Many patients with the type of diabetes that could easily be controlled with diet are turning to pills with side effects that could be worse than the disease itself.

According to Dr Sidney M. Wolfe of the US Public Citizen’s Health Research Group, and author of Worst Pills, Best Pills (Washington, DC: Public Citizen’s Health Research Group, 1993), “Doctors find it easier to prescribe a pill than to nag patients with type 2 diabetes to lose weight the safest way to treat the condition.”

Consequently, many patients with type 2 diabetes, which could easily be controlled by changes in lifestyle, are turning to pills (called oral hypoglycaemics) with side effects that are even worse than having the disease itself. Indeed, according to Diabetes UK (formerly the British Diabetic Association), around 50 per cent of type 2 diabetics take diabetic pills or roughly 525,000 individuals in the UK alone.

Type 2 diabetes (also known as non insulin dependent or adult onset diabetes) usually appears in individuals between 40 and 75 years of age. The condition develops when the body is still able to produce insulin, though not enough for its needs.

Insulin is a vital protein hormone secreted by the islet cells of the pancreas and serves as a signal of the fed state. It is secreted in response to elevated blood levels of glucose and proteins.

The condition may be hereditary and only reveal itself when sufferers become overweight. It tends to be more common in Asian and African Caribbean communities. It can also be triggered by excessive eating and drinking.

People are now eating more and exercising less on both sides of the Atlantic. The proportion of American adults between the ages of 20 and 74 years with a body mass index greater than 30 kg/m2 increased from 12á3 per cent during 1976-1980 to 22á5 per cent during 1988-1994 (Int J Obes Relat Metab Disord, 2000; 22: 39-47). In the UK, this proportion rose from 6 per cent to 16 per cent in men and from 8 per cent to 17á3 per cent in women between 1980 and 1996 (Prescott-Clark P, Primatesta P. Health Survey for England, London: Her Majesty’s Stationery Office, 1996).

Perhaps not surprisingly then, according to Diabetes UK, around 1.4 million people in the UK are now thought to be diabetic, of whom three quarters have the type 2 version of the condition.

According to the American Diabetes Association (ADA), nearly 16 million Americans have diabetes, and at least 90 per cent of those over the age of 20 are non insulin dependent (American Diabetes Association, Complete Guide to Diabetes, Alexandria, VA: ADA, 1996: 7).

According to leading nutritionist Dr Stephen Davies, planning your meals properly and getting regular exercise can help your body maintain healthy blood sugar levels (Lancet, 1991; 338: 774-8). If you’re overweight, losing weight will help your body use insulin better. Sometimes, losing just 10 or 20 pounds (about half a stone to one and a half stone) is enough to bring diabetes under control. Bringing your blood pressure down is also helpful. Ways to do this include ingesting less salt, and avoiding alcohol and smoking.

So, diet appears to be the safest and most effective way to treat type 2 diabetes. In this case, why do we need to take pills which have such a disturbing array of side effects particularly when there is, as yet, no conclusive evidence that improved glucose control with the use of oral drugs will decrease the risk of complications of type 2 diabetes (Therap Lett, 1998; issue 23, Jan-Mar)?

According to Dr Wolfe, there are three reasons pharmaceutical companies, doctors and patients.

The magic bullet

When these ‘oral hypoglycaemic agents’ first became available, they were meant to serve as insulin substitutes for those few type 2 diabetics who needed a treatment of both diet and insulin to control their diabetes.

“Instead, the pills became substitutes for the diet,” says Dr Wolfe. “With the availability of oral drugs, experts stopped stressing the role of diet in controlling the disease, mostly in those very people whose diabetes could have been controlled by an appropriate diet.”

According to Dr Wolfe, as it is assumed that older people won’t change their diet or lose weight, doctors won’t even suggest an initial trial weight loss period, opting instead to begin treatment with a diabetic pill.

“Patients, handed a complex diet by their doctor and referred to a dietitian for ins tructions on weighing food portions and memorising food choices, often find it easier to take a pill,” continues Dr Wolfe. “However, it is foolhardy to increase the already present risk of heart and blood vessel disease for the convenience of popping a pill when proper instruction, limited dietary changes and a little encouragement can help you to reach optimal weight, better health and normal blood sugar.”

Weight loss, restricted diets and exercise have all been advocated for the treatment of type 2 diabetes. Exercise as an adjunct to diet leads to greaterweight loss and prevention of weight gain among patients with type 2 diabetes. Although there are some inconsistencies, most studies have demonstrated the effectiveness and feasibility of exercise over the long term in treating adult onset diabetes (Diabetologia, 1987; 30: 930-3; Diabetes Care, 1992; 15 [Suppl]: 1800-10).

