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Cardiorenal diseases in type 2 diabetes mellitus: clinical trials and real-world practice

Abstract

Patients with type 2 diabetes mellitus (T2DM) can have multiple comorbidities and premature mortality due to atherosclerotic cardiovascular disease, hospitalization with heart failure and/or chronic kidney disease. Traditional drugs that lower glucose, such as metformin, or that treat high blood pressure and blood levels of lipids, such as renin–angiotensin-system inhibitors and statins, have organ-protective effects in patients with T2DM. Amongst patients with T2DM treated with these traditional drugs, randomized clinical trials have confirmed the additional cardiorenal benefits of sodium–glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1RA) and nonsteroidal mineralocorticoid receptor antagonists. The cardiorenal benefits of SGLT2i extended to patients with heart failure and/or chronic kidney disease without T2DM, whereas incretin-based therapy (such as GLP1RA) reduced cardiovascular events in patients with obesity and T2DM. However, considerable care gaps exist owing to insufficient detection, therapeutic inertia and poor adherence to these life-saving medications. In this Review, we discuss the complex interconnections of cardiorenal–metabolic diseases and strategies to implement evidence-based practice. Furthermore, we consider the need to conduct clinical trials combined with registers in specific patient segments to evaluate existing and emerging therapies to address unmet needs in T2DM.

Key points

  • In patients with type 2 diabetes mellitus (T2DM), improved risk factor control and the use of renin–angiotensin system inhibitors and statins have reduced the incidence of cardiovascular-renal events and related deaths.

  • Despite these improvements, cardiovascular and/or renal events and related death in patients with T2DM remain higher than in patients without T2DM.

  • Among patients with newly diagnosed or short duration of T2DM, early intensive glycaemic control to achieve near-normal blood levels of glucose might offer potential legacy effects on cardiovascular outcomes.

  • Sodium–glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists are preferred to prevent cardiovascular and/or renal complications and related death among patients with T2DM at high cardiorenal risk.

  • Multi-stakeholder engagement is needed to combine research and practice to close treatment gaps in guideline-directed medical therapy among patients at high cardiorenal risk through care re-organization with ongoing benchmarking.

  • Future research should address data gaps in risk stratification for cardiorenal complications, while clinical trials are required in women and patients with T2DM who are young or at low cardiorenal risk to address unmet needs.

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Fig. 1: Interlinked pathways to cardiorenal diseases in patients with T2DM.
Fig. 2: Combining research and practice to create a learning health-care system in T2DM management.

References

  1. International Diabetes Federation. IDF Diabetes Atlas 10th edn (IDF, 2021).

  2. Franks, P. W. & Poveda, A. Lifestyle and precision diabetes medicine: will genomics help optimise the prediction, prevention and treatment of type 2 diabetes through lifestyle therapy? Diabetologia 60, 784–792 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Chan, J. C. N. et al. The Lancet Commission on Diabetes: using data to transform diabetes care and patient lives. Lancet 396, 2019–2082 (2021).

    Article  PubMed  Google Scholar 

  4. GBD 2019 Risk Factors Collaborators. Global burden of 87 risk factors in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 396, 1223–1249 (2020).

    Article  Google Scholar 

  5. Magliano, D. J. et al. Trends in incidence of total or type 2 diabetes: systematic review. BMJ 366, l5003 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  6. American Diabetes Association. Economic costs of diabetes in the U.S. in 2017. Diabetes Care 41, 917–928 (2018).

    Article  PubMed Central  Google Scholar 

  7. Magliano, D. J., Martin, V. J., Owen, A. J., Zomer, E. & Liew, D. The productivity burden of diabetes at a population level. Diabetes Care 41, 979–984 (2018).

    Article  PubMed  Google Scholar 

  8. Gregg, E. W., Hora, I. & Benoit, S. R. Resurgence in diabetes-related complications. JAMA 321, 1867–1868 (2019).

    Article  PubMed  Google Scholar 

  9. Rossing, P. et al. Executive summary of the KDIGO 2022 clinical practice guideline for diabetes management in chronic kidney disease: an update based on rapidly emerging new evidence. Kidney Int. 102, 990–999 (2022).

