Research

Professor Avijit Lahiri

Director, British Cardiac Research Trust, Wellington Hospital, and the Middlesex University & Imperial College, London, UK.

In 2003 WHO predicted that the world diabetes burden would increase a figure of 196 million to 390 million by year 2035; however the burden of diabetes increased at a phenomenal rate, and the recent WHO survey in 2013 suggests that there are already 382 million people with diabetes; by 2035 this is predicted to rise to a colossal figure of about 600 million.

The number of people with type 2 diabetes is increasing in every country, 80% of people with diabetes live in low- and middle-income countries. The greatest number of people with diabetes is between 40 and 59 years of age.

There are 3 million diabetics in UK (2013, 85% – Type 2 Diabetes), 850,000 are undiagnosed, it is predicted that there will be 5 million diabetics by 2025 in the UK, and 10% of the United Kingdom NHS budget (£9 Billion GBP) is spent for the management of this disease. I feel that these are underestimates of the true problem, as seen worldwide.

It is thought that approximately as much as 30% of the population of India and China either have diabetes or are pre-diabetic conditions, the figures rise to 42% in the Middle East!

Cardiovascular disease (CVD) accounts for approximately 70% of all deaths in diabetics, and 25% of all patients hospitalised with acute heart disease and heart attacks suffer from diabetes (from the GRACE registry). Diabetes causes rapid ‘ageing’ of the blood vessels, and is responsible for heart attacks, strokes, blindness, kidney failure and gangrene amongst other complications. Furthermore, the vascular diseases progresses rapidly when present.

According to WHO, cardiovascular disease is commonest cause of death worldwide. Cardiovascular death is considerable higher than cancer, infections (eg. TB & HIV), starvation, war and natural disasters!

Risk factor evaluation programs (eg. Framingham Risk Score or UK-PDS) underestimates risk of heart disease in type 2 diabetics by as much as 32%.

Diabetic heart disease is mostly ‘silent’, the diagnosis of heart disease in these patients are often missed by standard tests, and therefore these patients either present with unheralded heart attacks or attend at a late stage with very advanced heart disease.

There is a clear cut need for the development of comprehensive protocols to assess heart disease risk in diabetic patients at an early stage.

The Wellington Diabetes Trial– 2003-2008 (funded by British Cardiac Research Trust): We have used a novel protocol combining biomarkers and CT technology for the first time to evaluate underlying coronary artery disease (Ref 1). The trial was very successful in identifying early and silent heart disease. The data has influenced the American Heart Association, the European Society of Cardiology and recently the European Diabetic Society to recommend more advanced testing in high risk diabetic patients. The scientific publications from this trial (Ref 1-5) have been widely quoted and data were presented at multiple national and international meetings.

The PROCEED Trial was developed to test a comprehensive ‘model’ to detect early (Phase1) and progression (Phase2) of heart disease in Type 2 diabetic patients.

The trial methods include the combination of various tests which reflect different disease processes: Phase1– baseline assessment of ‘silent’ disease

1) 92 novel biomarkers
2) vascular imaging using carotid ultrasound
3) EndoPat measurement of vascular endothelial function
4) Strain-gage Echocardiography for cardiac function measurement
5) Ultra-fast CT for coronary artery calcium imaging
6) Ultra-fast Dual source CT angiography for coronary artery imaging
7) Risk factor assessment
8) Myocardial SPECT (nuclear SPECT) analysis in selected patients
9) Phase 2 (Progression phase): Follow up investigations repeated at 18 months
10) Statistical “modelling” for predicting risk of heart disease and progression of disease in diabetic patients

Joint projects: With Prof Jan Nilsson (Malmo University, Sweden) and Prof Prediman Kishor Shah (Cedars Sinai Hospital and UCLA, LA, USA)

Measurement 92 novel biomarkers will be performed in the University of Malmo (Prof Jan Nilsson). An exciting development is the development of the cardio-vaccine (vaccine against coronary atherosclerosis- CardioVax) by Prof Shah and Prof Nilsson. Since diabetes forms a large proportion of heart disease patients, joint studies will be carried out with these institutions from the blood samples and imaging data from the PROCEED trial based on previous research between our groups (Ref 6,7).

The Phase 1 of the PROCEED trial was completed in July 2014. The PROCEED trial is funded by the British Cardiac Research Trust (UK Charity). Generous grants from our supporters have made it possible to carry out this large and complex trial.