In one trial, 577 people with impaired glucose tolerance (a milder form of hyperglycaemia) were randomly allocated into diet, exercise and control groups. During the six year trial period, 67 per cent of the control group, but only 41 per cent and 43 per cent of the diet and exercise groups, respectively, developed type 2 diabetes, a risk reduction of approximately 25 per cent (Diabetes Care, 1997; 20: 537-44).

In several large scale studies with follow up periods of 6-14 years, there was a decrease of 30-50 per cent in the development of type 2 diabetes among those who exercised regularly compared with those who were sedentary (N Engl J Med, 1991; 325: 147-52; Lancet, 1991; 338: 774-8; Am J Epidemiol, 1995; 41: 360-8). This result was found in both obese and non obese men and women.

However, the evidence of longer term trials suggests that diet alone does not always improve glucose control or reduce deaths due to type 2 diabetes (Ann Intern Med, 1996; 124: 136-45).

So, which drug treatments have been shown to lower blood glucose?

Preliminary results from a large trial examining glucose control and risk of diabetes complications in type 2 diabetics show an improvement in hemoglobin A1c (HbA1c) levels in patients who received treatment whether with sulphonylurea, metformin or insulin (Ann Intern Med, 1998; 128: 165-75). Levels of HbA1c, which has links to sugar, are raised in poorly controlled diabetics.

A trial of 2520 patients comparing diet alone with diet plus sulphonylurea (chlorpropamide or glyburide [glibenclamide]), insulin or metformin, found that all of the drugs were equally good at lowering glucose and were better than diet alone (BMJ, 1995; 310: 83-8).

In this study, patients showed significant weight gains with the sulphonyl ureas and insulin (means of 5 kg and 7 kg, respectively), but not with metformin (1 kg gain). Also, hypoglycaemic reactions or ‘hypos’, abnormally low levels of blood glucose leading to tremors, cold sweats and headache accompanied by irritability, confusion and hallucinations, and ultimately resulting in convulsions and coma were least frequent with metformin. Glucose control deteriorated steadily over time with all treatments whether diet, sulphonylureas, metformin or insulin due to decreased pancreas islet cell function.

After four to five years of therapy, HbA1c levels rose to even higher values than before treatment (Ann Intern Med, 1996; 124: 136-45). However, sulphonyl ureas, metformin and insulin all reduced levels of HbA1c by 0.7-0.8 per cent more than diet alone.

In other studies, troglitazone reduced HbA1c by 0.5 per cent more than diet alone (Diabetes Care, 1996; 19: 151-6) whereas acarbose reduced HbA1c by 0.55-0.90 per cent (Ann Intern Med, 1994; 121: 928-35; Am J Med, 1995; 98: 443-5). However, these trials also questioned the long term effectiveness of these drugs as well as their dangers.

The University Group Diabetes Program (UGDP) study, involving insulin and antidiabetes drugs, failed to prove that diabetes pills could prevent the long term complications of diabetes such as heart and kidney disease, and blindness (Diabetes, 1970; 19 [Suppl 2]: 813). Instead of preventing disease, it is likely that these drugs increase the risk of death due to cardiovascular disease (J Am Med Assoc, 1975; 231: 624).

Unlike insulin, oral hypoglycaemics are only somewhat effective in lowering blood sugar. They fail to adequately control blood sugar in 20-40 per cent of patients. But even if they work at first, they may later fail in as many as 30 per cent of patients per year (ADIS Health Science Press, 1984: 231).

After the UGDP report was released, two clinics that stopped using oral hypoglycaemics found no change in blood sugar in about one third to one half of patients who’d been taken off the drugs. This indicates that these patients didn’t need the drugs in the first place (J Am Med Assoc, 1975; 231: 624). The remaining patients were able to lower their blood sugar with diet alone or with a combination of diet and insulin.

These results suggest that a majority of the diabetics who take oral hypoglycaemics could get along with only mild dietary changes and avoid the risk of premature heart disease.

Drug dangers

The sulphonylurea chlorpropamide may cause dangerous, long lasting periods of low blood sugar. It may also produce breathing difficulties, drowsiness, muscle cramps, seizures, swelling of the face, hands or ankles, unconsciousness, water retention, or weakness that could be life threatening in those who tend to retain water, or who have congestive heart failure or cirrhosis of the liver

(Am Med Assoc, 1983: 1045. For these reasons, the World Health Organization recommends that this drug not be used by people aged 60 years or older. It is supplied in the UK on a named patient only basis to be taken only by the patient named on the scrip and is not recommended for general prescription.

Acetohexamide, another sulphonyl urea, is eliminated from the body mainly by the kidneys. Since kidney function decreases steadily with age, there is a possibility that toxic amounts of this drug may accumulate in older people.

