Diabetes and Heart Failure Theme

Background

Diabetes mellitus (DM) is a disease of epidemic proportions. Asia harbours 60% of the global DM population (4.7 billion) (PMID 27502121). Cardiovascular diseases (CVD) account for more than half the mortality and morbidity among patients with DM (WHO 2017). Our previous work from ASIAN-HF Registry revealed that Asian patients with heart failure are predisposed towards a unique lean-diabetic (diabetes in absence of high body mass index) (PMID 29584721). and lean-fat (low body mass index with abdominal obesity) (PMID 31550265) phenotypes. Together, these data suggested that visceral obesity could play a central role in cardiac pathology of lean diabetes. Epicardial fat tissue is the visceral fat distributed along the coronary arteries between the pericardium and the myocardium. Increase in epicardial fat is associated with both DM and CV disease.

Realising the dismal prognosis of lean diabetic patients with heart failure and the lack of proven therapies to improve their prognosis, the Asian Diabetes Outcome Prevention Trial (ADOPT) was launched. ADOPT is a multinational prospective trial, which aims to identify high-risk diabetic individuals (using elevated blood biomarker NT-proBNP levels) and intensify primary prevention to reduce future cardiovascular events. ADOPT is currently recruiting at 30 sites across Singapore, Malaysia, Taiwan, China, India and United Arab Emirates.

Leveraging on the various cores at NHCS and the data/samples collected from the ADOPT trial, we would like to gain further insights into diabetic HF through more detailed cardiometabolic imaging and mechanistic approaches, as detailed below:

1. To compare the differences in visceral fat distribution between high-risk DM patients and non-DM controls and correlate with changes in plasma metabolomics (Prof. Derek Hausenloy and Asst Prof Chrishan Ramachandra)
2. To use Hyperpolarized 13C MRI in high-risk DM patients with or without heart failure to elucidate the metabolic perturbations that predispose to developing heart failure (Asst Prof Calvin Chin)
3. To use hiPSC-derived cardiomyocytes from high-risk DM patients with or without heart failure to identify novel metabolic targets for preventing progression to heart failure (Dr. Jean-Paul Kovalik)
4. Data analytics on DM and heart using SingCLOUD and SingHeart (Asst Prof Jasper Tromp and Tay Wan Ting)
    

Research Area

Asian Diabetes Outcomes Prevention Trial (ADOPT) Among biomarker (N-terminal pro-B-type natriuretic peptide, NT-proBNP-identified high risk type 2 diabetic patients without pre-existing cardiovascular disease, to test if intensive preventive therapy (high dose renin-angiotensin-aldosterone system inhibitors [RAASi], beta-blockade, sodium-glucose co-transporter 2 inhibitors [SGLT2i]) may be associated with reduced cardiovascular events compared to standard of care. This investigator-initiated trial receives support from the National Medical Research Council of Singapore, philanthropic and industry partners

Highlighted in Singapore’s News & Top Stories: Asia-wide study on reducing chances of diabetes patients developing heart disease underway, Singapore News & Top Stories - The Straits Times

Press Coverage 

Links to key media interviews:

Carolyn Lam Expert discussion on latest update on cardiovascular outcome data in diabetes:
https://www.youtube.com/watch?v=C8OrAGyYdB4

Money89.3FM Interview of Carolyn Lam and Chanchal Chandramouli on Women, diabetes and cardiovascular diseases: https://www.moneyfm893.sg/guest/prof-carolyn-lam-and-dr-chanchal-chandramouli-national-heart-centre-singapore-nhcs/

CNA938 Interview of Carolyn Lam on ‘Discovery of skinny diabetics in Asian heart failure patients and launch of new multinational clinical trial’ Facebook link to interview extract here

Arresting Heart Disease In Diabetics by Chanchal Chandramouli, Murmurs 30th Oct 2020: https://www.nhcs.com.sg/news/research/arresting-heart-disease-in-diabetics

Channel 8 News Online featuring Dr. Yong Mong Bee on the Study Low-weight Asian diabetic patients with heart failure have higher mortality
https://www.8world.com/news/singapore/article/nhcs-heart-disease-1234166

