Editorial

Stratifying Risk using a Bio-marker in Patients with Type-2 Diabetes Mellitus

A Component of the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF) Programme

Professor John GF Cleland

Hull York Medical School, University of Hull

Kingston-upon-Hull. UK

The research has received funding from the European Union Seventh Framework Programme [FP7/2007-2011] under grant agreement n° 241558 (SICA-HF) and from the Russian Ministry of Science and Education within the FTP "R&D in priority fields of the S&T complex of Russia 2007-2012 under state contract n° 02.527.11.0007.

Recent clinical trials show that the risk of a patient with Type-2 Diabetes Mellitus (T2DM) dying is about 1% per year and the risk of death or a major cardiovascular problem is about 2% per year. Most clinical trials operate within a 5-year time-horizon and therefore most patients with T2DM (~90%) do not develop serious cardiac problems. Problems that don’t happen cannot be prevented! There are at least three main responses to the above:-

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1. Acceptance. Patients and investigators could accept that the patients have only a small chance of developing problems in the next 5 years and be content with existing management. In this case, further research may be futile.  
2. Increase the study size. A popular choice that is expensive and produced little scientific reward. Although increasing the number of patients increases the number of events, this ‘blunder-buss’ approach accumulates large numbers of patients at low risk. All patients are at risk of adverse effects from intervention but only those who have or were going to develop a problem can profit from a beneficial effect. Also, if an intervention does require a large number of patients to show benefit it is highly unlikely to be cost-effective. There is an argument that no study investigating the efficacy of a longer-term intervention should enrol >5,000 patients as, if a larger study is required, the effect will be so small as to be of little value and not cost-effective. For short-term interventions and safety studies, larger numbers may be required.
3. Increase the time-horizon. Many will point out that the medium-term prognosis may be good but that events might accelerate if the duration of the trial were increased to 10-15 years. In an ideal world, this would be the most relevant and important approach to the problem. However, running trials of this duration presents major logistical problems and there is little incentive either for investigators or industry to conduct very long-term trials in the current regulatory environment. Long patent extensions would be required to ensure return on investment should a trial be positive.
4. Stratify patients according to risk. This could be done clinically, using simple markers such as age, previous medical history or renal dysfunction, but these measures may either be too restrictive or too crude to be optimal. Other bio-markers could be a useful alternative or additional approach.

We have investigated the ability of a plasma marker of cardio-renal stress, amino-terminal pro-brain natriuretic peptide (NT-proBNP) to identify the risk of death or cardiovascular events in patients more than 1,000 patients aged >40 years with T2DM requiring pharmacological intervention to improve glycaemia. Patients with pre-existing heart failure or a recent major cardiovascular or surgical event were excluded. The median age of patients was 65 (IQR: 58-72) years and 469 (42%) were women. About 70% of patients had a plasma NT-proBNP concentration <125ng/L (the threshold proposed by the European Society of Cardiology below which a diagnosis of heart failure is highly unlikely) – Figure 1. Increases in NT-proBNP were most often associated with left atrial dilatation (LA Dil) Figure 2 and less frequently with left ventricular systolic dysfunction (LVSD), atrial fibrillation (AF) or renal dysfunction (eGFR). For those with an NT-proBNP <125ng/L, mortality was <1% and the risk of death or hospitalisation ~2.5% at one year. However, in those with an NT-proBNP >250ng/L mortality was >7% and risk of death or hospitalisation almost 20%.

This research highlights the potential role of bio-markers not only for the identification of risk but for the identification of patients with unmet needs who may benefit from more aggressive or innovative therapy and participation in research programmes.