Rapid Responses to:

NEWS: Janice Hopkins Tanne Study indicates diabetes drug linked to cardiovascular death BMJ 2007; 334: 1073 [Full text]

Rapid Responses: Submit a response to this article

Rapid Responses published:

Glycaemic control is more myth than fact

Illtyd R Thomas   (30 May 2007)

Glitazones: Don't throw the baby out with the bath water.

Tahseen A Chowdhury   (30 May 2007)

Rosiglitazone: where do we stand?

Sujoy Ghosh, Damellington Road, Ayr, Ayrshire, KA6 6DX   (31 May 2007)

Glycaemic control is more myth than fact 30 May 2007
Illtyd R Thomas, GP SA1 5LF Send response to journal: Re: Glycaemic control is more myth than fact	Tight control of HbA1c levels has assumed great importance in diabetes management. It has been enshrined in the QOF (Quality and Outcomes Framework) of the New GP Contract as being an evidence based proposal. Multiple drugs are licenced on the understanding that they reduce HbA1c levels and that this is a good thing. So should it surprise us that a meta - analysis of trials of roisiglitazone shows a raised risk of myocardial infarction and an increase in cardiovascular deaths? (1) I think the evidence to support tight glylcaemic control in reducing complications of type 2 diabetes is poor. In fact the reduction in diabetes related endpoints, mortality and stroke from using metformin is not explicable on the basis of glycaemic control. This isn’t just my opinion, it is what was written in the original paper of UKPDS 34, which is still the paper I see quoted as showing that tight glycaemic control reduces diabetic complications. (2) Should you choose to review the data of UKPDS 33 which compared tight glycaemic control with sulphonylureas or insulin with conventional treatment you will see little benefit from tight control. (3) Tight control made no difference to absolute rates of angina, heart failure, stroke, renal failure, nor vitreous haemorrhage. Tight control reduced the risk of going blind in one eye, of suffering a fatal MI or of having an amputation by fewer than 1 per 1000 patient years, and then with no statistical significance. The outcomes which did show some clinical benefit were cataract extractions, retinal photocoagulation and non-fatal MI and all –cause mortality, that is if you can call absolute risk reductions of between 1 and 3 per 1000 patient years as being clinically relevant. Would you make the major lifestyle changes required by these two groups of treatment if after 10 years your largest single risk reduction was a 1 in 30 chance of not needing retinal photocoagulation? I wouldn’t. The wonder with drug licencing is that we continue to accept surrogate endpoints in trials to licence new treatments for conditions for which we already have treatments. Our patients deserve better than they are currently being offered by those who promote tight glycaemic control. Show me better data or accept that the control of blood glucose means metformin –anything else is merely for symptom control. References 1. Study links diabetes drug to heart deaths. BMJ 2007; 334: 1073 2. Effect of Intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854-865 3. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risks of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837- 853 Competing interests: I have co-authored with Adrian Edwards , Glyn Elwin and Rhys Williams a paper on explaining risk information over the internet to patients with diabetes. That project was funded by the BMJ group
Glitazones: Don't throw the baby out with the bath water. 30 May 2007
Tahseen A Chowdhury, Consultant in Diabetes The Royal London Hospital, London E1 1BB Send response to journal: Re: Glitazones: Don't throw the baby out with the bath water.	The recent report from and colleagues reporting excess myocardial infarctions in people with diabetes treated with rosiglitazone provides cause for concern for patients and their health professionals using such therapy [1]. Since their launch, the glitazones have a chequered history, with the first in class, troglitazone, being withdrawn prematurely due to hepatotoxicity. Excess heart failure has been noted in patients treated with glitazones, and more recently, further concerns have been raised about increased fracture risk [2]. The accompanying editorial in the New England Journal of Medicine, however, is overly critical of glitazones, and lacks balance [3]. An important point that should be emphasised is that the power of the meta- analysis to detect significant effects on the basis of 158 events is weak, and just a small number of events in either direction could have led to completely different results. Data was not specifically collected or independently confirmed, and patient level data was not analysed. It is also important to note a significantly greater number of men in the rosiglitazone treated group, compared to the non-rosiglitazone treated group, which may have further skewed the results. Exclusion of studies that did not report cardiovascular events may also be of importance as their inclusion may have changed the results. The conclusion that rosiglitazone leads to increased cardiovascular disease is not convincing based on the data presented, although it may be reasonable to surmise that glitazones are unlikely to afford significant protection against vascular disease. More convincing data will be provided large randomised studies looking at cardiovascular outcomes. One such study involving rosiglitazone is the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study [4]. This has randomised 4,458 patients with type 2 diabetes to rosiglitazone or metformin, with a primary end point of time to first CV hospitalisation or death, and is due to report in 2008. An interim analysis of the RECORD study data should be urgently undertaken to determine whether any similar trend in increase in cardiovascular disease is noted. A final