Interview of David Sim on ‘Discovery of skinny diabetics in Asian heart failure patients and launch of new multinational clinical trial https://www.facebook.com/963haofm.anna/videos/364173054741324/

Achievements

Awards

2022 Carolyn Lam was recognized as Expertscape Expert in Obesity

2021 Carolyn Lam Clarivate’s Highly Cited Researcher 2021 in the category of Clinical Medicine https://recognition.webofscience.com/awards/highly-cited/2021/

2021 Chanchal Chandramouli won Young Investigator Award, Heart Failure Seoul for talk titled “Microvascular dysfunction in diabetic heart failure”

2021 Carolyn Lam recognized as a World Expert by Expertscape’s PubMed-based algorithms.Top 0.1% of scholars writing about Heart Failure over the past 10 years. Heart Failure: Worldwide - Expertscape.com

2021 Carolyn Lam - Worldwide CardioDiabetes Board Member, Worldwide Diabetes Foundation

2021 Chanchal Chandramouli - Worldwide CardioDiabetes Junior Board Member, Worldwide Diabetes Foundation

2020 Carolyn Lam Research Group won 2nd prize for SingHealth Duke-NUS Research Team Award 2020 - “Asian neTwork for Translation Research and Cardiovascular Trials (ATTRaCT program)

2019 Carolyn Lam won National Medical Research Council Clinician Scientist Award

2019 A*STAR Awards 2019: Borderless Award (ATTRaCT program; Program director: Carolyn Lam)

2019 Jin Xuanyi *won the Best Research Achievement Award at Heart Failure Seoul

2019 for excellence achieved in scientific session

2019 Dr Go Yun Yun won the “Singhealth Publish Award 2019”

2018 Chia May Fen Yvonne *won 2nd Prize in Singapore Cardiac Society Young Investigator Award

2018 Chanchal Chandramouli won the Early Career Researcher Award for the talk titled “Impact of obesity on heart failure outcomes” at HF Seoul

2018 Chanchal Chandramouli won travel grant of 955€ for European Society of Cardiology Heart Failure Congress

Grants

1. PROgram for Transforming & Evaluating outcomes in CardiomeTabolic disease (PROTECT) Diabetes & Heart Disease, Funding agency: NMRC Theme Leads: Carolyn Lam & Chanchal Chandramouli
2. A Collaborative CG Program - IMplementing a PArtnership for Cardiovascular Trials-2 (IMPACT-2), Asian Diabetes Outcome Prevention Trial Funding agency: NMRC Team Leaders: Asst Prof. Chanchal Chandramouli (NHCS) | Prof. Carolyn SP Lam (NHCS), Asst Prof Shir Lynn Lim (NUHCS) Loh Seet Yoong (NHGHI)
3. Arresting Heart Disease in Diabetics’ under the Singhealth Duke NUS Cardiovascular Sciences Academic Clinical Programme, Funding agency: Lee Foundation Principal Investigators: Chanchal Chandramouli & Carolyn Lam
4. Asian Diabetes Outcome Prevention Trial (ADOPT), Funding agency: NMRC CTG ICT Principal Investigator: Carolyn Lam
5. NMRC Clinician Scientist Award: Cardiovascular Clinical Trials in Asia: Asian Diabetes Outcomes Prevention Trial (ADOPT) Funding agency: NMRC Principal Investigator: Carolyn Lam
6. Cardiovascular Clinical Trials in Asia: Asian Diabetes Outcomes Prevention Trial (ADOPT), Funding partner: Roche Diagnostics Principal Investigator: Carolyn Lam
7. Centre of Excellence for Experimental Cardiovascular Trials, Bayer Principal Investigator Funding Agency: Bayer Principal Investigator: Carolyn Lam

