NEED OF COMBINATION OF ANTI-DIABETIC DRUGS IN TYPE 2 DIABETES

ABOUT AUTHORS:
Karri Deviprasanna, Metla Vennela, Bandla Rajyalakshmi
Avanthi institute of pharmaceutical sciences,
Vizianagaram-535003, Andhra Pradesh, india
devi.lowkya@gmail.com

ABSTRACT
The recommendation for first line therapy for diabetics remains a metformin. Two or more agents from different pharmacological classes are often needed to achieve adequate blood glucose control. Combination therapy is an important option that combines efficacy of blood glucose reduction and a low side effect profile with convenient once daily dosing to enhance compliance. Combination of anti- diabetics include biguandies+sulfonylureas, biguanides+glitazones, biguandies+α glucosidase inhibitors and miscellaneous combinations.

REFERENCE ID: PHARMATUTOR-ART-1780

INTRODUCTION
The subject of combination therapies:- Benefits and challenges in drug, device and biological development examines the numerous advantages of combination products for both the marketing company and the patient. It is always beneficial to switch over the patients on combination therapy, when there is high secondary failure associated with mono therapy and devasting longterm consequence of poor glycemic control. A reasonable goal of treatment is to maintain good glycemic control through combination therapy so as to keep HBA1C value below 7% for a particular patient. Initiation of combination drug therapy at low dosages can minimize the side effects associated with high dose therapy of either agent and yield additive clinical benefits.

DEFINITION OF DIABETES MELLITUS
It is a group of metabolic diseases in which a person has high blood sugar either because the body does not produce enough insulin or because cells do not respond to the insulin that is produced.

SYMPTOMS
Polyurea (frequent urination)
Polydipsia(Increased thirst)
Polyphagia(Increased hunger)

There are two main types of diabetes mellitus
TYPE1/ INSULIN DEPENDENT DIABETESMELLITUS (IDDM)/ JUVENILE DIABETES
It is a form of diabetic mellitus ie., most common in children but can be diagnosed at any age. Type 1 is an auto immune disease that permanently destroys beta cells in the pancreas therefore require regular insulin delivery to manage their diabetes.

TYPE2/ NON-INSULIN DEPENDENT DIABETESMELLITUS(NIDDM)/ MATURITY DIABETES
Type2 diabetes is accompanied both by insulin resistance and by impaired insulin secretion, each of which are important in its pathogenesis. Such patients are often obese and usually present in adult life, the incidence rising progressively with age as beta cell function declines. Oral hypoglycaemic drugs are necessary for treatment of type2 diabetes.

In healthy persons the normal fasting plasma blood glucose level is 70-130mg/dl(3.89-7.22mmol/L) and postprandial glucose level is <180mg/dl (10mmol/L)

HbA1c TEST:- It is a lab test that shows the average amount of sugar in your blood over 3months. It shows how well you are controlling your diabetes,

Normal HbA1c value less than 5.7%
Pre diabetic patients have 5.7%-6.4%
Diabetic patients have >6.5%

DRUGS ASSOCIATE WITH DIABETES
The following drugs and medications are in some way related to or used in the treatment of diabetes. This service should beused as supplement to and not a substitute for the expertise, skill, knowledge and judgement of health care practitioner.

TYPE2/NON-INSULIN DEPENDENT DIABETESMELLITUS(NIDDM)/ MATURITY DIABETES
Type2 diabetes is accompanied both by insulin resistance and by impaired insulin secretion, each of which are important in its pathogenesis. Such patients are often obese and usually present in adult life, the incidence rising progressively with age as beta cell function declines. Oral hypoglycaemic drugs are necessary for treatment of type2 diabetes.

In healthy persons the normal fasting plasma blood glucose level is 70-130mg/dl(3.89-7.22mmol/L) and postprandial glucose level is <180mg/dl (10mmol/L)

HbA1c TEST:- It is a lab test that shows the average amount of sugar in your blood over 3months. It shows how well you are controlling your diabetes,

Normal HbA1c value less than 5.7%
Pre diabetic patients have 5.7%-6.4%
Diabetic patients have >6.5%

DRUGS ASSOCIATE WITH DIABETES
The following drugs and medications are in some way related to or used in the treatment of diabetes. This service should be used as supplement to and not a substitute for the expertise, skill, knowledge and judgement of health care practitioner.

