Almoutaz Alkhier Ahmed, MBBCh, Senior Resident, Gurayat General Hospital, Diabetic Center, Gurayat North, P.O.Box 672, Saudi Arabia

Although diabetes mellitus is a treatable disease, failure with oral treatment has been reported. There are three types of anti-diabetic drug failure. All efforts should be made to establish that the patient has developed failure before starting the patient on insulin therapy. The Moutaz hypothesis explains the relation between the level of glucose and diabetic drug failure and how to deal with this problem properly.

Introduction 
From ancient times, people have sought effective treatment for diabetes mellitus. It is only comparatively recently that knowledge about diabetes has expanded and treatment has been scientifically based. The history of treatment has progressed from magic to traditional, herbal, insulin and lastly chemical therapy. Has each successive method failed? Or is it simply our human tendency to look for the new that has increased our understanding of diabetes mellitus, resulting in changes of treatment?
The discovery of insulin in 1920 by Banting and colleagues at the University of Toronto in Canada led to chemical therapy for diabetes. In 1926, biguanides were tried, following a report in 1918 that guanidine had hypoglycaemic effects.1 In 1930, it was noted that sulphonamide might produce hyperglycaemia.1 The first sulphonylureas were introduced into clinical practice in 1954.1 Every few years since then a new group of compounds has been added to the list of diabetes treatments. In 2002, combined tablets containing more than one group appeared on the market. It may not be long before we see pills which contain most of the daily drugs needed by the diabetic patient.
Diabetes mellitus is a dynamic disease; its pathology is time related. Humans do not suffer from diabetes mellitus unless they have lost 80% of their beta cell mass.2 There is a direct relationship between the rate of deterioration of the remaining part of the beta cell mass and the dose of antidiabetic drug needed to keep the blood glucose within an acceptable range. This relationship continues to a certain limit, beyond which no response is observed. Some studies have tried to predict this point during the course of antidiabetic drug therapy. One of these investigations evaluated beta cell function by HOMA (Homeostasis Model Assessment) as a predictor of secondary sulphonyl­urea failure in type 2 diabetes. This study found that HOMA is a simple and good predictor of the stage of insulin requirement in cases of type 2 diabetes mellitus.3

Definition of antidiabetic drug failure
Failure is described when antidiabetic drugs at maximal dosages fail to maintain or decrease blood glucose markers (blood glucose level and glycated proteins), after recommendations as to diet and physical activity have been accurately followed. The failure can be measured by the values of markers or can be judged clinically by the re-occurrence of symptoms of hyperglycaemia.

Types of failure
There are three types of antidiabetic drug failure. It is important to inform the patient about the possibility of ultimate failure when initiating treatment.

Primary failure
This is defined as initial failure, occurring when antidiabetic drugs are introduced to the patient for the first time. This failure was noticed first with sulphonylurea; approximately 20-25% of people with type 2 diabetes mellitus encounter primary failure of sulphonylurea therapy. The drug works through a specific receptor which is a member of the ATP-binding cassette superfamily (traffic adenosine triphosphate superfamily). This receptor associates with certain potassium channels to form ATP-sensitive potassium channels (KATP channels).These channels are inhibited and closed by intracellular ATP, which creates a channel-metabolic circle. ATP is usually related to energy production by glycolysis inside the cells. Glucose is the fuel of this process. More ATP means more intracellular glucose and more need for insulin. Closure of these channels will open calcium voltage-related inward channels. Increased intracellular calcium stimulates release of endogenous insulin. Hence these drugs are called insulin secretagogues.
The ATP-sensitive potassium channel is a multimeric complex of four Kir6 (including Kir6.1 and Kir6.2) and three common isoforms of sulph­onylurea subunits (SUR1, SUR2A, SUR2B).The beta cell KATP channels are formed from SUR1 and Kir6.2. Sulphonylureas binding to SUR produce a conformational signal that results in closure of the tetramic pore created by Kir6.2. Nucleotides interact in complex ways; ATP and ADP close the channels when binding to Kir6.2 and open them when combined with Mg-nucleotides.4 If nucleotide (ADP, ATP) is not added, the high-affinity block of the KATP current structured by sulphonylureas is not complete, reaching a maximum of approximately 60-80%. In higher concentrations, the sulphonylureas produce a low-affinity block, which is probably related directly to interaction with Kir6.2.4
Major causes of primary failure include faulty selection of patients (e.g. people with type 1 diabetes are insulin dependent and do not respond to antidiabetic drugs), severely impaired beta function (this can occur in the advanced stage of type 2 diabetes mellitus) and mutation of the sulphonylurea receptor 1 gene (SUR1).

Secondary failure
This is defined as failure to decrease or maintain blood glucose after a period of successful use of antidiabetic medication. Test results that indicate good control should be clearly understood by both physician and patient at the first visit, after confirming the diagnosis of diabetes5 (Table 1). The aim of the management plan is to maintain the condition within safe margins. A single abnormal blood glucose test does not mean that secondary failure has developed; repeatedly abnormal blood glucose test results are required, or the physician should rely on other parameters, such as levels of glycated haemoglobin (more than 8% HbA1c) and fructosamine (more than 285 mmol/l), to judge the efficacy of current therapy6 (Table 2). Before diagnosing secondary failure of the drug(s) used, the physician should also find answers to the following questions. 