Publications

1. Subodh Verma, Nitish K Dhingra, Javed Butler, Stefan D Anker, Joao Pedro Ferreira, Gerasimos Filippatos, James L Januzzi, Carolyn SP Lam, Naveed Sattar, Barbara Peil, Matias Nordaby, Martina Brueckmann, Stuart JPocock, Faiez Zannad Milton Packer. Empagliflozin in the treatment of heart failure with reduced ejection fraction in addition to background therapies and therapeutic combinations (EMPEROR-Reduced): a post-hoc analysis of a randomised, double-blind trial. Lancet Diabetes & Endocrinology. 2021 Nov 30;S2213-8587(21)00292-8. doi: 10.1016/S2213-8587(21)00292-8.
2. Carolyn SP Lam, Chinthanie Ramasundarahettige, Kelley R.H. Bran ch,Naveed Sattar, Julio Rosenstock, Richard Pratley, Stefano Del Prato, Renato D. Lopes, Elisabeth Niemoeller, Nardev S. Khurmi, Seungjae Baek, Hertzel C. Gerstein. Efpeglenatide and Clinical Outcomes with and without Concomitant Sodium-Glucose Co-Transporter-2 Inhibition Use in Type 2 Diabetes: Exploratory Analysis of the AMPLITUDE-O Trial. Circulation. November 2021.
3. Subodh Verma, Nitish K. Dhingra, Javed Butler, Stefan D. Anker, Joao Pedro Ferreira, Gerasimos Filippatos, James L. Januzzi, Carolyn SP Lam, Naveed Sattar, Barbara Peil, Matias Nordaby, Martina Brueckmann, Stuart J. Pocock, Faiez Zannad, and Milton Packer for the EMPEROR-Reduced Trial Committees and Investigators. Efficacy and Safety of Empagliflozin According to Doses and Combinations of Other Treatments for Heart Failure: A Post Hoc Analysis of the EMPEROR-Reduced Randomized Trial. The Lancet Diabetes & Endocrinology. November 2021
4. Jasper Tromp, Milton Packer, Carolyn SP Lam. The diverging role of epicardial adipose tissue in heart failure with reduced and preserved ejection fraction: not all fat is created equal. European Journal of Heart Failure. 2021 Oct 16. doi: 10.1002/ejhf.2363.
5. S.D. Anker, J. Butler, G. Filippatos, J.P. Ferreira, E. Bocchi, M. Böhm, H.-P. Brunner–La Rocca, D.-J. Choi, V. Chopra, E. Chuquiure-Valenzuela, N. Giannetti, J.E. Gomez-Mesa, S. Janssens, J.L. Januzzi, J.R. Gonzalez-Juanatey, B. Merkely, S.J. Nicholls, S.V. Perrone, I.L. Piña, P. Ponikowski, M. Senni, D. Sim, J. Spinar, I. Squire, S. Taddei, H. Tsutsui, S. Verma, D. Vinereanu, J. Zhang, P. Carson, Carolyn SP Lam, N. Marx, C. Zeller, N. Sattar, W. Jamal, S. Schnaidt, J.M. Schnee, M. Brueckmann, S.J. Pocock, F. Zannad, and M. Packer, for the EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. The New England Journal of Medicine. August 2021
6. Kamlesh Khunti, Mikhail Kosiborod, Dae Jung Kim, Shun Kohsaka, Carolyn SP Lam, Su-Yen Goh, Chern-En Chiang, Jonathan E Shaw, Matthew A Cavender, Navdeep Tangri, Josep Franch-Nadal, Reinhard W Holl, Marit E Jørgensen, Anna Norhammar, Johan G Eriksson, Francesco Zaccardi, Avraham Karasik, Dianna J Magliano, Marcus Thuresson, Hungta Chen, Eric Wittbrodt, Johan Bodegård, Filip Surmont, Peter Fenici. Cardiovascular Outcomes with Sodium-Glucose Cotransporter-2 Inhibitors vs Other Glucose-Lowering Drugs in 13 Countries Across Three Continents: Analysis of CVD-REAL Data. Cardiovascular Diabetology. 2021 Jul 31;20(1):159.