    Article  PubMed  Google Scholar 

  10. Draznin, B. et al. 4. Comprehensive medical evaluation and assessment of comorbidities: standards of medical care in diabetes-2022. Diabetes Care 45, S46–S59 (2022).

    Article  PubMed  Google Scholar 

  11. Flegal, K. M., Kit, B. K., Orpana, H. & Graubard, B. I. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA 309, 71–82 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kim, Y. H. et al. Underweight increases the risk of end-stage renal diseases for type 2 diabetes in Korean population: data from the national health insurance service health checkups 2009–2017. Diabetes Care 43, 1118–1125 (2020).

    Article  CAS  PubMed  Google Scholar 

  13. Yokomichi, H. et al. All-cause and cardiovascular disease mortality in underweight patients with diabetic nephropathy: BioBank Japan cohort. J. Diabetes Investig. 12, 1425–1429 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Di Angelantonio, E. et al. Association of cardiometabolic multimorbidity with mortality. JAMA 314, 52–60 (2015).

    Article  PubMed  Google Scholar 

  15. Magliano, D. J. et al. Trends in all-cause mortality among people with diagnosed diabetes in high-income settings: a multicountry analysis of aggregate data. Lancet Diabetes Endocrinol. 10, 112–119 (2022).

    Article  PubMed  Google Scholar 

  16. Harding, J. L., Pavkov, M. E., Gregg, E. W. & Burrows, N. R. Trends of nontraumatic lower-extremity amputation in end-stage renal disease and diabetes: United States, 2000–2015. Diabetes Care 42, 1430–1435 (2019).

    Article  PubMed  Google Scholar 

  17. Ling, W. et al. Global trend of diabetes mortality attributed to vascular complications, 2000–2016. Cardiovasc. Diabetol. 19, 182 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wu, H. et al. Trends in diabetes-related complications in Hong Kong, 2001–2016: a retrospective cohort study. Cardiovasc. Diabetol. 19, 60 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Ali, M. K., Pearson-Stuttard, J., Selvin, E. & Gregg, E. W. Interpreting global trends in type 2 diabetes complications and mortality. Diabetologia 65, 3–13 (2022).

    Article  PubMed  Google Scholar 

  20. Rawshani, A. et al. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 379, 633–644 (2018).

    Article  PubMed  Google Scholar 

  21. Wu, H. et al. Secular trends in all-cause and cause-specific mortality rates in people with diabetes in Hong Kong, 2001-2016: a retrospective cohort study. Diabetologia 63, 757–766 (2020).

    Article  CAS  PubMed  Google Scholar 

  22. Norhammar, A. et al. Cost of healthcare utilization associated with incident cardiovascular and renal disease in individuals with type 2 diabetes: a multinational, observational study across 12 countries. Diabetes Obes. Metab. 24, 1277–1287 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ahlqvist, E. et al. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol. 6, 361–369 (2018).

    Article  PubMed  Google Scholar 

  24. Xiong, X. F. et al. Identification of two novel subgroups in patients with diabetes mellitus and their association with clinical outcomes: a two-step cluster analysis. J. Diabetes Investig. 12, 1346–1358 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Grundy, S. M. et al. Diabetes and cardiovascular disease. Circulation 100, 1134–1146 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Kannel, W. B. & McGee, D. L. Diabetes and cardiovascular disease. the Framingham study. JAMA 241, 2035–2038 (1979).

    Article  CAS  PubMed  Google Scholar 

  27. American Diabetes Association Professional Practice Committee. 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2022. Diabetes Care 45, S144–s174 (2022).

    Article  Google Scholar 

  28. Poznyak, A. et al. The diabetes mellitus–atherosclerosis connection: the role of lipid and glucose metabolism and chronic inflammation. Int. J. Mol. Sci. 21, 1835 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Creager, M. A., LüScher, T. F., Cosentino, F. & Beckman, J. A. Diabetes and vascular disease. Circulation 108, 1527–1532 (2003).

    Article  PubMed  Google Scholar 

  30. Giugliano, D., Maiorino, M. I., Bellastella, G. & Esposito, K. The residual cardiorenal risk in type 2 diabetes. Cardiovasc. Diabetol. 20, 36 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Giugliano, D., Maiorino, M. I., Bellastella, G. & Esposito, K. Glycemic control in type 2 diabetes: from medication nonadherence to residual vascular risk. Endocrine 61, 23–27 (2018).

