Skip to main content
SpringerLink
Log in

Clinical Phenotypes in Patients With Type 2 Diabetes Mellitus: Characteristics, Cardiovascular Outcomes and Treatment Strategies

  • Comorbidities of Hearth Failure (J. Tromp, Section Editor)
  • Published:
Current Heart Failure Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

With recent advances in the pharmacological management of type 2 diabetes mellitus (T2DM), there is a growing need to understand which patients optimally benefit from these novel therapies. Various clinical clustering methodologies have emerged that utilise data-agnostic strategies to categorise patients that have similar clinical characteristics and outcomes; broadly, this characterisation is termed phenotyping. In patients with T2DM, we aimed to describe patient characteristics from phenotype studies, their cardiovascular risk profiles and the impact of antihyperglycemic treatment.

Recent Findings

Numerous phenotypic studies have been undertaken that have utilised a combination of clinical, biochemical, imaging and genetic variables. Each of these has produced phenotypes that display a spectrum of cardiovascular risk. Studies that aimed to describe pathophysiological phenotypes generally identified five phenotypes: autoimmune phenotype, insulin-related phenotypes (including permutations of insulin deficiency and resistance), obesity phenotype, ageing phenotype, and a sex-related phenotype. Studies examining risk profiles have demonstrated that across such phenotypes there is a spectrum of risk for diabetic complications. Few studies have examined treatment effects across these phenotypes, and thus provide little insights towards making phenotype-guided treatment decisions

Summary

Clustering analyses in patients with T2DM have identified distinct phenotypes with unique risk profiles. Further studies are needed that harness the use of clinical, biochemical, imaging and genetic data to explore therapeutic heterogeneity and response to antihyperglycemic treatment across the spectrum of patient phenotypes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes research and clinical practice. 2019;157:107843.

  2. Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007–2017. Cardiovasc Diabetol. 2018;17(1):83.

    Article  Google Scholar 

  3. Rawshani A, Rawshani A, Franzén S, Eliasson B, Svensson A-M, Miftaraj M, et al. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med. 2017;376(15):1407–18.

    Article  Google Scholar 

  4. Lipscombe L, Butalia S, Dasgupta K, Eurich DT, MacCallum L, Shah BR, et al. Pharmacologic glycemic management of type 2 diabetes in adults: 2020 update. Can J Diabetes. 2020;44(7):575–91.

    Article  Google Scholar 

  5. Association AD. 10. Cardiovascular disease and risk management: standards of medical care in diabetes—2021. Diabetes Care. 2021;44(Supplement 1):S125-S50.

  6. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD). Eur Heart J. 2020;41(2):255–323.

    Article  Google Scholar 

  7. Food, Administration D. Guidance for industry: diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Food and Drug Administration, Center for Drug Evaluation and Research (CDER). 2008.

  8. Allan GM, Nouri F, Korownyk C, Kolber Michael R, Vandermeer B, McCormack J. Agreement among cardiovascular disease risk calculators. Circulation. 2013;127(19):1948–56.

    Article  Google Scholar 

  9. Kavakiotis I, Tsave O, Salifoglou A, Maglaveras N, Vlahavas I, Chouvarda I. Machine learning and data mining methods in diabetes research. Comput Struct Biotechnol J. 2017;15:104–16.

    Article  Google Scholar 

  10. Eshghi A, Haughton D, Legrand P, Skaletsky M, Woolford S. Identifying groups: a comparison of methodologies. Journal of Data Science. 2011;9(2):271–91.

    Article  Google Scholar 

  11. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet (London, England). 1998;352(9131):854–65.

  12. Gnesin F, Thuesen ACB, Kähler LKA, Madsbad S, Hemmingsen B. Metformin monotherapy for adults with type 2 diabetes mellitus. Cochrane Database of Systematic Reviews. 2020(6).

  13. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327–35.

    Article  CAS  Google Scholar 

  14. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26.

    Article  CAS  Google Scholar 

  15. Rosenstock J, Kahn SE, Johansen OE, Zinman B, Espeland MA, Woerle HJ, et al. Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial. JAMA. 2019;322(12):1155–66.

    Article  CAS  Google Scholar 

  16. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232–42.

    Article  CAS  Google Scholar 

  17. Hernandez AF, Green JB, Janmohamed S, D’Agostino RB Sr, Granger CB, Jones NP, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. The Lancet. 2018;392(10157):1519–29.

    Article  CAS  Google Scholar 

  18. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. The Lancet. 2019;394(10193):121–30.

    Article  CAS  Google Scholar 

  19. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22.

    Article  CAS  Google Scholar 

  20. Verma S, Poulter Neil R, Bhatt Deepak L, Bain Stephen C, Buse John B, Leiter Lawrence A, et al. Effects of liraglutide on cardiovascular outcomes in patients with type 2 diabetes mellitus with or without history of myocardial infarction or stroke. Circulation. 2018;138(25):2884–94.