Doubts have also been raised following a review of a new class of drugs called thiazolidinediones. Rezulin (troglitazone) was one of the first to be licensed both in the UK and US. One recent study, carried out in France, found that 2 per cent of patients developed liver dysfunction, which can lead to liver failure, a potentially lethal side effect not noted by the drug company (Lancet, 2000; 355: 1008-10).

Released in the US in March 1997, troglitazone reached Europe later that year, but was withdrawn within weeks. Meanwhile, it went on to generate sales of over $2 billion in the US, and caused at least 90 cases of liver failure (70 resulting in death or transplantation) before it was finally withdrawn in March 2000.

Rosiglitazone and pioglitazone reached the US market in 1999 as first line agents to be used alone or in combination with other drugs. But in Europe, the same dossiers were used a year later to apply for a limited license as second line agents restricted to oral combination therapy. It seems extraordinary that these ‘glitazones’ could achieve blockbuster status without any clear evidence of advantage over existing therapy (Lancet, 2001; 357: 1870-5).

The side effects of one of the latest pioglitazones (Actos) which has been on sale in the UK since November also include upper respiratory tract infection, sore throat, headache, sinusitis, muscle pain and oedema.

Research carried out by the US Public Citizen’s Health Research Group’s Dr Wolfe into Food and Drug Administration (FDA) databanks also discovered that thiazolidinediones can lead to cardiac failure, “a serious finding not previously adequately acknowledged in the product labelling or on the company Web sites,” he states.

Health threats are also present from other kinds of drugs.

Overweight diabetics often turn to weight loss drugs, but these come with their own problems. Fenfluramine can cause nausea, vomiting, headache, nervousness, irritability, bad dreams, insomnia, visual disorders, hypotension, impotence and loss of libido. Prolonged use may cause damage to the blood vessels of the lungs. Another drug for losing weight phentermine is also known to cause blurred vision, constipation, diarrhoea, dizziness, dry mouth, a false sense of well being, insomnia and nausea.

A recent report suggests that AIDS patients taking the antiviral drug abacavir might develop diabetes, although this reaction may be brought on by interactions with other drugs, such as hydro chlorothiazide and didanosine (N Engl J Med, 2001; 344: 142-4). In this case, the blood glucose levels in a 47 year old man with no family history of diabetes dropped dramatically while taking abacavir. However, within two weeks of coming off the drug, his blood glucose levels were back to normal.

Long term survivors of bone marrow transplants have a substantial risk of developing insulin resistance, impaired glucose tolerance and type 2 diabetes. These disorders increased in frequency in relation to time since the bone marrow transplant, and it looks as though glucose and insulin levels must now be added to the list of regular health checks in this vulnerable group of patients (Lancet, 2000; 356: 993-7).

And as if this wasn’t enough, there’s also the dangers with the use of insulin or oral hypoglycaemics with other drugs you may already be taking.

The AMA [American Medical Association] Drug Evaluations (Chicago: AMA, 1991) says that insulin taken with alcohol, clofibrate, fenfluramine, guanethidine, l-thyroxine, oxytetracycline, phenelzine, propranolol or timolol could cause “highly clinically significant” or “clinically significant” interactions, especially with prednisone. In the United States Pharmacopeia Drug Information (1992), this lattermost drug is described as having an interaction of “major significance”.

In addition, alcohol, aspirin, chloramphenicol, cholestyramine, cimetidine, clofibrate, cortisone, dicumarol, doxepin, fenfluramine, gemfibrozil, hydrochlorothiazide, oxytetracycline, phenelzine, phenylbutazone, propanolol and sulphamethizole may interact with any oral hypoglycaemics to cause severe adverse effects (AMA Drug Evaluations, Chicago: AMA, 1991).

For example, Diabetes UK says that metformin taken with alcohol or a sulphonylurea could trigger a ‘hypo’). They also say that thiazolidinediones should only be used in combination with either a sulphonylurea or metformin, and should not be used on their own to avoid the possibility of liver damage. And as with metformin, acarbose (Glucobay, the only one in the UK), a gut maltase inhibitor, can bring on ‘hypos’ if taken with a sulphonylurea.

Your doctor may also try different combinations and doses of diabetes pills if it’s thought that one of them alone cannot control your blood glucose level well enough.

Unlike insulin and pills, however, a diet carries no risk of low blood sugar or any other serious complications. Oral hypoglycaemics should therefore only be used by type 2 diabetics whose blood sugar is not controlled by diet alone and who cannot inject insulin.

If you do take a diabetes pill, you should make sure that you are taking the safest one possible. However, to prevent doctors from being tempted to follow a ‘treatment of laziness’prescribing tablets if they think it’s going to be too difficult for you to change your dietary habits or lifestyle you’ve got to become your own expert. Effective diabetes control hinges on your ability to manage the disease yourself.

!AClive Couldwell

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Written by What Doctors Don't Tell You

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