Diabetes and the pharmaceutical industry

Complications of diabetes, their prevention and treatment

In type 1 diabetes, the Diabetes Control and Complications Trial (DCCT) showed that, over a 6.5 year period, intensive insulin treatment aimed at lowering HbA1C levels reduced the risk of newonset:

• retinopathy by 76 per cent
• neuropathy by 69 per cent
• microalbuminuria, the first stage of nephropathy, by 34 per cent, compared with conventional insulin treatment.

In type 2 diabetes The United Kingdom Prospective Diabetes Study (UKPDS) found that tight control of hyperglycaemia reduced the risk of microvascular complications (retinopathy and kidney disease) by 37 per cent for each reduction of 1 per cent in HbA1C level. By contrast, the risk of macrovascular complications (such as heart attack and stroke) was much less sensitive to hyperglycaemia. However, the UKPDS also showed that strict blood pressure control reduced macrovascular complications and even microvascular complications such as retinopathy.

Much research effort has been devoted to discovering the mechanisms by which high glucose levels may cause the tissue damage that results in long-term complications in diabetes. It is outside the scope of this booklet to review the details here, but recently a “unifying mechanism” has been proposed that identifies the root cause of disturbances in several major biochemical pathways involved in tissue damage. This underlying change is the overproduction of so-called reactive oxygen species, in particular the superoxide radical, in susceptible tissues in response to excess glucose.

This discovery may act as a stimulus for the development of new medicines to prevent complications. It is too soon for such global approaches to have reached the stage of clinical trials. Some other promising studies, including some intervening in one or other of these key pathways, will, however, now be briefly described, under the heading of each main complication.

Retinopathy
Retinopathy, a disease of the small blood vessels of the retina at the back of the eye, is one of the more common complications of both types of diabetes. The earliest sign of retinopathy are micro-aneurysms (tiny outgrowths of small blood vessels in the retina) and small haemorrhages. These do not normally affect vision, but can be detected by an eye examination. They follow hyperglycaemic damage that weakens the tiny blood vessels (capillaries) of the retina. Diabetes also accelerates the formation of cataracts.

As retinal capillary damage worsens, hard masses (lipoprotein) may form on the retina as a result of leakage from the blood vessels and “cotton wool spots” may develop, following areas of cell death in the nerve fibre layer of the retina. Changes may also be observable in small branched retinal blood vessels.

Retinopathy may then spread, with the formation of new, small blood vessels over the retina. Maculopathy (disease of the macula - the central area of the retina that is responsible for detailed central vision) can also follow. Both can cause severe sight loss.

The start of insulin treatment can bring a worsening of retinopathy in the short term in both type 1 and type 2 diabetes, but is followed by benefit over the longer term (one year and onwards). Significant worsening is unlikely in those without pre-existing retinopathy in type 2 diabetes. Duration of diabetes and high HbA1C levels are predictors of the risk of progression over time.

Treatment for retinopathy has been mainly confined to laser treatment late in the progress of the disease, to prevent blindness. At present, there are no medicines for it.

There is, however, evidence that inhibitors of the renin-angiotensin-aldosterone (RAA) system, antihypertensive medicines such as beta-blockers, ACE-inhibitors and angiotensin receptor blockers (ARBs), can delay progression of retinopathy. The UKPDS found that both a beta-blocker (atenolol) and an ACE-inhibitor (captopril) were effective in type 2 diabetes and the EUCLID study in type 1 diabetes found that two years of treatment with the ACE-inhibitor lisinopril caused a 50 per cent reduction in progression.

A major Phase 3 study programme (the Diabetic Retinopathy Candesartan Trials or DIRECT programme) is now underway to investigate whether the ARB candesartan (Takeda) can prevent or slow progression of retinopathy in both type 1 and type 2 diabetes. Worldwide, more than 5,000 patients have been enrolled into the three studies in this programme, which is expected to continue until 2008.

Another agent being tested in Phase 3 trial is the somatostatin analogue octreotide (Novartis), which inhibits production in the eye of growth hormone and insulin-like growth factor 1, which stimulate new blood vessel formation and proliferation. It is hoped that the long-acting injected version of octreotide being used in this study will prevent progression of late-stage retinopathy and slow vision loss. This study is expected to report in 2006.