GENERAL PRINCIPLE
There are now many classes of potentially anti diabetic drugs of which four (Biguanides, sulfonylureas, glitazones, α-gluconidase inhibitors ) are suitable for initial or single drug therapy based on efficacy and tolerability. A number of considerations enter into the selection of the initial drug for the given patient, these include the weight of evidence for beneficial effects on clinical outcomes, the safety and tolerability of the drug, it cost demographic differences in responses, concomitant medical conditions and lifestyle issues
The specific classes of anti diabetic medications are discussed below.

BIGUANIDES
These drugs are effective in anti diabetes. They lower blood glucose initially by increase glucose uptake and utilization in skeletal muscle and decrease gluconeogenesis. These drugs does not cause hypoglycaemia so metformin is widely used. These drugs should not be used in renal or hepatic disorders. Metformin long term use may interfere with absorption of vitamin B12. These drugs are useful in obese patients because weight loss occur.

Biguanides administered alone control blood glucose in 50% of patients with mild to moderate diabetes and can be used effectively in combination with all other agents.

The adverse effects of Biguanides are diarrhoea, nausea. In rare cases lactic acidosis also observed.

These drugs does not stimulate appetite because these drugs are widely used in Type-2 obese patients and these drugs are best choice for patients having heart failure.

SULFONYLUREAS:-
These drugs are effective in type 2 diabetes. They lower blood glucose by stimulate insulin secretion on β cells they act by inhibiting KATP channels in extra pancreatic tissues and cause depolarisation. they also further increase insulin by decrease hepatic clearance of hormone these drugs are contraindicated in pregnancy and Brest feeding. these drugs action like that of antidiuretic harmone on distal nephron it leads to hyponatraemia so these are drugs contraindicated in thiazide diuretics and corticosteroids. if higher doses of sulfonylureas are required the drug should be used in combination therpy with other agents because they cause hypoglycaemia. Their hypoglcemic effect is evident for 12-24 hours can be administered once dialy.

sulfonylureas 1st generation drugs are less potent than 2nd generation drugs. 1st generation drugs are tolbutamide(orinase)and chlorpropamide(diabinese). now a days chlorpropamide not used because of severe hypoglycaemia effect and increased dose it cause jaundice. 2nd generation drugs are glibenclamide (glynase), glipizide(glucotrol). longer acting sulfonylureas are resulted in greater prolongence of hypoglcemia certainly proved in case of chlorpropamide(longacting) but 2nd generation sulfonylureas have differing incidences of causing hypoglcemia. example gluburide(diabeta) has been reported to result in hypoglcemia in upto 20% to 30% of users where as longacting glimepride(amaryl) results in hypoglcemia in up to 2-4% of users because the glucose dependent inhibition of insulin secretion during hypoglcemia occurs with glimepiride(amaryl) but not with glyburide(diabeta) . additionally the major anti insulin counter regulatory hormone glucagon appears to be reduced by glyburide during hypoglycemia but it is preserved during glimepride therapy.

NON-SULFONYLUREASECRETAGOGUES:
These drugs are modulate β cell insulin release by regulating k+ efflux. they are short acting drugs and same mechanism as sulfonylureas but different binding site. these drugs used to treat postprandial hyperglycemia but it has minimal effect on overnight or fasting glucose level. these drugs are repaglinide(prandin) and nateglinide(starlix) . these drugs are given alone or combination with biguandies. these drugs have no sulphur in structure so given in patients with sulphur or sulfonylurea allergy. adverse effects are weight gain, hypoglycemia.

