Phase-3 Studies of Welchol on Anti-diabetic Activity

LK Kanthal¹*, P Mondal¹, Vaswani L² and B Mahanti¹

¹Bharat Technology, Banitabla, Howrah, W.B, India.

²Calcutta Institute of Pharmaceutical Technology and AHS, Uluberia, Howrah, India.

ABSTRACT:

Diabetes is a condition primarily defined by the level of hyperglycaemia giving rise to risk of macro and micro vascular complication and diminished quality of life. Roman physician Areataeus was introduced the name diabetes in 1^st century A.D. Diabetes treatment include a number of drugs either can be used alone or in combination. The present articles concentrate on the phase -3 studies of Welchol as an adjunct to Metformin in type –ll diabetes who are not responding to other combination of anti-diabetic drugs.

KEYWORDS: Diabetes, Hyperglycaemia, complications, Welchol.

INTRODUCTION

In developing countries, the majority of people with diabetes are in the 45 to 64 year age range, In contrast , the majority of people with diabetes in developed countries are >64 years of age. ”. As per WHO, India will be the nation with highest number of diabetics in the world by 2030¹followed by China and then USA. WELCHOL (Colesevelam hydrochloride) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2diabetes mellitus^2,3. Diabetes mellitus is considered an IHD risk equivalent⁴. In addition to glycemic control, intensive lipid control is warranted. WELCHOL is an off-white, oval, film-coated, solid tablet containing 625 mg Colesevelam hydrochloride⁵. In addition, each tablet contains the following inactive ingredients: magnesium stearate, microcrystalline cellulose, silicon dioxide, HPMC (hydroxypropyl methylcellulose), and acetylated monoglyceride. The tablets are imprinted using a water-soluble black ink. Colesevelam hydrochloride is a bile acid sequestrant⁶ that wasapproved as a cholesterol-lowering agent in the United Statesin 2000 and approved in January 2008 to improve glycemic controlin adults with type 2 diabetes mellitus (T2DM)^7,.

Complications of Diabetes:

All the complications are severed (in fig.1), if this condition is not treated properly and most of the times it leads to the death of individual. The complication parameters^{8, 9} are given in table-1. For the treatment of diabetes anti-diabetic agents having different types of mechanism of action are used either solely or in combinations¹⁰. The sites of action of anti diabetic agents are in fig.2.

Sometimes even the combination also failed to reduce this condition. In such subjects, who are resistant to given combination of most potent anti-diabetic agents Welchol can be used as an adjunct to the combination of anti-diabetic agents.

Description of Welchol:

WELCHOL (Colesevelam hydrochloride) is a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent intended for oral administration. Colesevelam hydrochloride is a high-capacity bile acid-binding molecule¹². It is poly (allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide.

The chemical name (IUPAC) of Colesevelam hydrochloride is allylamine polymer with 1-chloro-2,3-epoxypropane, [6-(allylamino)-hexyl]trimethylammonium chloride and N-allyldecylamine, hydrochloride. wherein (a) represents allyl amine monomer units that have not been alkylated by either of the 1-bromodecane or (6-bromohexyl)-trimethylammonium bromide alkylating agents or cross-linked by epichlorohydrin; (b) represents allyl amine units that have been alkylated with a decyl group; (d) represents allyl amine units that have been alkylated with a (6trimethylammonium) hexyl group, and m represents a number 100 to indicate an extended polymer network⁵.

A small amount of the amines are di alkylated, and are not depicted in the formula above. No regular order of the groups is implied by the structure; cross-linking and alkylation are expected to occur randomly along the polymer chains. A large amount of the amines are protonated. The polymer is depicted in the hydrochloride form; a small amount of the halides are bromide. Colesevelam hydrochloride is hydrophilic and insoluble in water. Welchol was approved for its usage as a hypercholesteric agent¹⁰. The study was conducted by using Welchol as an adjunct to the metformin mono therapy. With the objective to evaluate the efficacy and safety of WELCHOL (Colesevelam hydrochloride) in Type-2 Diabetics with inadequate glycemic control on Metformin therapy.