• Has the patient followed the recommended diet? 
• Is the patient physically active? 
• Did the patient have any components of insulin resistance syndrome? 
• Was the patient receiving the optimal drug regimen? 
• Had the patient previously responded well to the drug(s)? 

If the answers are all in the affirmative, the physician can inform the patient that secondary failure to the current therapy has developed.7
There are two types of secondary failure, monotherapy secondary failure and multiple therapy secondary failure.
Annually, 5-10% of people with diabetes mellitus develop monotherapy secondary failure to their drugs, i.e. to either sulphonylurea or biguanide. Such failure was reported in the UK Prospective Diabetes Study 26 (UKPDS 26), in which the failure rate of sulphonylureas was assessed over 6 years. This part of the trial concluded that sulphonylureas fail mono­therapeutically at rates that depend on the phenotype at presentation (more failure with lean individuals than with the obese) and perhaps also on the agent used initially. A higher failure rate was found in people with higher blood glucose concentration (glucose toxicity to beta cells), those with lower beta cell reserve and those randomised to glibenclamide compared with chloropropamide.7 Monotherapy secondary failure does not indicate future failure of combined therapy.
Multiple therapy secondary failure is judged to have occurred when the blood glucose is not maintained within an acceptable range by a combination of drugs. The physician should be clear about the expected effects of any medication added to monotherapy8 (Table 3). Many studies have assessed the effect of new agents. The most commonly used combination is sulphonylurea with biguanides.9 This is a very effective combination, but can fail. Thiazolidinediones were approved by the Food and Drug Administration in the US for additional antidiabetic medication in 1995.10,11 This triple combination is also very effective,10 but is not immune from failure. Hypo­glycaemia is the worse side effect. Individuals who do not respond to multiple therapy become candidates for insulin therapy.

Tertiary failure
Tertiary failure is rebound failure after recovery from secondary failure, and is rarely seen clinically.

Management of antidiabetic drug failure
Before apparent drug failure (Figure 1) is investigated, other factors possibly affecting the degree of control should be sought. The appropriateness of the primary drug to the case should also be checked.

Primary failure
The diet regimen and physical activity plan should be reviewed first, and the patient’s lifestyle should be discussed with him or her. Components of insulin resistance syndrome should be sought and, if present, should be treated immediately. In the UKPDS, fewer than 25% of people following regimens of diet and physical exercise were able to maintain HbA1c to levels less than 7% after 3 years, and fewer than 10% had such values after 9 years.12 If all recommendations are complied with and the level of blood glucose markers does not improve, the current antidiabetic drug(s) should be replaced by another drug from a different group; changing the current drug for another from the same group will not be of any benefit. If the patient can not tolerate the new drug, insulin therapy should be discussed with her or him.

Secondary failure
The physician should take the general precautions described above before deciding that secondary failure is present. If the patient was receiving monotherapy, a multiple therapy regimen should be initiated, e.g. if failure of a drug from the sulphonylurea group has developed, combination with a compound from the biguanides group should be tried. If the blood glucose still does not respond, a drug from a third group may be added. Thiazolidine­diones comprise a new group that is useful in combined therapy.10 If the blood glucose is still not controlled, the possibility of insulin therapy should be discussed with the patient. However, good management will save the patient from early exposure to insulin therapy.

The Muotaz hypothesis
When a person with type 2 diabetes mellitus becomes a candidate for drug therapy, the following points should be kept in mind.
1. The aim of the treatment should be to keep the blood glucose above 80 mg/dl (4.5 mmol/l).13 Endogenous insulin will be suppressed if the blood glucose drops to below 80 mg/dl and the counter-regulatory system will be activated. Transient hyperglycaemia may occur, which will prompt the physician and the patient to increase the dose of the drug. Hypoglycaemia may then follow, causing the patient to eat more to alleviate its symptoms, with subsequent hyperglycaemia. Again, the physician and patient may plan to further increase the dose. The overall picture will mimic drug failure, whereas the real cause is bad management.
2. The second aim should be to keep the blood glucose at not more than 170 mg/dl (9.4 mmol/l). Chronic hyperglycaemia affects beta cell function, causing first desensitisation and then exhaustion of beta cells, both of which conditions are reversible.14 Finally beta cell destruction takes place, which is irreversible. If the blood glucose is controlled at below 170 mg/dl (9.4 mmol/l), the beta cells should remain healthy and efficient.
3. If severe hyperglycaemia presents, initial therapy with insulin is recommended to reduce the blood glucose rapidly to an acceptable level, from which a low dose of drugs should maintain it within a satisfactory range.
4. Multiple therapy in low doses is preferable to monotherapy in high doses. It has been found that sulphonylurea at high concentration will produce a low-affinity block which is independent of SUR and probably involves direct interaction with Kir6.2. This will reduce the efficacy of this drug group. Multiple therapy in low doses will decrease the side effects related to high doses. Involvement of multiple drug groups will activate different pathways which will work synergistically to decrease and keep the blood glucose within a satisfactory range.