Name: Takeda Pharmaceuticals America, Inc.
Introduction
Actos (pioglitazone HCl), a member of the thiazolidinediene (TZD) insulin-sensitizing class of drugs, was recently approved by the FDA for marketing in the US. Actos, developed by Takeda America Research and Development Center, Inc., is indicated for glycemic control in people with type 2 diabetes. It can be used alone or in combination with sulfonylurea, metformin, or insulin when these three agents prove to be ineffective on their own. Whether used as monotherapy or as a component of combination therapy, treatment should also include proper diet and exercise.
Clinical Study Results
Three randomized, double-blinded, placebo-controlled clinical trials were conducted in the United States to determine the safety and efficacy of Actos monotherapy. The first study lasted 26 weeks and included 408 patients with type 2 diabetes. They were randomized to receive 7.5 mg, 15, mg, 30 mg, 45 mg, or placebo once daily. Statistically significant differences were noted in the HbA1c and in the fasting blood glucose levels at endpoint in the patients who received 15, mg, 30 mg, and 45 mg compared to placebo. There was a one percentage point difference in HbA1c between both the 15 mg and 30 mg Actos patients and the control patients, and a 1.6 percentage point difference between the 45 mg patients and the control group (p < 0.05). After treatment, FBG increased by 9 mg/dL in placebo patients and decreased by 30, 32, and 56 mg/dL in patients who received 15, 30, and 45 mg of Actos, respectively (p < 0.05). A total of 260 patients participated in the second 24-week study. Patients were randomized to receive one of two forced-Actos titration regimens or placebo titration. The first Actos titration group received 7.5 mg of Actos for four weeks, with doses increasing to 15 mg and then 30 mg in four-week intervals. The second group followed a similar pattern of dosage increases, but began with 15 mg/day and went up to 45 mg/day. HbA1c levels were significantly lower in both treatment groups compared to the control group (1.5 percentage point difference for both, p < 0.05 for both).
There was a 68 mg/dL difference between patients in the higher dose Actos regimen and those in the placebo group, and a 62 mg/dL difference between those in the lower dose Actos regimen and patients in the placebo group (p < 0.05). Lastly, in a 16-week study with 197 participants, 30 mg Actos was compared to placebo. A 1.4 percentage point difference in HbA1c from placebo and a 58 mg/dL difference in FBG from placebo were observed.
Three 16-week, randomized, double-blind, placebo-controlled studies were conducted to evaluate the effects of Actos on glycemic control in type 2 diabetes patients as part of combination therapy. The addition of Actos to a treatment regimen consisting of sulfonylurea significantly reduced the mean HbA1c by 0.9% and 1.3%, with 15 mg and 30 mg of Actos, respectively. Treatment with metformin also benefited from the addition of Actos to the regimen, with a 0.8% reduction in HbA1c and a 38 mg/dL decrease in FBG. Patients with unsuccessful glycemic control with insulin alone experienced a 0.7 percentage point and 1.0 percentage point decrease in HbA1c with 15 mg Actos and 30 mg Actos, respectively. FBG levels decreased as well by 35mg/dL and 49 mg/dL with the addition of 15 mg Actos and 30 mg Actos to the insulin regimen.
What the Patient Should Know
Some of the patients in the clinical trials experienced upper respiratory tract infection, headache, sinusitis, muscle pain, and sore throat. Patients should also be aware of the possibility of moderate to mild edema and anemia. Using Actos in combination with insulin and sulfonylurea is associated with a greater risk for hypoglycemia. As a result, lowering the doses of insulin or sulfonylurea may be necessary.
Few Antidiabetic Drugs
Buformin
(US Adopted Name, rINN)
Drug Nomenclature
Profile
Buformin is a biguanide antidiabetic. It has been given orally in the treatment of type 2 diabetes mellitus in doses of up to 300 mg daily. Buformin is also used as the hydrochloride.
Proprietary Preparations
Czech Republic: Adebit † Silubin- †
Hungary: Adebit
Spain: Silubin †
Switzerland: Silubin †
Carbutamide
Drug Approvals
(British Approved Name, rINN)
International Nonproprietary Names (INNs) in main languages (French, Latin, Spanish):
Profile
Carbutamide is a sulfonylurea antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus in single daily doses of 0.5 to 1 g, but is more toxic than chlorpropamide.
Proprietary Preparations
France: Glucidoral
Epalrestat
(rINN)
Drug Nomenclature
Profile
Epalrestat inhibits the enzyme aldose reductase which catalyses the conversion of glucose to sorbitol. It has been suggested that accumulation of sorbitol in certain cells, occurring only in conditions of hyperglycaemia and resulting in a hyperosmotic effect, may be involved in the pathogenesis of some diabetic complications. Aldose reductase inhibitors have no influence on blood-glucose concentrations. Epalrestat is given orally for the treatment of diabetic complications including neuropathy, in a usual dose of 50 mg three times daily before meals.
Proprietary Preparations
Japan: Kinedak
Glibornuride
Drug Approvals
(British Approved Name, US Adopted Name, rINN)
INNs in other languages (French, Latin, and Spanish):
Note. The name glibornuride has frequently but erroneously been applied to glibenclamide.
