The Downside of Diabetes Drugs

  • 6 Sep 2010
  • Reading time 10 mins
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The treatment of diabetes, say the medical guidelines, should be done as a partnership. You and your doctor collaborate on what fits your needs best. It’s a fine idea but it can be tricky if you are relying on drugs to keep your blood sugar under control because to make sensible decisions, you need to have good information. And with drugs, that can be hard to come by.

Just how hard has become much clearer recently as a result of the Avandia saga, which is the subject of a Panorama programme (A Risk Worth Taking? BBC1, 8.30pm, 6 September 2010). Here’s a quick update in case you’ve heard nothing about it: Avandia (rosiglitazone), licensed almost exactly a decade ago to treat diabetes, works by increasing your body’s sensitivity to insulin. It’s very effective at bringing blood sugar levels down, but at a cost. Well-known side effects include significant weight gain, fluid retention, a raised risk of heart failure and a link with osteoporosis.

What you may not have been warned about is growing evidence that it can increase your risk of a heart attack, even though the first warning bells were sounded three years ago. It was only in July that both the American drug regulator – the FDA – and the European one – the EMA – considered taking it off the market and strengthening the warnings about it. As of writing, neither has come to a conclusion, although an FDA committee has found that Avandia did raise the risk of having a heart attack and recommended that warnings should be added to its label, but that the evidence didn’t warrant taking it off the market. However the FDA committee was split by deep disagreements.

For instance, a major plank in GlaxoSmithKline's evidence was a big trial that reported no increase in the risk of heart disease among nearly 4,500 patients getting Avandia. Called Record, this trail began in 2002/3 and the results were published last year. However, Dr Thomas Marciniak, a scientist working for the Food and Drug Administration, described it as “seriously flawed” because, he claimed in his evidence to the committee, the data had been tampered with. He reported that his detailed examination of only a small percentage of all the cases had found a dozen instances where patients taking Avandia appeared to suffer serious heart problem that were not counted in the total of adverse events.

For instance, one patient was hospitalised after a severe stroke but the study record doesn’t list them as having a cardiovascular problem. In reply, GlaxoSmithKline (GSK) said that it stood by the Record Study and that five further studies had all concluded Avandia was safe. This reassuring picture was challenged further by the most high-profile and persistent critic of Avandia, cardiologist Dr Steven Nissen of the Cleveland Clinic in Ohio. He had carried out the study in 2007 which first set alarm bells ringing with its conclusion that Avandia raised the risk of heart attack or stroke by 43%. At the hearing, he presented new data which estimated the number of people who would have to take Avandia for one of them to be harmed. “Even if you accept the favourable Record data, you would still get one extra heart attack for every 52 people treated with Avandia,” he said.

The fierce disagreements over the safety data is a prime example of why making informed decisions about drugs can be tricky. During the years between Dr Nissen’s original paper and July’s hearings, the official advice from the European regulator has been that the “benefits outweighed the risks” for Avandia. However, many diabetes clinicians didn’t agree. "We have had serious doubts about the safety of Avandia for a number of years," says Dr Ralf Abraham who heads a private clinic, the London Diabetes and Lipid Centre. “We rarely prescribe Avandia now because of the risks and because there’s a very similar drug called Actos (pioglitazone) that is just as effective in controlling blood sugar but it doesn’t carry the same risks.

So why use Avandia?” Sadly, not all patients have access to such informed advice. Last year over a million prescriptions were written for the drug in the UK. But it’s not just Avandia that has been under scrutiny recently. There are some new kids on the block which work in a completely different way and claim to avoid the problems of weight gain and raised risk of heart failure that come with both Avandia and Actos. It is possible that the companies making these new drugs are being totally straightforward about the lack of potential risks – but even so, rarer serious side effects are unlikely to appear until they have been on the market for several years.

A new breed of diabetes drug The new drugs all focus on manipulating a peptide called GLP-1, which is naturally released from your gut as soon as you’ve had a meal and tell the beta cells in your pancreas to start releasing insulin to clear away any excess sugar in the blood. These drugs increase the amount of GLP-1 that’s around at meal times to compensate for the loss of insulin sensitivity that is one of the effects of diabetes. Often, this is achieved by blocking an enzyme called DPP-4 whose job is to clear away GLP-1, so more stays around for longer. It’s the same approach that’s taken by anti-depressant drugs that block the system for clearing away the “feel-good” brain chemical serotonin.