7. Naveed Sattar, Matthew M. Y. Lee, Søren L. Kristensen, Kelley Branch, Stefano Del Prato, Carolyn S P Lam, Renato D. Lopes, John J. V. McMurray, Richard Pratley, Julio Rosenstock, Hertzel C. Gerstein. Cardiovascular, mortality and kidney outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes – an updated systematic review and meta-analysis of randomised trials. The Lancet Diabetes & Endocrinology. July 2021.
8. Hertzel C. Gerstein, Naveed Sattar, Julio Rosenstock, Chinthanie Ramasundarahettige, Richard Pratley, Renato D. Lopes, Carolyn SP Lam, Nardev S. Khurmi, Laura Heenan, Stefano Del Prato, Leanne Dyal, Kelley Branch. Efpeglenatide, Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes. June 2021. New England Journal of Medicine. doi:10.1056/NEJMoa2108269
9. Shih-Chieh Chien, Chanchal Chandramouli, Chi-In Lo, Chao-Feng Lin, Kuo-Tzu Sung, Wen-Hung Huang, Yau-Huei Lai, Chun-Ho Yun, Cheng-Huang Su, Hung-I Yeh, Ta-Chuan Hung, Chung-Lieh Hung, Carolyn SP Lam. Associations of obesity and malnutrition with cardiac remodelling and cardiovascular outcomes in Asian adults: A cohort study. PLOS Medicine. May 2021
10. Gerasimos Filippatos, George L. Bakris, Bertram Pitt, Rajiv Agarwal, Peter Rossing, Luis M. Ruilope, Javed Butler, Carolyn SP Lam, Peter Kolkhof, Luke Roberts, Christoph Tasto, Amer Joseph, Stefan D. Anker on behalf of the FIDELIO-DKD Investigator. Finerenone Reduces New-Onset Atrial Fibrillation in Patients With Chronic Kidney Disease and Type 2 Diabetes. Journal of the American College of Cardiology. April 2021
11. Carolyn SP Lam, Avraham Karasik, Cheli Melzer-Cohen,,Matthew A. Cavender, Shun Kohsaka, Anna Norhammar, Marcus Thuresson, Hungta Chen, Eric Wittbrodt, Peter Fenici, Mikhail Kosiborod on behalf of the CVD-REAL Investigators and Study Group. Association of SGLT2 inhibitors with outcomes in Type 2 diabetes with reduced and preserved left ventricular ejection fraction — Analysis from the CVD-REAL 2 Study. Diabetes, Obesity and Metabolism. February 2021.
12. Hertzel C. Gerstein, Kelley Branch, Laura Heenan, Stefano Del Prato, Nardev Khurmi, Carolyn SP Lam, Richard Pratley, Julio Rosenstock, Naveed Sattar. Design and Baseline Characteristics of the AMPLITUDE-O Cardiovascular Outcome Trial of Efpeglenatide, a weekly glucagon-like peptide-1 receptor agonist. Diabetes Obesity and Metabolism (DOM). 2021 Feb;23(2):318-323. doi: 10.1111/dom.14223. Epub 2020 Oct 22
13. Stefan D. Anker, Javed Butler, Gerasimos Filippatos, Muhammad Shahzeb Khan, Nikolaus Marx, Carolyn SP Lam, Sven Schnaidt, Anne Pernille Ofstad, Martina Brueckmann, Waheed Jamal, Edimar Bocchi, Piotr Ponikowski, Sergio V. Perrone, James L. Januzzi, Subodh Verma, Michael Böhm, João Pedro Ferreira, Stuart J. Pocock, Faiez Zannad MD, Milton Packer, on behalf of the EMPEROR-Reduced Trial Committees and Investigators. Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status – Results from the EMPEROR-Reduced Trial. Circulation 2021
14. Chandramouli C, Tay WT, Bamadhaj NS, Tromp J, Teng TK, Yap JJL, MacDonald MR, Hung CL, Streng K, Naik A, Wander GS, Sawhney J, Ling LH, Richards AM, Anand I, Voors AA and Lam CSP. Association of obesity with heart failure outcomes in 11 Asian regions: A cohort study. PLoS medicine. 2019;16:e1002916.
15. Chandramouli C, Teng TK, Tay WT, Yap J, MacDonald MR, Tromp J, Yan L, Siswanto B, Reyes EB, Ngarmukos T, Yu CM, Hung CL, Anand I, Richards AM, Ling LH, Regensteiner JG and Lam CSP. Impact of diabetes and sex in heart failure with reduced ejection fraction patients from the ASIAN-HF registry. European journal of heart failure. 2019;21:297-307.