    Article  CAS  Google Scholar 

  21. Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019;381(9):841–51.

    Article  CAS  Google Scholar 

  22. Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228–39.

    Article  CAS  Google Scholar 

  23. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–57.

    Article  CAS  Google Scholar 

  24. Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383(15):1425–35.

    Article  CAS  Google Scholar 

  25. McMurray JJ, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995–2008.

    Article  CAS  Google Scholar 

  26. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413–24.

    Article  CAS  Google Scholar 

  27. Ahlqvist E, Storm P, Käräjämäki A, Martinell M, Dorkhan M, Carlsson A, et al. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol. 2018;6(5):361–9.

    Article  Google Scholar 

  28. Tanabe H, Saito H, Kudo A, Machii N, Hirai H, Maimaituxun G, et al. Factors associated with risk of diabetic complications in novel cluster-based diabetes subgroups: a Japanese retrospective cohort study. J Clin Med. 2020;9(7):2083.

    Article  Google Scholar 

  29. Li L, Cheng W-Y, Glicksberg BS, Gottesman O, Tamler R, Chen R, et al. Identification of type 2 diabetes subgroups through topological analysis of patient similarity. Science translational medicine. 2015;7(311):311ra174–311ra174.

  30. Dennis JM, Shields BM, Henley WE, Jones AG, Hattersley AT. Disease progression and treatment response in data-driven subgroups of type 2 diabetes compared with models based on simple clinical features: an analysis using clinical trial data. Lancet Diabetes Endocrinol. 2019;7(6):442–51.

    Article  Google Scholar 

  31. Bello-Chavolla OY, Bahena-López JP, Vargas-Vázquez A, Antonio-Villa NE, Márquez-Salinas A, Fermín-Martínez CA, et al. Clinical characterization of data-driven diabetes subgroups in Mexicans using a reproducible machine learning approach. BMJ Open Diabetes Research and Care. 2020;8(1):e001550.

  32. Kahkoska AR, Geybels MS, Klein KR, Kreiner FF, Marx N, Nauck MA, et al. Validation of distinct type 2 diabetes clusters and their association with diabetes complications in the DEVOTE, LEADER and SUSTAIN-6 cardiovascular outcomes trials. Diabetes Obes Metab. 2020;22(9):1537–47.

    Article  CAS  Google Scholar 

  33. Zaharia OP, Strassburger K, Strom A, Bönhof GJ, Karusheva Y, Antoniou S, et al. Risk of diabetes-associated diseases in subgroups of patients with recent-onset diabetes: a 5-year follow-up study. Lancet Diabetes Endocrinol. 2019;7(9):684–94.

    Article  Google Scholar 

  34. Safai N, Ali A, Rossing P, Ridderstråle M. Stratification of type 2 diabetes based on routine clinical markers. Diabetes Res Clin Pract. 2018;141:275–83.

    Article  CAS  Google Scholar 

  35. Karpati T, Leventer-Roberts M, Feldman B, Cohen-Stavi C, Raz I, Balicer R. Patient clusters based on HbA1c trajectories: a step toward individualized medicine in type 2 diabetes. PLOS ONE. 2018;13(11):e0207096.

  36. Sharma A, Ofstad AP, Ahmad T, Zinman B, Zwiener I, Fitchett D, et al. Patient phenotypes and SGLT-2 inhibition in type 2 diabetes: insights from the EMPA-REG OUTCOME Trial. JACC: Heart Failure. 2021.

  37. Segar MW, Patel KV, Vaduganathan M, Caughey MC, Jaeger BC, Basit M, et al. Development and validation of optimal phenomapping methods to estimate long-term atherosclerotic cardiovascular disease risk in patients with type 2 diabetes. Diabetologia. 2021.

  38. Li P-F, Chen W-L. Are the different diabetes subgroups correlated with all-cause, cancer-related, and cardiovascular-related mortality? J Clin Endocrinol Metab. 2020;105(12):e4240–51.

    Article  Google Scholar 

  39. Jones AG, McDonald TJ, Shields BM, Hagopian W, Hattersley AT. Latent Autoimmune Diabetes of Adults (LADA) is likely to represent a mixed population of autoimmune (type 1) and nonautoimmune (type 2) diabetes. Diabetes Care. 2021.

  40. Anjana RM, Baskar V, Nair ATN, Jebarani S, Siddiqui MK, Pradeepa R, et al. Novel subgroups of type 2 diabetes and their association with microvascular outcomes in an Asian Indian population: a data-driven cluster analysis: the INSPIRED study. BMJ Open Diabetes Research and Care. 2020;8(1):e001506.