Eli Lilly recently completed a Phase 3 trial of the oral protein kinase C-beta inhibitor ruboxistaurin in moderate to severe retinopathy. While it did not prevent proliferative disease, it appeared to slow vision loss and is expected to be submitted for approval shortly.

Lastly, Pfizer is developing the injectable monoclonal antibody pegaptinib for the treatment of diabetic macular oedema and various aspects of retinopathy. A recently completed Phase 2 trial showed pegaptinib treatment resulted in vision gain and a reduced need for laser treatment as compared with usual therapy.

These new approaches give hope that retinopathy may become preventable or treatable with medication, and this would be an important step in the fight against vision loss in diabetes.

Neuropathy
Neuropathy (nerve damage) is another frequent complication of diabetes. It most commonly affects the legs and feet, and can produce numbness that may lead to foot problems (diabetic foot) such as ulceration. It can also affect the hands. Often it can result in an incapacitating, burning nerve pain. Neuropathy has also seen a substantial research effort, which has been devoted to developing new medicines that could reduce new onset disease or progression, as well as providing better pain management.

Neuropathic pain is treated with conventional analgesics, but these may not be sufficient. In 2004, Pfizer's pregabalin was approved in Europe and this was followed in early 2005 by Eli Lilly's serotonin/noradrenaline reuptake inhibitor duloxetine. Additional compounds under development for pain relief include Avanir's AVP923, Sativex oral spray (GW Pharmaceuticals), and perzinfotel (Wyeth), all of which are in Phase 2 trials. At the Phase 1 stage, Abbott is testing ABT-894.

Several compounds are also in development that are intended to affect the progression of neuropathy. Eli Lilly is completing a Phase 3 study of ruboxistaurin. Sankyo currently has fidarestat in Phase 2 development. Takeda is developing TAK 428and TAK 128, both also at Phase 2

Finally, the US company Sangamo BioSciences has an injectable compound (SB-509) designed to turn on the naturally occurring gene for vascular endothelial growth factor-A (VEGF A) - a growth factor that has been shown to have neuroprotective properties. SB-509 is undergoing Phase 1 trials to establish safety and a suitable dose.

Nephropathy
Compared to retinopathy and neuropathy, nephropathy (kidney disease) is a less common complication of type 2 diabetes. However, its earlier stages of microalbuminuria and macroalbuminuria are not infrequent.

As with retinopathy, agents affecting the reninangiotensin- aldosterone (RAA) system can slow progression of deterioration of kidney function. Medicines for this include the ACE-inhibitors captopril (in type 1 diabetes) and lisinopril (in type 2 diabetes) and the ARBs losartan and irbesartan (for type 2 diabetes). Since many people with type 2 diabetes also have high blood pressure, and these medicines are used for controlling it, it is likely that the benefit of slowing progression of kidney complications will be obtained without needing to add additional medication.

However, for patients with relatively advanced nephropathy, RAA inhibitors may not be adequate. Treating late-stage kidney disease is expensive, and also burdensome for the patient, as it requires repeated dialysis and, ultimately, kidney transplantation. There is thus a place for new medicines in this area too. There are, however, fewer new substances under development for this indication than for retinopathy or neuropathy.

• The Swiss company Speedel has an oral endothelin A receptor antagonist (SPP301) that has just started Phase 3 trial.
• Eli Lilly is studying ruboxistaurin in nephropathy, and this project has reached Phase 2.
• BioStratum is testing pyridoxamine, an inhibitor of advanced glycosylation endproducts (AGEs) that has completed Phase 2.
• FibroGen is running a Phase 1 study of FG- 3019, a human monoclonal antibody against connective tissue growth factors.

Macrovascular complications
Although microvascular complications - retinopathy, nephropathy and neuropathy - seriously affect the health of many people with diabetes, macrovascular complications - stroke, angina, heart attack, heart failure, peripheral vascular disease - are actually more common. They are also substantially more frequent in people with diabetes. Diabetes is therefore clearly a risk factor for macrovascular complications.

Despite this, the prevention and treatment of macrovascular complications does not differ in principle from their management in people without diabetes. The UKPDS trials showed that tight control of blood pressure was essential in preventing macrovascular complications in type 2 diabetes and this is also true in the absence of diabetes. Medicines such as antihypertensives, aspirin and statins, which are taken by people who do not have diabetes, are also useful in those with diabetes, and so diabetes-specific medications are not being actively developed.