point that should be made is that not all glitazones are the same. Rosiglitazone has for some time been noted to cause a mild elevation in LDL cholesterol, and indeed conversion from rosiglitazone to pioglitazone results in improved lipid profiles in diabetic subjects [5]. This may be due to the greater PPAR alpha agonist activity of pioglitazone compared to rosiglitazone, and hence a modest LDL and triglyceride lowering effect. Furthermore, a major cardiovascular outcomes study has been published using Pioglitazone in high risk diabetic patients, showing a 16% reduction in cardiovascular death [6]. Glitazones have been a major therapeutic advance in the therapy of type 2 diabetes, and a number of newer therapeutic options are becoming available in the treatment of type 2 diabetes. Whilst the presented data provide an important signal for patients and clinicians to continue careful pharmacovigilance with new drugs for diabetes, more robust data are required before assigning glitazones to the pharmaceutical dustbin. 1. Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med 2007 May 21; [Epub ahead of print]. 2. Hampton T. Diabetes drug tied to fractures in women. JAMA 2007; 297: 1645. 3. Psaty BM, Furberg CD. Rosiglitazone and Cardiovascular Risk. N Engl J Med 2007 May 21. [Epub ahead of print]. 4. Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Dargie H, Komadja M, Gubb J, Biswas N, Jones NP. Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD): study design and protocol. Diabetologia. 2005; 48: 1726-35. 5. Berhanu P, Kipnes MS, Khan MA, Perez AT, Kupfer SA, Spanheimer RC, Demissie S, Fleck PR. Effects of pioglitazone on lipid and lipoprotein profiles in patients with type 2 diabetes and dyslipidaemia after treatment conversion from rosiglitazone while continuing stable statin therapy. Diab Vasc Dis Res 2006; 3: 39-44. 6. Dormandy JA, Charbonnel B, Eckland DJ. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (Prospective Pioglitazone Clinical Trial in Macrovascular Events): a randomised controlled trial. Lancet 2005; 366: 1279-89. Competing interests: None declared
Rosiglitazone: where do we stand? 31 May 2007
Sujoy Ghosh, Clinical Teaching & Clinical Research Fellow The Ayr Hospital, Damellington Road, Ayr, Ayrshire, KA6 6DX Send response to journal: Re: Rosiglitazone: where do we stand?	Dr. Sujoy Ghosh* ,Dr. Nabanita Bose, Dr. Andrew Collier, Dr. Iqbal Malik The Ayr Hospital, Ayr, Ayrshire, Scotland, United Kingdom * Corresponding author. E-mail: drsujoyghosh@rediffmail.com We have read with interest the news article suggesting possible raised myocardial infarction and increased cardiovascular deaths in type 2 diabetes patients treated with rosiglitazone.[1-3] It was only recently that another glitazone/glitazar (Muraglitazar) was found to increase the risk of cardiovascular events (MI/Stroke/TIA).[4] In a prospective randomised trial pioglitazone (PROACTIVE) showed reduction of cardiovascular events.[5] This could be due to its more favourable effects on lipids. We observe that in the meta-analysis 15,560 patients were randomly assigned to a regimen that included rosiglitazone while 12,283 were not given rosiglitazone (control). There were 86 cases of MI and 39 deaths from cardiovascular diseases in the rosiglitazone group compared to 72 cases of MI and 22 deaths from cardiovascular diseases in the control group. It was on the basis of these differences that the authors concluded that rosiglitazone increases the risk of MI and deaths from cardiovascular diseases. The results, if true would be cause for great concerns. What could be the possible underlying mechanism for the apparent effect? The reasons are unclear. Could it be because of effects of rosiglitazone on serum lipids (particularly LDL-cholesterol)? In addition it produces a modest reduction of haemoglobin levels and is know to precipitate congestive cardiac failure in susceptible patients. The authors admit that the study had several flaws. The analysis was based on limited access to trial results from publicly available sources and not on patient-level source data. In addition a relatively small number of events occurred. Hence even random small changes in the number of events could result in alteration of the statistical analysis. The studies analysed included some small studies as well as short term trials that were not originally intended to explore cardiovascular outcomes. However the results would suggest ruling out of any possible cardio- protective effect of rosiglitazone. The ongoing Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes (RECORD) trial may provide useful insight into the cardiovascular effects of Rosiglitazone. So where do we stand right now? What advice do we give our patients? We would agree with the Diabetes UK statement: "Glitazones are not presently recommended for people who have had, or who are at high risk of having, heart failure……….. Any suggested link into an increased risk of stroke and death from cardiovascular complications for people taking rosiglitazone needs much more research.”[6] REFERENCES [1] Tanne JH. Study indicates diabetes drug linked to cardiovascular death. BMJ. 2007 May 26;334 (7603):1073 [2] Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med. (doi: 10.1056/NEJMoa072761) [3] Psaty BM, Furberg CD. Rosiglitazone and Cardiovascular Risk. N Engl J Med (doi: 10.1056/NEJMe078099) [4] Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005 Nov 23;294(20):2581-6. [5] Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J; PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005 Oct 8;366 (9493):1279-89. [6] Rosiglitazone heart attack risk “not cause for alarm”. Diabetes UK. 22 May 2007 (News: Press enquires). http://www.diabetes.org.uk/About_us/News_Landing_Page/Rosiglitazone-heart- attack-risk-not-cause-for-alarm/ (last accessed 31st May 2007) Competing interests: None declared