    Article  CAS  PubMed  Google Scholar 

  32. Zinman, B. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373, 2117–2128 (2015).

    Article  CAS  PubMed  Google Scholar 

  33. Wiviott, S. D. et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 380, 347–357 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Neal, B. et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N. Engl. J. Med. 377, 644–657 (2017).

    Article  CAS  PubMed  Google Scholar 

  35. Cherney, D. Z., Kanbay, M. & Lovshin, J. A. Renal physiology of glucose handling and therapeutic implications. Nephrol. Dial. Transplant. 35 (Suppl. 1), i3–i12 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kashiwagi, A. & Maegawa, H. Metabolic and hemodynamic effects of sodium-dependent glucose cotransporter 2 inhibitors on cardio-renal protection in the treatment of patients with type 2 diabetes mellitus. J. Diabetes Investig. 8, 416–427 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Thomas, M. C. & Cherney, D. Z. I. The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure. Diabetologia 61, 2098–2107 (2018).

    Article  CAS  PubMed  Google Scholar 

  38. Inzucchi, S. E. et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care 41, 356–363 (2018).

    Article  CAS  PubMed  Google Scholar 

  39. Hilton, P. J. Na+ transport in hypertension. Diabetes Care 14, 233–239 (1991).

    Article  CAS  PubMed  Google Scholar 

  40. Ferrannini, E. et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J. Clin. Invest. 124, 499–508 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tomita, I. et al. SGLT2 inhibition mediates protection from diabetic kidney disease by promoting ketone body-induced mTORC1 inhibition. Cell Metab. 32, 404–419.e6 (2020).

    Article  CAS  PubMed  Google Scholar 

  42. Rosenstock, J. & Ferrannini, E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 38, 1638–1642 (2015).

    Article  CAS  PubMed  Google Scholar 

  43. Drucker, D. J. The cardiovascular biology of glucagon-like peptide-1. Cell Metab. 24, 15–30 (2016).

    Article  CAS  PubMed  Google Scholar 

  44. Burgmaier, M. et al. Glucagon-like peptide-1 (GLP-1) and its split products GLP-1(9-37) and GLP-1(28-37) stabilize atherosclerotic lesions in apoe-/- mice. Atherosclerosis 231, 427–435 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Nyström, T. et al. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am. J. Physiol. Endocrinol. Metab. 287, E1209–1215 (2004).

    Article  PubMed  Google Scholar 

  46. Sattar, N. et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 9, 653–662 (2021).

    Article  CAS  PubMed  Google Scholar 

  47. Joseph, J. J. et al. Comprehensive management of cardiovascular risk factors for adults with type 2 diabetes: a scientific statement from the American Heart Association. Circulation 145, e722–e759 (2022).

    Article  PubMed  Google Scholar 

  48. Emdin, C. A. et al. Blood pressure lowering in type 2 diabetes. A systematic review and meta-analysis. JAMA 313, 603–615 (2015).

    Article  PubMed  Google Scholar 

  49. Cushman, W. C. et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N. Engl. J. Med. 362, 1575–1585 (2010).

    Article  PubMed  Google Scholar 

  50. Wright, J. T. Jr et al. A randomized trial of intensive versus standard blood-pressure control. N. Engl. J. Med. 373, 2103–2116 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Buckley, L. F. et al. Effect of intensive blood pressure control in patients with type 2 diabetes mellitus over 9 years of follow-up: a subgroup analysis of high-risk ACCORDION trial participants. Diabetes Obes. Metab. 20, 1499–1502 (2018).

    Article  CAS  PubMed  Google Scholar 

  52. Kearney, P. M. et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 371, 117–125 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Baigent, C. et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 376, 1670–1681 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. Giugliano, R. P. et al. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus. Circulation 137, 1571–1582 (2018).

    Article  CAS  PubMed  Google Scholar 

  55. Keech, A. et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366, 1849–1861 (2005); erratum 368, 1415 (2006).

  56. Chew, E. Y. et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N. Engl. J. Med. 363, 233–244 (2010).

    Article  PubMed  Google Scholar 

  57. Sabatine, M. S. et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med. 376, 1713–1722 (2017).

    Article  CAS  PubMed  Google Scholar 

  58. Sabatine, M. S. et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 5, 941–950 (2017).

    Article  CAS  PubMed  Google Scholar 

  59. Ray, K. K. et al. Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial. Lancet Diabetes Endocrinol. 7, 618–628 (2019).