Profile
Glibornuride is a sulfonylurea antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus in doses of 12.5 to 75 mg daily. Daily doses of 50 mg or more are given in 2 divided doses.
Proprietary Preparations
Austria: Glutril
France: Glutril
Germany: Gluborid Glutril
Switzerland: Gluborid Glutril
Turkey: Glutril
Glisentide
Drug Nomenclature
Profile
Glisentide is a sulfonylurea antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus in doses of 2.5 to 20 mg daily.
Proprietary Preparations
Spain: Staticum
Glisolamide
Drug Nomenclature
Profile
Glisolamide is a sulfonylurea antidiabetic. It has been given in the treatment of type 2 diabetes mellitus.
Proprietary Preparations
Italy: Diabenor
Glisoxepide
Drug Nomenclature
Profile
Glisoxepide is a sulfonylurea antidiabetic. It has been given in the treatment of type 2 diabetes mellitus.
Proprietary Preparations
Austria: Pro-Diaban
Glybuzole
Drug Nomenclature
Profile
Glybuzole is an oral antidiabetic with a structure distinct from that of the sulfonylureas, biguanides, or sulfonamidopyrimidines.
Proprietary Preparations
Japan: Gludiase
Glycyclamide
Drug Nomenclature
Profile
Glycyclamide is a sulfonylurea antidiabetic. It is given by mouth in the treatment of type 2 diabetes mellitus.
Preparations
Proprietary Preparations
Italy: Diaborale
Mitiglinide
Profile
Mitiglinide is a meglitinide antidiabetic that is under investiga tion in the treatment of type 2 diabetes mellitus.
Muraglitazar
Profile
Muraglitazar is a dual alfa/gamma peroxisome proliferator-activated receptor (PPAR) activator. It has been investigated in the treatment of type 2 diabetes mellitus.
Adverse effects. A review of data from 5 studies suggested that muraglitazar may be associated with an increased risk of adverse cardiovascular events and heart failure.
Phenformin Hydrochloride
Pharmacopoeias. In China
Profile
Phenformin hydrochloride is a biguanide antidiabetic. Although it is generally considered to be associated with an unacceptably high incidence of lactic acidosis, often fatal, it is still available in some countries for the treatment of type 2 diabetes mellitus.
Phenformin was implicated in the controversial reports of excess cardiovascular mortality associated with oral hypoglycaemic therapy (see under Sulfonylureas, Effects on the Cardiovascular System).
Proprietary Preparations
Greece: Informin
India: DBI
Portugal: Debeina
Multi-ingredient
Greece: Daopar †
India: Chlorformin †
Italy: Bi-Euglucon Bidiabe Gliben † Gliformin Suguan
Pimagedine
Pimagedine Hydrochloride
Drug Approvals
(US Adopted Name, rINNM)
INNs in main languages (French, Latin, and Spanish):
Profile
Pimagedine reportedly inhibits the formation of glycosylated proteins (advanced glycosylation end-products) and has other actions including inhibition of aldose reductase. It has been investigated for the prevention of diabetic complications.
Ruboxistaurin
Profile
Ruboxistaurin is an oral inhibitor of the p-isoform of the enzyme protein kinase C, which is thought to play a role in the development of diabetic microvascular complications. It is under investigation as an adjunct in the treatment of diabetic retinopathy.
Voglibose
Pharmacopoeias. In Japan.
Profile
Voglibose is an alpha-glue osidase inhibitor with general properties similar to those of acarbose. It is used in the treatment of diabetes mellitus in oral doses of 200 to 300 micrograms three times daily before meals.
Hepatic encephalopathy. Vbglibose has been investigated in the management of hepatic encephalopathy.
Proprietary Preparations
Japan: Basen
Philippines: Basen
Thailand: Basen.
Miglitol
(British Approved Name, US Adopted Name, rINN)
Drug Nomenclature
International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):
Adverse Effects and Precautions
As for alpha-glucosidase inhibitors in general (see Acarbose). Skin rash may occur. Miglitol should be used with caution in patients with renal impairment.
Interactions
As for alpha-glucosidase inhibitors in general (see Acarbose). Miglitol may reduce the bioavailability of propranolol and ranitidine.
Pharmacokinetics
Miglitol is completely absorbed at a dose of 25 mg, but only 50 to 70% is absorbed at a dose of 100 mg. It is not metabolised, and is excreted unchanged in the urine with a plasma elimination half-life of about 2 hours.
Uses and Administration
Miglitol is an alpha-glucosidase inhibitor similar in action to acarbose. It is given orally in the management of type 2 diabetes mellitus, alone or with a sulfonylurea. Usual initial doses are 25 mg three times daily with meals, increased if necessary to a maximum of 100 mg three times daily.
Proprietary Preparations
Austria: Diastabol
Czech Republic: Diastabol
France: Diastabol
Germany: Diastabol
Hungary: Diastabol
India: Diamig Mignar †
Mexico: Diastabol
Poland: Diastabol
Portugal: Diastabol Limarcan
Spain: Diastabol Plumarol
Sweden: Diastabol
Switzerland: Diastabol
USA: Glyset