16. Chia YMF, Teng TK, Tay WT, Anand I, MacDonald MR, Yap J, Chandramouli C, Richards AM, Tromp J, Ouwerkerk W, Ling LH and Lam CSP. Prescription patterns of anti-diabetic medications and clinical outcomes in Asian patients with heart failure and diabetes mellitus. European journal of heart failure. 2019;21:685-688.
17. Chien SC, Chandramouli C, Lo CI, Lin CF, Sung KT, Huang WH, Lai YH, Yun CH, Su CH, Yeh HI, Hung TC, Hung CL and Lam CSP. Associations of obesity and malnutrition with cardiac remodeling and cardiovascular outcomes in Asian adults: A cohort study. PLoS medicine. 2021;18:e1003661.
18. Khunti K, Kosiborod M, Kim DJ, Kohsaka S, Lam CSP, Goh SY, Chiang CE, Shaw JE, Cavender MA, Tangri N, Franch-Nadal J, Holl RW, Jørgensen ME, Norhammar A, Eriksson JG, Zaccardi F, Karasik A, Magliano DJ, Thuresson M, Chen H, Wittbrodt E, Bodegård J, Surmont F and Fenici P. Cardiovascular outcomes with sodium-glucose cotransporter-2 inhibitors vs other glucose-lowering drugs in 13 countries across three continents: analysis of CVD-REAL data. Cardiovascular diabetology. 2021;20:159.
19. Lam CSP, Chandramouli C, Ahooja V and Verma S. SGLT-2 Inhibitors in Heart Failure: Current Management, Unmet Needs, and Therapeutic Prospects. Journal of the American Heart Association. 2019;8:e013389.
20. Lam CSP, Karasik A, Melzer-Cohen C, Cavender MA, Kohsaka S, Norhammar A, Thuresson M, Chen H, Wittbrodt E, Fenici P and Kosiborod M. Association of sodium-glucose cotransporter-2 inhibitors with outcomes in type 2 diabetes with reduced and preserved left ventricular ejection fraction: Analysis from the CVD-REAL 2 study. Diabetes, obesity & metabolism. 2021;23:1431-1435.
21. Tan ESJ, Tay WT, Teng TK, Richards AM, Doughty RN and Lam CSP. The diabetes-atrial fibrillation paradox. Heart (British Cardiac Society). 2019;105:893.
22. Tromp J, Lim SL, Tay WT, Teng TK, Chandramouli C, Ouwerkerk W, Wander GS, Sawhney JPS, Yap J, MacDonald MR, Ling LH, Sattar N, McMurray JJV, Richards AM, Anand I and Lam CSP. Microvascular Disease in Patients With Diabetes With Heart Failure and Reduced Ejection Versus Preserved Ejection Fraction. Diabetes care. 2019;42:1792-1799.
23. Yap J, Tay WT, Teng TK, Anand I, Richards AM, Ling LH, MacDonald MR, Chandramouli C, Tromp J, Siswanto BB, Zile M, McMurray J and Lam CSP. Association of Diabetes Mellitus on Cardiac Remodeling, Quality of Life, and Clinical Outcomes in Heart Failure With Reduced and Preserved Ejection Fraction. Journal of the American Heart Association. 2019;8:e013114.
24. Penna C, Andreadou I, Aragno M, Beauloye C, Bertrand L, Lazou A, Falcão-Pires I, Bell R, Zuurbier CJ, Pagliaro P, Hausenloy DJ. Effect of hyperglycaemia and diabetes on acute myocardial ischaemia-reperfusion injury and cardioprotection by ischaemic conditioning protocols. Br J Pharmacol. 2020 Dec;177(23):5312-5335. doi: 10.1111/bph.14993. Epub 2020 Mar 9.
25. Crisafulli A, Pagliaro P, Roberto S, Cugusi L, Mercuro G, Lazou A, Beauloye C, Bertrand L, Hausenloy DJ, Aragno M, Penna C. Diabetic Cardiomyopathy and Ischemic Heart Disease: Prevention and Therapy by Exercise and Conditioning. Int J Mol Sci. 2020 Apr 21;21(8):2896
