What’s the point of Victoza asks Professor Anthony Barnett

From a talk given by Professor Anthony Barnett (Professor of Medicine and Honorary Consultant Physician at the University of Birmingham and Heart Of England NHS Foundation Trust,Birmingham.1) at the launch of the new Type 2 treatment Victoza from Novo Nordisk held in July 2009:

“The first question with any new drug is to ask why bother?, ‘The United Kingdom Prospective Diabetes Study,UKPDS2), a 10-year study that came out at the end of the ‘90s showed that every 1% improvement in your HbA1c3 leads to a 21% decrease in deaths relating to diabetes, a 37% reduction in micro vascular complications (eye and kidney problems problems) and 14% reduction in cardiovascular events (heart attack and stroke).

There is proof that even if good control is gained in type 2 diabetes, the condition itself is progressive. The way Type 2 diabetes is currently treated is via ‘mono’ treatments – we try one drug, then add another drug and so on. The patient is only moved from one treatment to addition of another once the earlier one is not producing the required results – shown by a measurable lack of good blood glucose control. In other words, there is a tendency to wait for poor control before the patient is moved to the next treatment.

What is also clear is that most people when diagnosed with diabetes already have a raised HbA1c. In fact it’s the poor control giving symptoms such as tiredness, thirst,increased passage of urine and possibly blurring of vision commonly leads to a diagnosis of diabetes. People with diabetes may have had the condition for years without realising it.

An initial diagnosis is usually addressed by the patient being advised to amend their lifestyle through diet and exercise. Often blood sugars are not improved sufficiently.Therefore they are started on mono therapy which is usually one of the pill treatments such as Metformin. That is used alone until their HbA1c creeps up due to a rise in blood sugar.

Arguably, patients with Type 2 diabetes are doomed to years of poor control, setting them up for long term complications. It is bad medicine to wait for “failure” ie until the diabetes control is poor before adding in the next therapy.This is fully recognised by recent NICE Guidelines on diabetes management.

There are questions about the cost of treating the growing numbers of people with Type 2 diabetes. It is currently estimated that £10-13m per day is spent on diabetes care by the NHS . Nearly 50% of all dialysis treatments for kidney failure in the US are due to diabetes and currently 25% of all dialysis treatment in the UK are also due to diabetes. Diabetes is the commonest cause of blindness in people of working age in the UK. It is also the single most common reason for non-traumatic lower limb amputation. The cost of drugs to treat diabetes is a small fraction of the costs of treating its long term complications!

Then there is the fact that at diagnosis 80% of people with type 2 are overweight, yet many of the available treatments5 promote weight gain. The idea of then giving a medication that maintains or even increases that weight seems ludicrous, but it is simply one of the aspects of the how those drugs work.

There is the dual impact in type 2 diabetes of insulin resistance and pancreatic beta cell dysfunction – the latter in particular gets worse over time and is the reason why the diabetes control also tends to deteriorate over time.. These two factors — insulin resistance and beta cell dysfunction — lead to impaired glucose tolerance and therefore type 2 diabetes.

Which brings us to GLP-1. This is one of the hormones released in the gut in response to food.GLP-1 has a number of important natural functions in the body.These include stimulation of the pancreas to produce insulin in a ‘glucose dependent’manner.This means it only works when glucose levels are high or rising.Once glucose levels fall the hormone switches off so the glucose levels don’t fall too low.No glucose, no GLP-1! This is what happens in non-diabetics and is the reason why they do not get hypoglycaemia (low blood sugar).

Secondly, GLP-1 suppresses glucagon production — stopping the liver from producing glucose. Thirdly, it slows the gut from emptying, so people feel fuller longer. This means there is the sense of ‘satiety’, the idea that you just feel sated and full, therefore you don’t keep eating.

We know that the production of GLP-1 is reduced in patients with Type 2 diabetes – that is part of the problem. There is not just reduced beta cell function but reduced pancreatic function as a whole. It’s not simply that the beta cells that make insulin aren’t working but the alpha cells of the pancreas which produce glucagon also don’t work properly.

The practical problem we have in giving GLP-1 to people with diabetes is that the hormone is broken down very rapidly in the body and would need to be given as a continous drip into a vein which is just not practical for longterm treatment and would also be extremely expensive. What is needed is an easily deliverable version of GLP-1which is not broken down rapidly in the body and can therefore be given as a once daily subcutaneous injection-this is essentially what Victoza is.

It is presently licensed in Europe for use in combination with several oral treatments already available including metformin,sulphonylureas and glitazones.It works well by improving the insulin secretory response to a rise in blood sugar level and by the other mechanisms just discussed. Novo Nordisk has undertaken research in 40 countries with different variations and combinations of Victoza as a mono treatment or as a combination treatment across the whole spectrum of Type 2 diabetes management under clinical trial conditions.

The challenge for the research was to establish the possibility of a good diabetes control with no weight gain, or increase in blood pressure. One of the things about the trial was it provided a consistency of data. After 26 weeks on the Victoza treatments, most patients had reported weight loss and reduced glucose. It was also discovered that is there is a very low risk of hypos – in fact they’re very rare indeed when the drug is used in combination with Metformin or Glitazones. It’s less well known that people with diabetes
treated with one of the Sulphonlyurea range of drugs account for 5,000 hospital admissions a year for severe hypos.This problem is also common in people treated with insulin. Once a patient has had a severe hypo it is very difficult to persuade them to re-engage in gaining tight control after such an experience.

So what is Victoza? In essence it has a 97% similarity to natural GLP-1. The 3% difference is why it lasts longer.

In terms of how it is taken, it’s another advantage that while it has to be injected you do not have to take it with a meal and it needs to be only injected once a day. The research has shown it is safe, reduces HbA1c, there is a very low risk of hypos, it’ commonly causes weight loss and may also reduce blood pressure.

As a clinician, I think this is an important advance in treatment. I work at one of the biggest diabetes clinics in the country and we are very excited about now being able to discuss this new treatment with our patients.

1. Anthony Barnett is Professor of Medicine and Honorary Consultant Physician at Birmingham University and Heart of England NHS Foundation Trust,Birmingham. His current research areas cover (1). Molecular genetics of type 1 diabetes and other autoimmune diseases; (2). Molecular genetics of diabetic microvascular disease; (3). Obesity and metabolism and its relationship to diabetes and cardiovascular disease; (4). Development of new therapies for management of diabetes and its long term vascular complications; (5). Health Service research concerning provision of diabetes care within the community.

3. HBA1c: a measure of glycosylated (or glycated) hemoglobin (it’s often called hemoglobin A1c ,HbA1c), a form of haemoglobin used primarily to identify the average plasma glucose concentration over prolonged periods of time. Glycation of proteins in the body has been implicated in kidney and eye disease in diabetes mellitus..A diabetic person with good glucose control has a HbA1c level that is close to 6.5 to 7%. High blood sugars — and therefore high HbA1c results — increase the risk of the long-term complications of diabetes.

4. The UK Prospective Diabetes Study (UKPDS): the largest clinical study of diabetes ever attempted, showed that the life-threatening complications of type 2 (non-insulin dependent) diabetes, often regarded as inevitable, can be reduced by more intensive management using existing treatments.

5. Sulfonylureas: drugs that allow the pancreas to release more insulin into the blood which lowers the glucose level but hypoglycemia is a common side effect. Biguanides(metformin): drugs that work by reducing the production of glucose from the liver and improve the sensitivity of cells to naturally produced insulin). Glitazones-drugs that improve sensitivity of cells in the muscle and liver to naturally produced insulin.

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