THIAZOLIDINEDIONE
These drugs are effective in type 2 diabetes . They lower blood glucose by increasing glucose uptake and bind to nuclear receptor PPAR?(Peroxisome proliferator-activated receptor) and complexes with retinoid x receptor. a transcription factor that regulates the expression of specific genes especially in fat cells but also other cell types such as vascular smooth muscle cells, endothelial cells, macrophages, monocytes. thiazolidinediones have been shown to interfere with expression and release of insulin resistance originating in adipose tissue(ex:-Increased free fatty acids, decreased adiponectin) in a way that results in net improvement of insulin sensitivity in muscle and liver)

The drugs are rosiglitazone(avandia),pioglitazone(actos).The maximum effect has been achieved after 1-2 months. These drugs increase plasma volume due to amiloride effect on collecting ducts and cause haemodilution. These drugs are contraindicated in children, pregnant women, heart failure cases. These drugs increase endogenous insulin and decrease exogenous insulin. Thiazolidinediones generally decrease triglycerides and increase high density lipoprotein cholesterol(HDL-C) and low density lipoprotein cholesterol(LDL-C)

The adverse effects are water retention, weight gain and water retention leads to edema. significant water retention leads to a decompensation of potentially previously unrecognized heart failure. Therefore these drugs should be prescribed with both caution and patient warnings about the potential for water retention or weight gain, especially in patients with decreased ventricular function(Heart failure)

α-GLUCOSIDASE INHIBITORS:
These drugs are effective in type 2 diabetes and act by delays carbohydrate absorption. These drugs are used to establish greater glycaemic control over hyperglycaemia in diabetic mellitus type2 particularly with regard to postprandial hyperglycemias. They may be used as mono therapy in conjunction with an appropriate diabetic diet and exercise or they may be used in conjunction with other anti diabetic drugs.

α-glucosidase inhibitors are act as competitive inhibitors of enzymes needed to digest carbohydrates specifically α-glucosidase enzymes in the brush border of small intestine. It also blocks pancreatic α-amylase in addition to inhibiting membrane bound α-glucosidases.

α-glucosidase inhibitors are miglitol(glyset), acarbose(precosel glucobay), voglibase. Culinary mushroom maitake(grifola frondosa) acting as a natural α-glucosidase. The adverse effects are flatulance, diarrhoea.

INJECTABLE INCRETIN MIMETICS
Incretins are insulin secretagogues. Incretin contain 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.

INJECTABLE GLUCAGON-LIKE PEPTIDE ANALOGS AND AGONISTS
GLP agonists bind to a membrane GLP receptor. As a consequance, insulin release from the pancreatic beta cells is increased. agonists activate the GLP-1 receptor and have been modified to become resistant to the degradation action of DPP-4.

Exenatide(Byetta) is the first GLP-1 agonist approved for the treatment of type 2 diabetes. and Liraglutide(Victoza) these agents may also cause a decrease in gastric motility, responsible for the common side effect of nausea and weight loss also occur.

DIPEPTIDYLPEPTIDASE-4 INHIBITORS
The drugs also called as gliptins. They can be used to treat diabetes mellitus type-2. These drugs block DPP-4 enzyme. This enzyme responsible for glucagon release glucagon increases blood glucose levels. DDP-4 reduce glucagon and blood glucose levels. The mechanism of DPP-4 is to increase incretin levels (GLP-1 AND GIP) which inhibits glucagon. GLP-1 analogs resulted in weight loss and had more gastrointestinal side effects ,while DPP-4 Inhibitors were weight neutral and increased risk for infection ,but both classes appear to present an alternative to other antidiabetic drugs. The drugs are sitagliptin (janvvia), vidagliptin(novartis), Saxagliptin(onglyza), linagliptin (tradjenta).

INJECTABLE AMYLIN ANALOGUES
Amylin agonist analogues slow gastric emptying and suppress glucagon. They have all the incretin actions expect stimulation of insulin secretion. Pramlinitide administered by subcutaneous injection and side effect is nausea.

PHARMACOKINETICS OF COMBINATION OF MEDICATION:-
Combination medications may offer substantially more benefits to many patients than the literature currently suggests. Many patients take multiple medications, most often for diabetes and hypertension. For example many combination products have given several benefits along with cost effectiveness and patient adherence. Combination of metformin+glimepiride can simplify dosing regimens, improve compliance, improve diabetes control, decrease dose dependent side effects.