Study details:

Multi-Center, Randomized, Double-Blind, Placebo controlled,¹³ Parallel-Group clinical Study of the Efficacy and Safety of WELCHOL® inType-2 Diabetics¹¹ with Inadequate Glycemic Control on Metformin monotherapy or metformin Therapy. Approximately 300 subjects, male or female of age group 18 to 75 years.

Approximately 316 subjects were enrolled in the study out of them the target number of 300 subjects were completed 26 weeks of application basing on the inclusion criteria and exclusion criteria⁵.

Table 1.Complication parameters:

Tissue or Organ Affected	Patho-Physiology¹¹	Complications
Blood vessels	Fatty material (atherosclerotic Plaque) builds up and blocks large or medium-sized arteries in the heart, brain, legs, and penis. The walls of small blood vessels are damaged so that the vessels do not transfer oxygen to tissues normally, and the vessels may leak.	Poor circulation causes wounds to heal poorly and can lead to heart disorders, strokes, gangrene of the feet and hands, erectile dysfunction (impotence), and infections.
Eyes	The small blood vessels of the retina are damaged.	Decreased vision and, ultimately, blindness occur.
Kidney	Blood vessels in the kidney thicken. Protein leaks into urine. Blood is not filtered normally.	The kidneys malfunction, and ultimately, kidney failure occurs.
Nerves	Nerves are damaged because glucose is not metabolized normally and because the blood supply is inadequate.	Legs suddenly or gradually weaken. People have reduced sensation, tingling, and pain in their hands and feet.
Autonomic nervous system	The nerves that control blood pressure and digestive processes are damaged.	Swings in blood pressure occur. Swallowing becomes difficult. Digestive function is altered, and sometimes bouts of diarrhea occur. Erectile dysfunction develops.
Skin	Blood flow to the skin is reduced, and sensation is decreased, resulting in repeated injury.	Sores and deep infections (diabetic ulcers) develop. Healing is poor.
Blood	White blood cell function is impaired.	People become more susceptible to infections, especially of the urinary tract and skin.
Connective tissue	Glucose is not metabolized normally, causing tissues to thicken or contract.	Carpal tunnel syndrome and Dupuytren's contracture develop.

Inclusion Criteria: An Inclusion criterion is as follows:

Age 18-75 years, inclusive

 Diagnosed with type 2 diabetes

 Hemoglobin (HbA1c) between 7.5% to 9.5%

 Prescribed an ADA (American Dietetic Association) accepted diet.

Receiving stable dose of metformin alone or in combination with

other oral anti-diabetic medications for 90 days before Visit 1.

Exclusion Criteria: Exclusion criteria is as follows:

History of type 1 diabetes or keto-acidosis.

History of chronic (more than 2 months) insulin therapy or the initiation of insulin for

chronic treatment.

Uncontrolled hypertension.

Recent severe cardiovascular disease.

Allergy or toxic response to Colesevelam or any of its components.

Body mass index (BMI) >45 kg/m2.

The study was completed in approximately 18 months from the date subjected for commencement of ethics committee permission. Recruitment of subjected were completed in 27 weeks only. The study was conducted by Daiichi Sankyo, Inc. Parsippany, New Jersey 07054 in well organized manner.^{14, 15}

CONCLUSION:

The present study ‘A literature review on double-blind, placebo controlled clinical study of WELCHOL® add on combination therapy with metformin in hyperglycemic patients’ shows that there is a statically significant decline in the severity of the problem starting from the end of 12 weeks of active treatment. At the end of 26 weeks, the problem nearly disappears in about 5% subjects and is improved in the rest. There is no worsening of the problem by trail medication.

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Received on 05.01.2010

Accepted on 24.03.2010

Research J. Pharmacology and Pharmacodynamics. 2(3): May-June 2010, 211-214