    Article  CAS  PubMed  Google Scholar 

  60. Duckworth, W. et al. Glucose control and vascular complications in veterans with type 2 diabetes. N. Engl. J. Med. 360, 129–139 (2009).

    Article  CAS  PubMed  Google Scholar 

  61. Reaven, P. D. et al. Intensive glucose control in patients with type 2 diabetes — 15-year follow-up. N. Engl. J. Med. 380, 2215–2224 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Turnbull, F. M. et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 52, 2288–2298 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Barer, Y., Cohen, O. & Cukierman-Yaffe, T. Effect of glycaemic control on cardiovascular disease in individuals with type 2 diabetes with pre-existing cardiovascular disease: a systematic review and meta-analysis. Diabetes Obes. Metab. 21, 732–735 (2019).

    Article  PubMed  Google Scholar 

  64. Wong, M. G., Heerspink, H. J. L. & Perkovic, V. ACCORDION: ensuring that we hear the music clearly. Clin. J. Am. Soc. Nephrol. 13, 1621–1623 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Agrawal, L. et al. Long-term follow-up of intensive glycaemic control on renal outcomes in the Veterans Affairs Diabetes Trial (VADT). Diabetologia 61, 295–299 (2018).

    Article  PubMed  Google Scholar 

  66. Wong, M. G. et al. Long-term benefits of intensive glucose control for preventing end-stage kidney disease: ADVANCE-ON. Diabetes Care 39, 694–700 (2016).

    Article  CAS  PubMed  Google Scholar 

  67. Wyatt, C. M. & Cattran, D. C. Intensive glycemic control and the risk of end-stage renal disease: an ADVANCE in the management of diabetes? Kidney Int. 90, 8–10 (2016).

    Article  PubMed  Google Scholar 

  68. Folz, R. & Laiteerapong, N. The legacy effect in diabetes: are there long-term benefits? Diabetologia 64, 2131–2137 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Holman, R. R., Paul, S. K., Bethel, M. A., Matthews, D. R. & Neil, H. A. 10-Year follow-up of intensive glucose control in type 2 diabetes. N. Engl. J. Med. 359, 1577–1589 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Matthews, D. R. et al. Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial. Lancet 394, 1519–1529 (2019).

    Article  CAS  PubMed  Google Scholar 

  71. Echouffo-Tcheugui, J. B. et al. Visit-to-visit glycemic variability and risks of cardiovascular events and all-cause mortality: the ALLHAT study. Diabetes Care 42, 486–493 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Ceriello, A. et al. HbA1c variability predicts cardiovascular complications in type 2 diabetes regardless of being at glycemic target. Cardiovasc. Diabetol. 21, 13 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Griffin, S. J., Leaver, J. K. & Irving, G. J. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia 60, 1620–1629 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352, 854–865 (1998).

    Article  Google Scholar 

  75. Chow, E., Yang, A., Chung, C. H. L. & Chan, J. C. N. A clinical perspective of the multifaceted mechanism of metformin in diabetes, infections, cognitive dysfunction, and cancer. Pharmaceuticals 15, 442 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Yang, A. et al. Attenuated risk association of end-stage kidney disease with metformin in type 2 diabetes with eGFR categories 1-4. Pharmaceuticals 15, 1140 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hong, J. et al. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care 36, 1304–1311 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Bergmark, B. A. et al. Metformin use and clinical outcomes among patients with diabetes mellitus with or without heart failure or kidney dysfunction: observations from the SAVOR-TIMI 53 trial. Circulation 140, 1004–1014 (2019).

    Article  CAS  PubMed  Google Scholar 

  79. White, W. B. et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N. Engl. J. Med. 369, 1327–1335 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Scirica, B. M. et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N. Engl. J. Med. 369, 1317–1326 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. Rosenstock, J. et al. Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes. JAMA 322, 1155 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Green, J. B. et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 373, 232–242 (2015).

