When I lecture medical students in our Graduate Entry Medical College in Swansea, one of the few things they know about the thiazolidinedione class of antidiabetic agents is that ‘rosiglitazone causes death through heart attacks’. They will, therefore, be puzzled to have read recent reports from the United States that “certain restrictions on the diabetes drug rosiglitazone (Avandia) are being removed because a new analysis…has found no increase in myocardial infarction risk”(1). What is the story behind this apparent U-turn?
Archives for 2013
The subject of retirement generally raises the mood of doctors, however, news that five QoF indicators are about to be ‘retired’ for diabetes in 2014/15 is likely to cause dismay in primary care, especially since they will not be replaced with alternatives.
The recent annual meeting of the European Association for the Study of Diabetes (EASD) in Barcelona took place 15 years after it was last held there, that conference being remembered for the publication of the ground breaking results from the UKPDS study. Running from 1977 – 1991 with patients being followed for approximately 10 years, it changed the way in which Type 2 diabetes is now treated. It was the first large study to recruit patients with recently diagnosed diabetes and assign them into a conventional and intensive treatment arm – at a time when it was unclear whether glycaemic control was actually important and if so, what was the impact of specific treatments (Sulphonylureas, Metformin or insulin).
Over the relatively short time since their launch, the use of DPP 4 inhibitors has accelerated to the point that they are widely used in the treatment of Type 2 diabetes, often being used early in the treatment pathway. This is despite the lack of significant evidence about their cardiovascular impact and the fact that the diabetes world has only just digested the impact of the Rosiglitazone debacle. This lead to new FDA guidelines regarding the development of new drugs for diabetes and their being subjected to CV risk studies.
The massive debate over links between the use of incretin drugs (DPP-4 inhibitors and GLP-1RA injectables) and pancreas safety has, to this point, been based on anecdote, controversial science and retrospective cohort analyses. These are all prone to various forms of bias leading, in my view, to the correct analysis and advice from the Federal Drugs Administration, European Medicines Agency (and any other legitimate body that has issued comment) to continue current prescribing.
Whilst most health care professionals are increasingly adept at managing all aspects of diabetes, what is often overlooked is the fact that the patient lives with the condition 24/7, the majority of this time away from their diabetes team. Most of patients are able to manage their diabetes without a problem but for some, living with a long term condition can cause a variety of psychological problems which impact on their diabetes control as well as their quality of life. Whilst patient education and empowerment can help with coping strategies, for some patients, this is not enough and they need access to more professional psychological help. Indeed access to psychological therapies is a recommendation within the National Service Framework back in 2001. Following this, NICE guidance regarding the management of Type 1 diabetes highlighted the importance of psychological support.
The National Diabetes Inpatient Audit for England & Wales for 2012 hit the press at the end of June with the strapline of ‘shocking failings in hospital care’. Diabetes UK led with the finding that, in the five-day period of the audit in September 2012, over sixty people with diabetes developed diabetic ketoacidosis (DKA). Whilst this is clearly not good, at least it is understandable, given that concomitant illness is a common factor in the development of DKA (and presumably the inpatients were all unwell). More worrying to me were the high levels of hypoglycaemia (‘hypo’) since these would have been iatrogenic, that is, caused by excessive drug administration and/or lack of nutrition, and therefore, be attributable to hospital staff.
Whilst lifestyle changes are the cornerstone of diabetes treatment, pharmacological therapies are usually required, not just for glycaemic control but also for cardiovascular risk management. Although therapies are launched following evidence that they show benefit to a particular facet of diabetes management (often marginal), their use in the real world often throws up major issues. These have included the impact of thiazolidendiones on CV risk, bladder malignancy and fractures, the impact of drugs acting on the GLP-1 pathway and pancreatitis and the potential link between insulin glargine and cancer (eventually dispelled). These post marketing complications only serve to cause concern to both patients and clinicians.
Despite advances in insulin technology and the development of different regimens including multiple daily injections (MDI), there still remain a group of patients with Type 1 diabetes who pose significant management problems. Problems include erratic blood glucose readings, unpredictable and debilitating hypoglycaemia and issues with injection sites. For this group of patients, an insulin pump is an option.
The withdrawal of Rosiglitazone from European markets in 2010 followed on from a meta-analysis, which suggested it increased the risk of myocardial infarction in people with type 2 diabetes. A direct consequence of this event was the FDA requirement for placebo-controlled cardiovascular outcome studies for new diabetes therapies. For the incretin drugs alone, there are currently over 66,000 patients enrolled into these studies with the first due to report later this year.
The last 5 years have seen a huge increase in the number of new anti-diabetes agents reaching the market, from new insulins to novel injectable and oral agents However, given changes to drug regulation following the Rosiglitazone debacle and the current financial climate, there are signs that the conveyor belt of agents is either slowing or coming to a halt. The two latest ‘blockbusters’, Novos new insulin Degludec (Tresiba) and Astra Zeneca’s SGLT2 inhibitor Dapaglafozin (Forxiga) have had major issues achieving either approval or formulary status.
In 2007, the Food and Drugs Administration (FDA) requested that information about acute pancreatitis should be included in the product label for the GLP-1 receptor agonist, exenatide. This followed review of 30 post-marketing reports of pancreatitis in patients receiving this drug: in six patients symptoms had begun or worsened after a dose increase; twenty-one patients were admitted to hospital and in 22 cases symptoms improved after drug withdrawal. In three cases, symptoms recurred after exenatide was reintroduced. Another way of looking at the data would be to point out that 9/30 (30%) weren’t admitted to hospital and in only 17 cases (57%) was the serum amylase reported – not typical of a diagnosis of ‘pancreatitis’, in the UK at least. Most would also be very wary of ‘re-challenging’ their patients with a drug they felt was responsible for this serious condition.
The Diabetes UK Professional Conference was hosted in the Manchester Central Convention Complex on 13-15 March 2013. With over 3,000 pre-registered delegates, there can be no doubt that Diabetes UK has found a successful formula for its annual get-together. However, it did lead me to compare and contrast with the last time its forerunner, the British Diabetic Association (BDA) held the Medical and Scientific Section Meeting in the same city.
Treating hyperglycaemia used to be straightforward. In fact, until the late 1990s, the clinicians choice was limited to Metformin, sulphonylureas and human insulin. However, over the last 15 years, our increasing understanding of the pathophysiology of diabetes has lead to a plethora of new agents belonging to a variety of classes – with more in the pipeline. Whilst metformin is universally considered first line therapy, increasingly the issue has been what next?
All subjects with type 1 diabetes need insulin and, given the current lack of disease-modifying drugs, all patients with type 2 diabetes will eventually need insulin if they live long lives. The data supporting the use of the new ‘ultra-long’ acting insulin analogue degludec which are currently being considered by the regulatory authorities show a continued improvement in duration and variability of action but the well-known downsides of weight-gain and hypoglycaemia (albeit diminished) remain.