26. Ying AF, Tang TY, Jin A, Chong TT, Hausenloy DJ, Koh WP. Diabetes and other vascular risk factors in association with the risk of lower extremity amputation in chronic limb-threatening ischemia: a prospective cohort study. Cardiovasc Diabetol. 2022 Jan 8;21(1):7.
27. Cong S, Ramachandra CJA, Mai Ja KM, Yap J, Shim W, Wei L, Hausenloy DJ. Mechanisms underlying diabetic cardiomyopathy: From pathophysiology to novel therapeutic targets. Cond Med. 2020 Apr;3(2):82-97. Epub 2020 May 5.
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29. Sia CH, Chan MH, Zheng H, Ko J, Ho AF, Chong J, Foo D, Foo LL, Lim PZ, Liew BW, Chai P, Yeo TC, Tan HC, Chua T, Chan MY, Tan JWC, Bulluck H, Hausenloy DJ. Optimal glucose, HbA1c, glucose-HbA1c ratio and stress-hyperglycaemia ratio cut-off values for predicting 1-year mortality in diabetic and non-diabetic acute myocardial infarction patients. Cardiovasc Diabetol. 2021 Oct 19;20(1):211.
30. Whittington HJ, Babu GG, Mocanu MM, Yellon DM, Hausenloy DJ. The diabetic heart: too sweet for its own good? Cardiol Res Pract. 2012;2012:845698. doi: 10.1155/2012/845698. Epub 2012 Feb 22
31. Chua J, Chee ML, Chin CWL, Tham YC, Tan N, Lim SH, Aung T, Cheng CY, Wong TY, Schmetterer L. Inter-relationship between ageing, body mass index, diabetes, systemic blood pressure and intraocular pressure in Asians: 6-year longitudinal study. Br J Ophthalmol. 2019 Feb;103(2):196-202. doi: 10.1136/bjophthalmol-2018-311897. Epub 2018 Apr 9.
32. Low S, Wang J, Moh A, Fen Ang S, Ang K, Shao YM, Ching J, Ning Wee H, Siang Lee L, Kovalik JP, Ee Tang W, Lim Z, Subramaniam T, Fang Sum C, Chi Lim S. Amino acid profile of skeletal muscle loss in type 2 diabetes: results from a 7-year longitudinal study in Asians. Diabetes Res Clin Pract. 2022 Feb 23:109803. doi: 10.1016/j.diabres.2022.109803. Epub ahead of print. PMID: 35218850.
33. Su L, Kong X, Loo SJ, Gao Y, Kovalik JP, Su X, Ma J, Ye L. Diabetic Endothelial Cells Differentiated From Patient iPSCs Show Dysregulated Glycine Homeostasis and Senescence Associated Phenotypes. Front Cell Dev Biol. 2021 May 31;9:667252.
34. Kovalik JP, Zhao X, Gao F, Leng S, Chow V, Chew H, Teo LLY, Tan RS, Ewe SH, Tan HC, Wee HN, Lee LS, Ching J, Keng BMH, Koh WP, Zhong L, Koh AS. Amino acid differences between diabetic older adults and non-diabetic older adults and their associations with cardiovascular function. J Mol Cell Cardiol. 2021 Sep;158:63-71.
35. Koh AS, Kovalik JP. Metabolomics and cardiovascular imaging: a combined approach for cardiovascular ageing. ESC Heart Fail. 2021 Jun;8(3):1738-1750. doi: 10.1002/ehf2.13274. Epub 2021 Mar 30.
36. Marton A, Kaneko T, Kovalik JP, Yasui A, Nishiyama A, Kitada K, Titze J. Organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation. Nat Rev Nephrol. 2021 Jan;17(1):65-77.
37. Gunther SH, Khoo CM, Tai ES, Sim X, Kovalik JP, Ching J, Lee JJ, van Dam RM. Serum acylcarnitines and amino acids and risk of type 2 diabetes in a multiethnic Asian population. BMJ Open Diabetes Res Care. 2020 Oct;8(1):e001315.
38. Chua J, Chee ML, Chin CWL, Tham YC, Tan N, Lim SH, Aung T, Cheng CY, Wong TY, Schmetterer L. Inter-relationship between ageing, body mass index, diabetes, systemic blood pressure and intraocular pressure in Asians: 6-year longitudinal study. Br J Ophthalmol. 2019 Feb;103(2):196-202.