  41. Wagner R, Heni M, Tabák AG, Machann J, Schick F, Randrianarisoa E, et al. Pathophysiology-based subphenotyping of individuals at elevated risk for type 2 diabetes. Nat Med. 2021;27(1):49–57.

    Article  CAS  Google Scholar 

  42. Carrillo-Larco RM, Castillo-Cara M, Anza-Ramirez C, Bernabé-Ortiz A. Clusters of people with type 2 diabetes in the general population: unsupervised machine learning approach using national surveys in Latin America and the Caribbean. BMJ Open Diabetes Research and Care. 2021;9(1):e001889.

  43. Standl E, Stevens SR, Armstrong PW, Buse JB, Chan JCN, Green JB, et al. Increased risk of severe hypoglycemic events before and after cardiovascular outcomes in TECOS suggests an at-risk type 2 diabetes frail patient phenotype. Diabetes Care. 2018;41(3):596.

    Article  Google Scholar 

  44. Ernande L, Audureau E, Jellis Christine L, Bergerot C, Henegar C, Sawaki D, et al. Clinical Implications of echocardiographic phenotypes of patients with diabetes mellitus. J Am Coll Cardiol. 2017;70(14):1704–16.

    Article  Google Scholar 

  45. Sharma A, Zheng Y, Ezekowitz JA, Westerhout CM, Goodman SG, Armstrong PW, et al. 4348Cluster analysis of cardiovascular risk phenotypes in patients with type 2 diabetes and established atherosclerotic cardiovascular disease: a potential approach to precision medicine. European Heart Journal. 2018;39(suppl_1).

  46. Group AtCCRiDS. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545–59.

    Article  Google Scholar 

  47. Group AS. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575–85.

    Article  Google Scholar 

  48. Group AS. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1563–74.

    Article  Google Scholar 

  49. Group BDS. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009;360(24):2503–15.

    Article  Google Scholar 

  50. Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369(2):145–54.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Cardiology, University of Alberta, Edmonton, AB, Canada

    Pishoy Gouda & Justin Ezekowitz

  2. Department of Medicine, McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC, H4A3J1, Canada

    Sijia Zheng, Nadia Giannetti & Abhinav Sharma

  3. Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Montreal, QC, Canada

    Tricia Peters

  4. Division of Endocrinology, Department of Medicine, The Jewish General Hospital, McGill University, Montreal, QC, Canada

    Tricia Peters

  5. Department of Medicine, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA

    Marat Fudim & Renato Lopes

  6. Department of Cardiovascular Medicine, Kaufman Center for Heart Failure and Recovery, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA

    Varinder Kaur Randhawa

  7. Canadian VIGOUR Centre, Alberta, Canada

    Justin Ezekowitz

  8. Division of Nephrology, Department of Medicine, McGill University Health Centre and Research Institute, Montreal, Canada

    Thomas A. Mavrakanas

  9. Division of Endocrinology, McGill University Health Centre, Montreal, Canada

    Michael Tsoukas

Authors
  1. Pishoy Gouda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sijia Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tricia Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marat Fudim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Varinder Kaur Randhawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Justin Ezekowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Thomas A. Mavrakanas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nadia Giannetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michael Tsoukas
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Renato Lopes
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Abhinav Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Abhinav Sharma.

Ethics declarations

Conflict of Interest

PG, SZ, TP, VR, JE, NG and RL report no disclosures or conflicts of interest. MF has no disclosures to report in relation to this work but is supported by NHLBI K23HL151744 from the National Heart, Lung, and Blood Institute (NHLBI), the American Heart Association grant No 20IPA35310955, Mario Family Award, Duke Chair’s Award, Translating Duke Health Award, Bayer and BTG Specialty Pharmaceuticals. He receives consulting fees from Axon Therapies, Bodyport, CVRx, Daxor, Edwards LifeSciences, Fire1, NXT Biomedical, Zoll and VisCardia. MT reports no disclosures in relation to this work but has received speaker honoraria from NovoNordisk, Eli Lilly, Boehringer-Ingelheim and AstraZeneca. TAM has received honoraria from Daiichi Sankyo and Bristol Myers Squibb Canada outside the submitted work and salary support from the Department of Medicine at McGill University. AS reports receiving support from the Fonds de Recherche Santé Quebec (FRSQ) Junior 1 clinician scholars programme, Alberta Innovates Health Solution, European Society of Cardiology young investigator grant, Roche Diagnostics, Boehringer-Ingelheim, Novartis and Takeda.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Comorbidities of Heart Failure

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 26 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gouda, P., Zheng, S., Peters, T. et al. Clinical Phenotypes in Patients With Type 2 Diabetes Mellitus: Characteristics, Cardiovascular Outcomes and Treatment Strategies. Curr Heart Fail Rep 18, 253–263 (2021). https://doi.org/10.1007/s11897-021-00527-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11897-021-00527-w

Keywords

Search

Navigation