260 patients with Type 2 diabetes (T2-d) without prior symptoms or signs of heart disease were recruited by our research nurses from 4 NHS Clinics in Northwest London. The patients were investigated at the Cardiac Imaging and Research Centre at the Wellington Hospital, St John’s Wood, London.

Interim analysis:

The preliminary results so far have been exciting.

80% of patients have shown evidence of ‘silent’ coronary heart disease

10% patients had such severe ‘silent’ heart disease (coronary calcium score >1000 Au) that they could not be included in the trial and were referred for urgent intervention.

7% of the remaining patients required urgent angioplasty (PTCA + stent) or coronary bypass surgery, based on the CT angiography and nuclear SPECT studies in the absence of symptomatic disease. These patients had no symptoms or signs of heart disease and were at extremely high risk of sudden death or heart attack.

18% of CT angiographic coronary artery segments showed > 70% stenosis (narrowing)

46% had carotid plaque disease

The interim findings of the PROCEED Phase1 are very exciting. There is considerable work involved in Phase2, which has now begun in earnest.

Blood samples will be analysed in 2 batches for phases 1 and 2.

A follow-up questionnaire will used to accumulate serious event rate in the patients.

We have benefited from the CardioVax program, since significant grants have been awarded by the EU and the Swedish Cardiac Society for the ‘vaccine’ program and Prof Nilsson will subsidise our costs.

Diabetes is evolving as a worldwide epidemic, the developing countries in Asia and Africa appear to be affected most of all. The economic burden of diabetes and heart disease is likely be extremely high in terms of medical cost and also ‘lost’ work time (Ref 8). The multisystemic effect of diabetes is already responsible for the other factors- such as the commonest cause blindness and the kidney transplantation amongst other complications.

A huge effort is required at an International and Governmental level to fight the ‘tsunami’ of diabetes and its associated cardiovascular disease.

References:

1) Anand V, Lim E, Hopkins D, Corder R, Shaw L, Sharp P, Lipkin D, Lahiri A. Risk stratification in uncomplicated type 2 diabetes: Prospective evaluation of the combined use of coronary artery calcium imaging and selective myocardial perfusion scintigraphy. European Heart Journal 2006; 27, 713-721.

2) Lahiri A, Lim E, Anand V. Diabetes: the looming economic disaster. The Contemporary Manager 2005; 10 (2), 1-3.

3) Anand V, Lim E, Hopkins D, Corder R, Lipkin D, Lahiri A. The relationship between plasma osteoprotegerin levels and coronary artery calcification in complicated type 2 diabetic subjects. Journal of American College of Cardiology 2006; 47; 9,1850-57.

4) Jain P, Lahiri A. Metabolic Syndrome: An Evolving Threat in the Genesis of Coronary Artery Disease. Journal of the CrdioMetabolic Syndrome 2007; Vol 2(3) 190-197.

5) Anand V, Lim E, Darko D, Bassett P, Hopkins D, Lipkin D, Corder R, Lahiri A. Determinants of progression of coronary artery calcification in Type 2 diabetes: Role of glycaemic control and inflammatory/vascular calcification markers. Journal of American College of Cardiology 2007 50(23); 2218-2225.

6) Fredrikson GN, Anand V, Hopkins D, Corder R, Alm RR, Bengtsson E, Shah PK, Lahiri A, Nilsson J. Associations between autoantibodies against apo B-100 peptides and vascular complications in patients with type 2 diabetes. Diabetologia 2009; 52; 1426-1433.

7) Engelbertsen D, Anand D, Fredrikson G, Hopkins D, Corder R, Shah P, Lahiri A, Nilsson J, Bengtsson E. High levels of IgM against methylglyoxal-modified apolipoprotein B100 are associated with less coronary artery calcification in patients with type 2 diabetes High levels of IgM against methylglyoxal-modified apolipoprotein B100. Journal of Internal Medicine, DOI: 10.1111/j.1365-2796.2011.02411.

8) Andrew Steptoe, Mark Hamer, Katie O’Donnell, Venuraju SM, Michael G Marmot, Avijit Lahiri. Socioeconomic status and subclinical coronary disease in the Whitehall II Epidemiological Study. PloS One; 2010; Vol 5; Issue 1.