Drugs that do this include Januvia (sitagliptin) and Galvus (vildagliptin), which are widely regarded as a big improvement, not least because rather than putting on weight as both Avandia and Actos do, they can cause weight to drop off. However, unpleasant side-effects include more vomiting, stomach ache and diarrhoea than you get with more traditional drugs. But there is also a more serious concern because the job of the blocked enzyme DPP-4 isn’t just to clear away GLP-1. It also cleans up a number of other bodily changes that you don’t want to go on for too long, such as inflammation and cells that are turning cancerous. There have been some early reports of raised risk of inflammatory problems with these drugs in patients with rheumatoid arthritis and of cancers, particularly melanoma, prostate and lung. Another approach to raising GLP-1 is by making a synthetic version of it.

Two dugs that do this are Victoza (liraglutide) and Byetta (exenatide), both of which stay around in the body much longer than the natural version and have to be injected. They are arousing a lot of interest because they can also produce considerable weight loss – but both can also cause nausea, which in the case of Victoza affects nearly half of the patients in trials. The drug is also being tested for possible cancer links. Treating the other risks that come with diabetes But it is not just new drugs and their possible long-term side effects that diabetics have to be aware of. Some doctors are rethinking the way high-risk diabetic patients are treated. Conventional wisdom says it should be as aggressively as possible to bring down their markers for heart disease. However, a recent trial, known as Accord, found that diabetics with a high risk of heart disease – because they had high blood pressure, high blood sugar and high cholesterol – actually turned out to have more deaths from heart attacks when they were intensively treated with higher doses of drugs, including statins, than those who got regular amounts.

In fact, it’s not really clear why diabetes causes heart disease. Diabetics are certainly at greater risk but their level of risk doesn’t seem to be related to the usual symptoms. “Very little of the additional risk is explained by obesity, blood pressure lipids (fats in the blood) or kidney problems,” says Dr Nadeem Sarwar of Cambridge University, discussing his recent study. So the drugs may not be doing much for those who need help. And with all this uncertainty deciding which drugs you should be taking is made even trickier by the fact that, even though you and your doctor are supposed to be rowing in the same direction, in about a third of cases that doesn’t happen. While both patients and doctors agreed that bringing down hypertension is important, twice as many doctors as patients rated it the most important goal.

What research shows is that more patients considered important was reducing pain and depression – problems which doctors all too often put on the back burner. Not surprisingly, given all this potential confusion, your doctor may not be taking into account the potential side-effects from additional drugs you may be getting to help with the side-effects from the diabetes drugs. This emerged strongly with a drug called Rimonabant which, until about 18 months ago, was used to help you lose any weight you had put on as a result of taking Avandia or Actos. But that turned out to have a side effect of increasing your risk of depression – something that diabetics are more prone to anyway – and it was taken off the market in January 2009. Of course, not everybody on diabetes drugs puts on substantial amounts of weight, suffers from depression, has a heart attack or develops cancer or inflammation problems.

Only a few do, although precise figures are impossible to come by. What is certain though is that if you treat your diabetes with a change of diet and lifestyle, then your chance of having any of those additional problems is vanishingly small. Diet and lifestyle changes more effective than drugs Nutritionists have of course been going on about this for years. But recently they got support from the August edition of the Lancet. “Because Type 2 diabetes is largely rooted in reversible social and lifestyle factors, a medical approach alone is unlikely to be a solution,” it concluded. “To lessen the burden of diabetes requires a substantial change in diet and routine... The fact that Type 2 diabetes, a largely preventable disorder, has reached epidemic proportions is a public health humiliation.”

Around the same time, the British Medical Journal (July issue) reported a randomised controlled trial of over 90 patients which found that getting patients onto a diet that they enjoyed – Mediterranean or high protein – produced results that were as good if not better than those with medication. They were already quite ill – overweight or with hypertension – and had blood sugar levels that weren’t well controlled despite being on “optimised” drug treatment. The authors concluded: “The extent of the improvement in glycaemic control should encourage patients to modify their eating habits.” And a study last year has found that cinnamon, a natural insulin sensitiser, is almost as effective at lowering a key marker for poor blood sugar control (HbA1C – or glycosolated haemoglobin) as some of the new breed of drugs such as sitagliptin – yet costs considerably less ($20 versus $556).

In this randomized controlled trial, 109 partipicants with poorly-controlled Type 2 diabetes were either allocated their usual care, or usual care plus 1g of cinnamon daily. At the end of 3 months, those receiving the cinnamon recorded a drop in HbA1C levels of 0.83% compared to 0.37% for those receiving just their usual care. “This study gives diabetes care providers and diabetic patients an easily accessible, likely safe, and cheap alternative to help treat type 2 diabetes,” concluded the study’s author Dr Paul Crawford. Further research directly comparing cinnamon with HbA1C-lowering drugs would be useful to see. So if you have diabetes, what should you do? A serious change of diet requires support and dedication but it has to be a sensible place to start. For more on controlling your glycaemic intake via a low-glycaemic-load diet, I suggest you read my book the Low-GL Diet Bible.