Institute of Diabetes for Older People

Report from the American Diabetes Association Annual Scientific Meeting, June 2010, Orlando, USA

My report focuses on selected highlights of this meeting that are of particular relevance to the older person with diabetes.  Several key articles were published in the Lancet simultaneously with presentations at the conference in a special issue devoted to diabetes.  Of these papers, data concerning new classes of glucose-lowering drugs merit consideration:

New glucose-lowering drugs

Dapagliflozin is an orally active agent with a mechanism of action that at first sight may appear counterintuitive.  Although the days of assessing - highly imperfectly! - diabetes control by measuring the amount of glucose excreted in the urine we have a new drug that promotes glucose loss via the kidney.  The crucial difference is that dapagliflozin acts directly within the kidney to reduce the amount of glucose that is re-absorbed into the blood after filtering into the urine.  When blood glucose is high more glucose is lost in the urine, but the blood glucose level remains elevated. With dapaglifozin blood glucose is lowered through the excretion of greater amounts of glucose via the kidney itself.  This loss of glucose does not necessarily indicate that blood glucose levels are high.  Indeed, a rare inherited syndrome causes large urinary glucose losses in people without diabetes with no apparent risk to health.  The excretion of glucose takes water along with it, so some increase in urine production is to be expected from the use of these drugs.  A bonus is that the loss of calories results in weight loss.  Whether this might cause urinary retention in the presence of benign prostatic enlargement gives pause for thought.  Another obvious concern is the potential for an increased frequency of genito-urinary infections.  Blood pressure is lowered, in part due to concomitant urinary sodium loss, and care might be necessary in older patients on drugs such as diuretics for fear of excessive falls in blood pressure or dehydration. Clinical trials are in their late stages and it seems likely that this novel class of drugs - the SGLT-2 inhibitors, of which dapagliflozin will probably be the first to be licensed - will soon become available.

To injectables: once-weekly administation of the recently introduced so-called GLP-1 receptor agonists (we’re still hoping for a more user-friendly name for these drugs as well!) appear promising.  A clinical trial in which one of these drugs was compared to a commonly used once daily insulin showed encouraging results with somewhat better glucose control and reductions in body weight.  Of necessity, of course, the long-term safety profile of these increasingly popular agents (not currently available as a weekly formulation) has yet to be established.  Weekly dosing with these drugs, that carry a low risk of hypoglycaemia, could be useful for some people who aren’t able to administer insulin on a daily basis and so rely on relatives or community nurses.

…and mixed new messages about older drugs

The storm of controversy about possible harm associated with a drug widely used for the last decade - rosiglitazone - underscores the need for vigilance.  Far from preventing heart attacks, the risk of which is substantially increased by diabetes, recent reports have suggested an increase.  This potentially devastating finding has seen fierce arguments between clinical investigators who point to the evidence for harm versus others (including the manufacturers of the drug) who maintain that the drug is safe.  This is one of the hottest safety issues in recent years; a US senate committee has become involved and the future of rosiglitazone appears to be in peril.  A new analysis of data from a recently completed clinical trial were presented at the ADA conference.  Opinions were split between doctors who felt that this new information did not support harmful vascular effects of rosiglitazone, and others who dismissed the data as unreliable and inconclusive.  Another issue common to rosiglitazone and the other drug in this class, pioglitazone, that has recently come to light is the increased risk of certain types of fractures, especially in postmenopausal women. That this unwelcome side effect only became evident after many years of clinical use of the drugs underscores the need for careful scrutiny of the long-term effects of glucose-lowering drugs.

On a more positive note, patients treated with metformin who have atherosclerotic vascular disease appeared to have approximately a 25% reduction in the risk of dying according to results from a large collection of patients who were followed up for 2 years.  This kind of study is generally not as reliable as results from clinical trials wherein one drug is compared with another by random allocation.  However, this new report adds to evidence accumulated over many years that have generally shown the benefits of metformin in terms of reducing heart attacks and death.  Not bad for a drug that’s been around for half a century!  The clear lesson is that we need to continue to explore unexpected benefits of well-established medications, as well as the well-known side effects and safety issues of drugs that we think have little more to tell us.  Recent data, which require confirmation, that metformin may also protect against the development of certain kinds of cancer point to the folly of this approach.