    Article  CAS  PubMed  Google Scholar 

  83. Rosenstock, J. et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk. JAMA 321, 69 (2019).

    Article  CAS  PubMed  Google Scholar 

  84. Pfeffer, M. A. et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N. Engl. J. Med. 373, 2247–2257 (2015).

    Article  CAS  PubMed  Google Scholar 

  85. Holman, R. R. et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 377, 1228–1239 (2017).

    Article  CAS  PubMed  Google Scholar 

  86. Marso, S. P. et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 375, 311–322 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Husain, M. et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 381, 841–851 (2019).

    Article  CAS  PubMed  Google Scholar 

  88. Marso, S. P. et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 375, 1834–1844 (2016).

    Article  CAS  PubMed  Google Scholar 

  89. Gerstein, H. C. et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 394, 121–130 (2019).

    Article  CAS  PubMed  Google Scholar 

  90. Giugliano, D. et al. GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs. Cardiovasc. Diabetol. 20, 189 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Tuttle, K. R. et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol. 6, 605–617 (2018).

    Article  CAS  PubMed  Google Scholar 

  92. Cannon, C. P. et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N. Engl. J. Med. 383, 1425–1435 (2020).

    Article  CAS  PubMed  Google Scholar 

  93. Kosiborod, M. et al. Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL 2 study. J. Am. Coll. Cardiol. 71, 2628–2639 (2018).

    Article  CAS  PubMed  Google Scholar 

  94. McMurray, J. J. V. et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N. Engl. J. Med. 381, 1995–2008 (2019).

    Article  CAS  PubMed  Google Scholar 

  95. Solomon, S. D. et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N. Engl. J. Med. 387, 1089–1098 (2022).

    Article  PubMed  Google Scholar 

  96. Packer, M. et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N. Engl. J. Med. 383, 1413–1424 (2020).

    Article  CAS  PubMed  Google Scholar 

  97. Anker, S. D. et al. Empagliflozin in heart failure with a preserved ejection fraction. N. Engl. J. Med. 385, 1451–1461 (2021).

    Article  CAS  PubMed  Google Scholar 

  98. Voors, A. A. et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat. Med. 28, 568–574 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bhatt, D. L. et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N. Engl. J. Med. 384, 117–128 (2021).

    Article  CAS  PubMed  Google Scholar 

  100. Wanner, C. et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N. Engl. J. Med. 375, 323–334 (2016).

    Article  CAS  PubMed  Google Scholar 

  101. Perkovic, V. et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N. Engl. J. Med. 380, 2295–2306 (2019).

    Article  CAS  PubMed  Google Scholar 

  102. Heerspink, H. J. L. et al. Dapagliflozin in patients with chronic kidney disease. N. Engl. J. Med. 383, 1436–1446 (2020).

    Article  CAS  PubMed  Google Scholar 

  103. EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with chronic kidney disease. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2204233 (2022).

    Article  Google Scholar 

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

  105. Cefalu, W. T. et al. Cardiovascular outcomes trials in type 2 diabetes: where do we go from here? Reflections from a Diabetes Care Editors’ Expert Forum. Diabetes Care 41, 14–31 (2018).

    Article  CAS  PubMed  Google Scholar 

  106. Hill, A. B. The environment and diseases: association or causation? Proc. R. Soc. Med. 58, 295–300 (1965).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Ke, C., Shah, B. R., Luk, A. O., Di Ruggiero, E. & Chan, J. C. N. Cardiovascular outcomes trials in type 2 diabetes: time to include young adults. Diabetes Obes. Metab. 22, 3–5 (2020).

    Article  PubMed  Google Scholar 

  108. Jin, X. et al. Women’s participation in cardiovascular clinical trials from 2010 to 2017. Circulation 141, 540–548 (2020).

    Article  PubMed  Google Scholar 

  109. Kidney Disease Improving Global Outcomes. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. Suppl. 3, 1–150 (2013).

    Google Scholar 

  110. Levin, A. et al. International consensus definitions of clinical trial outcomes for kidney failure: 2020. Kidney Int. 98, 849–859 (2020).

    Article  PubMed  Google Scholar 

  111. Siew, E. D. et al. Timing of recovery from moderate to severe AKI and the risk for future loss of kidney function. Am. J. Kidney Dis. 75, 204–213 (2020).