EFFECTS OF COMBINATION MEDICATIONS ON ADHERENCE:-
Surprisingly few studies are available on the effects on adherence of combination medications vs individual medication treatment regimens. one study demonstrated that fixed combinations of metformin+glimepiride raised adherence rates in diabetic patients by 31%. Reduction in the number of pills taken daily may improve adherence and the reduced number of pills resulting from the use of combinations may reduce the number of side effects patients might be expected to experience.

BIGUANIDES IN COMBINATION ANTIHYPERTENSIVE THERAPY
Biguanidies are effective antidiabetic drugs .Treatment with a metformin results in a dose dependent blood glucose reduction.

TABLE 1:- COMBINATION DRUGS FOR THE TREATMENT OF DIABETES

Sr. NO Combination Drug Amount of drug present Brand name

1 Biguanidies and sulfonylureas

Metformin and glibenclamide 400mg/5mg Benclamet

Metformin and glicazide 500mg/80mg Glychek-MForte

Metformin and glimepiride 1000mg/2mg) Amaryl M Forte

2 Biguanidies and Thiazolidinediones

Metformin and pioglitazone 500mg/15mg Glitafor-XR

Metformin and rosiglitazone 500mg/2mg Avandamet

3 Biguanidies and α glucosidase inhibitors

Metformin and voglibose 500mg/0.2 mg V-Bose

4 Sulfonylureas and thiazolidinediones

Glimepiride and pioglitazone 1mg/15mg Amary PAventis

5 New combinations

Metformin and Exenatide injection 500mg/5mg

Metformin and Sitagliptin 500mg/5mg Janumet

Metformin and pramlintide injection

TABLE 2 BLOOD GLUCOSE REDUCTIONS ACHIEVED WITH METFORMIN MONOTHERAPY

DOSAGE (mg per day) Blood glucose reduction

FPG PPPG HBA1C

2550 mg/day 59 83 1.8%

Metformin is used as 1st line agent to treat type 2 diabetic mellitus. Metformin recommended initial doses are 500mg twice daily or 850 mg per day. The maximum adult dosage is 2550 mg per day. Metformin should not be used in renal and hepatic disorders. They are the most commonly used medication in combination antidiabetic drugs. Metformin monotherapy should not control blood glucose level then go for metformin combination therapy.

1.BIGUANIDES AND SULFONYLUREAS
Biguanides lower blood glucose by increase glucose uptake and decrease gluconeogenesis. Sulfonylureas stimulate insulin secretion on β cells that leads to decrease blood glucose level. Metformin has an additive glcemic effect when given in combination with a sulfonylureas

In the combination therapy decrease fasting blood glucose level, post prandial blood glucose,HBA1C levels more than monotherapy. The choice of 2nd agent depends upon additional factors such as safety,cost. Sulfonylureas are preferred second line agents because of efficacy, side effect profile, relative cost.

A recent study showed assessed that safety and efficacy of antidiabetics therapy using the metformin and combination with glimepiride . The dosage of metformin 1000mg,500mg and glimepiride dosage is 2mg,1mg.The study showed that monotherapy with either agent was more effective than placebo, but that when combination therapy was used, The beneficial effects were greater than when either agent was used alone. Metformin and glimepiride combination therapy at low dosages can minimize the side effects associated with high dose therapy of either agent.

2.METFORMIN AND THIAZOLIDINEDIONES
Metformin and sulfonylureas combination donot reduce the HBA1C target level or patients contraindicated in sulfonylurea drugs then add thiazolidinediones on therapy. These drugs are used as 3 rd line agents.These drugs are contraindicated in heart failure, hypertension patients because these drugs cause water retention.Thiazolidinediones combined with metformin. The combination improves insulin resistance. Metformin primarily through decreasing hepatic glucose production and additionally inhibits hepatic gluconeogenesis and thiazolidinediones act by improving insulin sensitivity so this combination therapy effective to the patient.