On the other hand, another major issue with which diabetes specialists are wrestling is the suggestion - far from proven - that certain types of insulin might promote the development of some cancers.  The strong consensus is that the available data, presented at the conference, are highly unsatisfactory, and that other risk factors such as being overweight and possibly diabetes per se may be relevant.   To quote a senior diabetologist from the USA at the conference suggestions that a particular type of insulin is associated with cancer are ‘unsubstantiated, unwarranted, and unproven’.

Insulin - old, new and things to come?

Notwithstanding the scare about cancer, doctors have yet to discover the optimal way to use insulin.  This will sound surprising given the fact that we’ve had insulin - a drug that revolutionized the treatment of diabetes and has served countless patients well - for nearly an entire century.  Improvements and refinements have undoubtedly made insulin a safer and more acceptable option, and many patients will require insulin at some point.  It’s a good treatment but care is required to avoid hypoglycaemia. Weight gain is the other major unwanted effect.  The wide range of options has brought flexibility and ease of use at the expense of having to learn how best they should be used.  Clinical trials may start with the best of intentions but can sometimes generate surprises.  We still - and always will - need such trials as further advances in insulin therapy come along.  As ever, the challenge for the doctor and the patient is to pick a way through the evidence to ensure that insulin treatment is safe as well as effective.  Wherever possible, the objectives of therapy should be discussed with the person with diabetes being fully involved.  This can be tricky given the complexities of insulin therapy - for specialists as well as patients.

Continuing this theme, a topic of relevance to older people with diabetes who are at risk of hypoglycaemia, especially in the light of the aforementioned issues, included the potential application of continuous glucose monitoring technology.  This can identify treatment-induced hypoglycaemia - symptoms of which are not always present in this age group.  A study presented at the ADA conference demonstrated this very clearly in a group of insulin-treated patients with an average age of 75 years.  The frequency of hypoglycaemia was much higher than indicated by clinical symptoms.  Moreover, only a small fraction of episodes that occurred during the night were recognized by the patients.  Clarifying the place of this technology in routine clinical practice will require much more research.

Still at an experimental stage, and after an underwhelming reception for the first example of the class a few years ago, further attempts to produce a workable inhaled insulin formulation are underway.  Avoidance of injections and a reduced risk of hypoglycaemia compared with conventional insulin are attractive.  However, safety concerns about effects on lung function and the issue of bulky delivery devices have to be addressed: we will no doubt hear more of this approach, which could well be suitable for some older people who rely on multiple daily injections.

Technology does not have all the answers - don’t forget the person with diabetes

For all the advances in pharmaceuticals and drug delivery systems - some of which may be two-edged swords - the crucial issue of the impact of diabetes on quality of life must not be overlooked.  Indeed, evidence is accumulating that points to the importance of maintaining mental as well as physical health.  Diabetes requires daily self-management.  Depression and lesser sub-clinical levels of depression are major barriers to this fundamental aspect of diabetes that are not always specifically asked about by healthcare professionals. Of course, the burden of diabetes and its complications can be more than ample to induce depression.  However, it is noteworthy that people with depression, which is associated with dysfunction of inflammatory and immune function, have a heightened chance of developing diabetes.  A theory advanced at the conference is that long-term low levels of inflammation, which currently cannot be reliably picked up by standard blood tests, might be part of the explanation of the link.

Other data presented at the conference gave strength to evidence that diabetes in the older person is associated with an enhanced risk of decline in aspects of cognitive and executive function. The latter is the process that regulates the ability to organize thoughts and activities and to prioritize tasks. Such problems may not be picked up during routine medical consultations.  One of the current projects being performed by IDOP researchers is an evaluation of a simple and quick screening test for cognitive impairment.

Andrew J Krentz MD FRCP

Senior Research Fellow

IDOP