    Article  CAS  PubMed  Google Scholar 

  112. Ke, C., Narayan, K. M. V., Chan, J. C. N., Jha, P. & Shah, B. R. Pathophysiology, phenotypes and management of type 2 diabetes mellitus in Indian and Chinese populations. Nat. Rev. Endocrinol. 18, 413–432 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Draznin, B. et al. 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2022. Diabetes Care 45, S144–S174 (2022).

    Article  Google Scholar 

  114. Davies, M. J. et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 45, 2753–2786 (2022).

    Article  CAS  PubMed  Google Scholar 

  115. Cosentino, F. et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur. Heart J. 41, 255–323 (2020).

    Article  PubMed  Google Scholar 

  116. Mahaffey, K. W. et al. Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS program (Canagliflozin Cardiovascular Assessment Study). Circulation 137, 323–334 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Codina, P. et al. Head-to-head comparison of contemporary heart failure risk scores. Eur. J. Heart Fail. 23, 2035–2044 (2021).

    Article  CAS  PubMed  Google Scholar 

  118. Shao, H. et al. Addressing regional differences in diabetes progression: global calibration for diabetes simulation model. Value Health 22, 1402–1409 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Giorgino, F., Caruso, I., Moellmann, J. & Lehrke, M. Differential indication for SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with established atherosclerotic heart disease or at risk for congestive heart failure. Metabolism 104, 154045 (2020).

    Article  CAS  PubMed  Google Scholar 

  120. Dave, C. V. et al. Risk of cardiovascular outcomes in patients with type 2 diabetes after addition of SGLT2 inhibitors versus sulfonylureas to baseline GLP-1RA therapy. Circulation 143, 770–779 (2021).

    Article  CAS  PubMed  Google Scholar 

  121. Mancini, G. B. J. et al. 2022 Canadian Cardiovascular Society Guideline for use of GLP-1 receptor agonists and SGLT2 inhibitors for cardiorenal risk reduction in adults. Can. J. Cardiol. 38, 1153–1167 (2022).

    Article  PubMed  Google Scholar 

  122. Draznin, B. et al. 11. Chronic kidney disease and risk management: standards of medical care in diabetes-2022. Diabetes Care 45, S175–S184 (2022).

    Article  PubMed  Google Scholar 

  123. Birkeland, K. I. et al. How representative of a general type 2 diabetes population are patients included in cardiovascular outcome trials with SGLT2 inhibitors? A large European observational study. Diabetes Obes. Metab. 21, 968–974 (2018).

    Article  Google Scholar 

  124. So, W. Y. et al. Effects of protocol-driven care versus usual outpatient clinic care on survival rates in patients with type 2 diabetes. Am. J. Manag. Care 9, 606–615 (2003).

    PubMed  Google Scholar 

  125. Pressman, A., Avins, A. L., Neuhaus, J., Ackerson, L. & Rudd, P. Adherence to placebo and mortality in the beta blocker evaluation of survival trial (BEST). Contemp. Clin. Trials 33, 492–498 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  126. van den Driessen Mareeuw, F., Vaandrager, L., Klerkx, L., Naaldenberg, J. & Koelen, M. Beyond bridging the know-do gap: a qualitative study of systemic interaction to foster knowledge exchange in the public health sector in the Netherlands. BMC Public Health 15, 922 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Hunter, D. J. Meeting the challenge of the “Know-Do” gap comment on “CIHR Health System Impact Fellows: Reflections on ‘Driving Change’ Within the Health System”. Int. J. Health Policy Manag. 8, 498–500 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Kazemian, P., Shebl, F. M., McCann, N., Walensky, R. P. & Wexler, D. J. Evaluation of the cascade of diabetes care in the United States, 2005–2016. JAMA Intern. Med. 179, 1376–1385 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Chan, J. C. N. et al. From Hong Kong diabetes register to JADE program to RAMP-DM for data-driven actions. Diabetes Care 42, 2022–2031 (2019).

    Article  PubMed  Google Scholar 

  130. Van Spall, H. G. C., Fonarow, G. C. & Mamas, M. A. Underutilization of guideline-directed medical therapy in heart failure: can digital health technologies PROMPT change? J. Am. Coll. Cardiol. 79, 2214–2218 (2022).