A recent study showed assessed that safety and efficacy of anti diabetics therapy using the metformin and combination with rosiglitazone. In this study 348 patients aged 40 to 80 years with a mean fasting plasma glucose level 12.0mmol/L (216mg/dl), a mean glycosylated haemoglobin level of 8.8% and the study found that combination consisting of 500mg metformin and 2mg, 4mg of rosiglitazone was well tolerated. Glycosylated heamoglobin levels and fasting plasma blood glucose and insulin sensitivity and beta cell function improved significantly with metformin and rosiglitazone therapy. . The mean levels of glycosylated hemoglobin decreased by 1.0% in the 4 mg/d metformin-rosiglitazone group and by 1.2% in the 8 mg/d metformin-rosiglitazone group and fasting plasma glucose levels by 2.2 mmol/L (39.8 mg/dL) and 2.9 mmol/L (52.9 mg/dL) compared with the metformin-placebo group (P<.001 for all). Of patients receiving 8 mg/d of metformin-rosiglitazone, 28.1% achieved a glycosylated hemoglobin level of 7% or less.

MEAN CHANGE IN HbA1c LEVELS OVER TIME IN PATIENTS TAKING METFORMINHCL ALONE COMPARED WITH PATIENTS TAKING METFORMIN AND ROSIGLITAZONEMALEATE COMBINATION

3.BIGUANIDES AND α-GLUCOSIDASE INHIBITORS
Biguanides lower blood glucose by increase glucose uptake and α - Glucosidase inhibitors are inhibit the α glucosidase enzymes this enzyme is responsible for digestion of carbohydrates . The average glucise lowering effect of the major class of antidiabetic agents is broadly similar (Averaging a 1-2% reduction in HbA1c) . α glucosidase inhibitors are being rather less effective. combination of metformin and α glucisidase inhibitors show less side effects when compared with other oral hypoglycemic agents. α glucosidase inhibitors are used to establish greater glycemic control over hyperglycemia in diabetic mellitus type 2 particularly with regard to postprandial hyperglycemia. One study evaluate the efficacies of metformin in a dosage of 500 mg, Voglibose in a dosage of 0.2 mg . T he treatment compared with each other and with placebo. The greatest anti diabetic effect occured with the combination of 500 mg metformin and 0.2 mg of voglibose. Decrease Fasting blood glucose level , post prandial blood glucose, HbA1c levels more than monotherapy.

4 NEW COMBINATION AGENTS:-
New classes of antidiabetic agents first introduced in the year 2005(Exenatide) and 2007(Sitagliptin).The combinations include metformin with a Exenatide injection , Sitagliptin , pramlintide injection. These combination drugs are not well suited for initial monotherapy because no studies have provided conclusive evidence of increased tolerance when these agents are taken in combination with a metformin . Therefore , these combinations are not indicated for first line therapy. In recent study showed assessed that safety and efficacy of antidiabetics therapy using the metformin and combination with Sitagliptin . The incidence of overall clinical adverse experiences was similar in both groups. in this study the incidence of hypoglycemia was not significantly different between the groups(2.1% for Janumet, 1.8% for metformin p=0.686). Patients taking janumet compared to patients taking metformin alone , had significantly lower incidences of abdominal pain (1.1% vs 3.8% respectively p=0.002), Diarrhoea (12% vs 16.8% respectively p=0.015), vomiting(2.9% vs 2.6% respectively p=0.735). The combination therapy is more effective than monotherapy. These combinations are used when the patients are not responding to metformin and sulfonylureas, thiazolidinediones combination therapy.

COMMENT ON COMBINATION OF ANTIDIABETIC AGENTS
Metformin recommended as a initial treatment for the patients with diabetics. At the same time , It is recognised that monotherapy will not provide adequate glucose control in a large proportion of patients , and that many patients will experience unacceptable side effects with higher dosage of a single agent. Fixed dose combination antidiabetic medications are a usefull and appropriate treatment option in this large group of patients.

CONCLUSION:-
Combination therapy is more effective than monotherapy because a reasonable goal of treatment is to maintain good glycemic control. The combination drug therapy as to keep HbA1c value below 7% for a particular patient. Combination therapy at low doses can minimize the side effects associated with high dose therapy of either agent, yield additive clinical benefits.

AKNOWLEDGEMENT
Avanthi education society for their cooperation, encouragement and support

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