    Article  PubMed  Google Scholar 

  131. Nelson, A. J. et al. Gaps in evidence-based therapy use in insured patients in the United States with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. J. Am. Heart Assoc. 10, e016835 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Mosenzon, O. et al. CAPTURE: a multinational, cross-sectional study of cardiovascular disease prevalence in adults with type 2 diabetes across 13 countries. Cardiovasc. Diabetol. 20, 154 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Chan, J. C. What can we learn from the recent blood glucose lowering megatrials? J. Diabetes Investig. 2, 1–5 (2011).

    Article  PubMed  Google Scholar 

  134. Eichler, H. G. et al. Bridging the efficacy-effectiveness gap: a regulator’s perspective on addressing variability of drug response. Nat. Rev. Drug Discov. 10, 495–506 (2011).

    Article  CAS  PubMed  Google Scholar 

  135. Manne-Goehler, J. et al. Health system performance for people with diabetes in 28 low- and middle-income countries: a cross-sectional study of nationally representative surveys. PLoS Med. 16, e1002751 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Lim, L. L. et al. Aspects of multicomponent integrated care promote sustained improvement in surrogate clinical outcomes: a systematic review and meta-analysis. Diabetes Care 41, 1312–1320 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Hoo, J. X. et al. Impact of multicomponent integrated care on mortality and hospitalization after acute coronary syndrome: a systematic review and meta-analysis. Eur. Heart J. Qual. Care Clin. Outcomes https://doi.org/10.1093/ehjqcco/qcac032 (2022).

    Article  PubMed  Google Scholar 

  138. Lim, L. L. et al. Association of technologically assisted integrated care with clinical outcomes in type 2 diabetes in Hong Kong using the prospective JADE Program: a retrospective cohort analysis. PLoS Med. 17, e1003367 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Jiao, F. F. et al. Five-year cost-effectiveness of the multidisciplinary risk assessment and management programme-diabetes mellitus (RAMP-DM). Diabetes Care 41, 250–257 (2018).

    Article  PubMed  Google Scholar 

  140. Wan, E. Y. F. et al. Five-year effectiveness of the multidisciplinary risk assessment and management programme-diabetes mellitus (RAMP-DM) on diabetes-related complications and health service uses-a population-based and propensity-matched cohort study. Diabetes Care 41, 49–59 (2018).

    Article  PubMed  Google Scholar 

  141. Yeung, R. O. et al. Metabolic profiles and treatment gaps in young-onset type 2 diabetes in Asia (the JADE programme): a cross-sectional study of a prospective cohort. Lancet Diabetes Endocrinol. 2, 935–943 (2014).

    Article  CAS  PubMed  Google Scholar 

  142. Ke, C. et al. Excess burden of mental illness and hospitalization in young-onset type 2 diabetes: a population-based cohort study. Ann. Intern. Med. 170, 145–154 (2019).

    Article  PubMed  Google Scholar 

  143. Sattar, N. et al. Age at diagnosis of type 2 diabetes mellitus and associations with cardiovascular and mortality risks. Circulation 139, 2228–2237 (2019).

    Article  PubMed  Google Scholar 

  144. Magliano, D. J. et al. Young-onset type 2 diabetes mellitus - implications for morbidity and mortality. Nat. Rev. Endocrinol. 16, 321–331 (2020).

    Article  PubMed  Google Scholar 

  145. Lim, L. L. et al. Effects of a technology-assisted integrated diabetes care program on cardiometabolic risk factors among patients with type 2 diabetes in the Asia-Pacific Region: the JADE program randomized clinical trial. JAMA Netw. Open 4, e217557 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Chan, J. C. N. et al. Effect of a web-based management guide on risk factors in patients with type 2 diabetes and diabetic kidney disease: a JADE randomized clinical trial. JAMA Netw. Open 5, e223862 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Nauck, M. A., Wefers, J. & Meier, J. J. Treatment of type 2 diabetes: challenges, hopes, and anticipated successes. Lancet Diabetes Endocrinol. 9, 525–544 (2021).

    Article  CAS  PubMed  Google Scholar 

  148. Shah, N., Abdalla, M. A., Deshmukh, H. & Sathyapalan, T. Therapeutics for type-2 diabetes mellitus: a glance at the recent inclusions and novel agents under development for use in clinical practice. Ther. Adv. Endocrinol. Metab. 12, 20420188211042145 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Barrera-Chimal, J. & Jaisser, F. Pathophysiologic mechanisms in diabetic kidney disease: a focus on current and future therapeutic targets. Diabetes Obes. Metab. 22 (Suppl. 1), 16–31 (2020).

    Article  CAS  PubMed  Google Scholar 

  150. Zhou, G., Johansson, U., Peng, X. R., Bamberg, K. & Huang, Y. An additive effect of eplerenone to ACE inhibitor on slowing the progression of diabetic nephropathy in the db/db mice. Am. J. Transl. Res. 8, 1339–1354 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Bakris, G. L. et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N. Engl. J. Med. 383, 2219–2229 (2020).

    Article  CAS  PubMed  Google Scholar 

  152. Pitt, B. et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N. Engl. J. Med. 385, 2252–2263 (2021).

    Article  CAS  PubMed  Google Scholar 

  153. Wilding, J. P. H. et al. Once-weekly semaglutide in adults with overweight or obesity. N. Engl. J. Med. 384, 989 (2021).

    Article  CAS  PubMed  Google Scholar 

  154. Gerstein, H. C. et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet 394, 131–138 (2019).

    Article  CAS  PubMed  Google Scholar 

  155. Samms, R. J., Coghlan, M. P. & Sloop, K. W. How may GIP enhance the therapeutic efficacy of GLP-1? Trends Endocrinol. Metab. 31, 410–421 (2020).

    Article  CAS  PubMed  Google Scholar 

  156. Finan, B. et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci. Transl Med. 5, 209ra151 (2013).

    Article  PubMed  Google Scholar 

  157. Samms, R. J. et al. GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice. J. Clin. Invest. 131, e146353 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Adriaenssens, A. E. et al. Glucose-dependent insulinotropic polypeptide receptor-expressing cells in the hypothalamus regulate food intake. Cell Metab. 30, 987–996.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Jastreboff, A. M. et al. Tirzepatide once weekly for the treatment of obesity. N. Engl. J. Med. 387, 205–216 (2022).

    Article  CAS  PubMed  Google Scholar 

  160. Frías, J. P. et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N. Engl. J. Med. 385, 503–515 (2021).

    Article  PubMed  Google Scholar 

  161. Hernandez, A. F. et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 392, 1519–1529 (2018).

    Article  CAS  PubMed  Google Scholar 

  162. Gerstein, H. C. et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N. Engl. J. Med. 385, 896–907 (2021).

    Article  CAS  PubMed  Google Scholar 

  163. Bhatt, D. L. et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N. Engl. J. Med. 384, 129–139 (2021).

    Article  CAS  PubMed  Google Scholar 

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L.L.L. and E.C. researched data for the article, wrote the article, contributed substantially to the discussion of content, and reviewed and/or edited the manuscript before submission. J.C.N.C. contributed substantially to the discussion of content and reviewed and/or edited the manuscript before submission.

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Correspondence to Juliana C. N. Chan.

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L.L.L. reported receiving research grants through her affiliated institutions, honoraria for consultancy and speaker fees from Abbott, AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Novo Nordisk, Roche, Sanofi, Servier and Zuellig Pharma. E.C. has received speaker fees and/or institutional research support from Hua Medicine, Medtronic, Novartis and Sanofi. J.C.N.C. reported receiving research grants through her affiliated institutions, honoraria and speaker fees from Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Celltrion, Hua Medicine, Lee Powder, Lilly, Merck Sharpe Dohme, Merck Serono, Pfizer, Sanofi, Servier and Viatris Pharmaceutical; she holds patents of genetic markers for predicting diabetes and its complications; she is a co-founder of a biotechnology start-up company, GemVCare, with partial support from the Hong Kong Government Innovation and Technology Commission to provide precision diabetes care, and is Chief Executive Officer of Asia Diabetes Foundation on a pro bono basis.

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Lim, LL., Chow, E. & Chan, J.C.N. Cardiorenal diseases in type 2 diabetes mellitus: clinical trials and real-world practice. Nat Rev Endocrinol (2022). https://doi.org/10.1038/s41574-022-00776-2

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