Thomas Zelniker, MD, on How Diabetes, CVD, and Kidney Disease Go Hand in Hand
Cardiovascular disease (CVD), diabetes, and kidney disease are leading causes of death in the United States, all claiming a spot among the top 10 contemporary killers of Americans, according to the Centers for Disease Control and Prevention.
What may not be as well known, however, is how these 3 diseases are intertwined, said Thomas Zelniker, MD, research fellow at the TIMI Study Group at Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts.
Dr Zelniker discussed this topic in-depth at the American College of Cardiology's 67th Scientific Session & Expo, where he presented “Inflammatory and Cardiac Biomarkers Are Associated With Renal Outcomes in Patients With Type 2 Diabetes Mellitus: Insights From SAVOR-TIMI 53.”
Consultant360 recently spoke with Dr Zelniker about his presentation.
Consultant360: What cardiac and renal diseases and complications are common among patients with type 2 diabetes?
Thomas Zelniker: Patients with type 2 diabetes mellitus (T2DM) are at an increased risk of cardiovascular events (such as myocardial infarction, stroke, or peripheral artery disease), heart failure, and death.1,2 In addition, long-term complications from hyperglycemia are microvascular complications such as diabetic kidney disease, retinopathy, or polyneuropathy.3,4 In this context, diabetic nephropathy is the leading cause of end-stage renal disease requiring renal replacement therapy.
C360: What is the mechanism between diabetes and cardiac and renal diseases? How does one cause the other?
TZ: T2DM is regarded as a systemic disease that is involved in pathophysiological processes of cardiac and renal diseases. The pathophysiological processes between T2DM and their complications are only partially understood. While there is a well-established relationship between hyperglycemia and microvascular outcomes, hyperglycemia has not been proven to be linked to cardiovascular outcomes, such as myocardial infarction, stroke, or cardiovascular death.5,6
Until relatively recently, there was no evidence for antidiabetic treatment to reduce the risk of cardiovascular death. However, since 2015, glucagon-like-peptide 1 receptor agonists and sodium-glucose co-transporter 2 receptor blockers have been shown to reduce the primary composite of myocardial infarction, stroke, or cardiovascular death.7-10
At the same time, it is important to note that there is a well-established relationship between heart and kidney diseases with bidirectional interactions.11-13 These interactions between heart and kidneys are complex and multifactorial, including hemodynamic changes, inflammation, and fibrosis.
C360: What role do biomarkers play in predicting these conditions in this patient population?
TZ: Cardiac and inflammatory biomarkers such as natriuretic pro B-type peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), or high-sensitivity C-reactive protein (hsCRP) are widely available and have been shown to improve cardiovascular risk stratification in patients with T2DM.14,15
To date, no established biomarkers exist for risk stratification of microvascular outcomes.
A nested case cohort study from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial indicated that hsTnT and NT-proBNP were also associated with microvascular events.16 Our data from the “Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial,” presented at the American Heart Association’s Scientific Session, validates this hypothesis. We found that hsTnT, NT-proBNP, and hsCRP were associated with worsening of renal function in terms of reduction in eGFR (≥40%) and deterioration in UACR class in patients with T2DM at high risk.
C360: Are these complications adequately addressed in this patient population? What can happen if they are not?
TZ: Thanks to the substantial progress made in the treatment of T2DM, mortality among patients with T2DM has been reduced substantially but leading at the same time to prolonged exposure to increased hyperglycemia. Therefore, long-term complications are often observed in patients with T2DM. In order to reduce the risk of macro- and microvascular diseases, a close follow-up to optimize the medical management of these patients is mandatory. HbA1c should be monitored and targeted according to guideline recommendations. Treatment and control of cardiovascular risk factors including blood pressure and dyslipidemia are mandatory. Patients should be advised to cease smoking, modify their diet, and reduce weight.
C360: What types of treatment options exist for type 2 diabetes patients with renal and/or cardiac diseases? Does the presence of these complications make forming an appropriate treatment regimen more difficult?
TZ: A reduction of the glomerular filtration rate caused by diabetic nephropathy often requires dose adjustment in the selection of concomitant medication and influences the selection of antihyperglycemic medication. In addition, several antidiabetic agents (sulfonylureas, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors) may increase the risk for the development of heart failure in patients with T2DM.17-21
- Booth GL, Kapral MK, Fung K, Tu JV. Recent trends in cardiovascular complications among men and women with and without diabetes. Diabetes Care. 2006;29(1):32-37.
- McMurray JJ, Gerstein HC, Holman RR, Pfeffer MA. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol. 2014;2(10):843-851.
- Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR; UKPDS Group. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 2003;63(1):225-232.
- American Diabetes Association. Microvascular complications and foot care: standards of medical care in diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S105-S118.
- Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
- Cushman WC, Evans GW, Byington RP, et al; ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585.
- Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128.
- Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee and LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322.
- Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844.
- Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657.
- Ronco C, Haapio M, House AA, Anavekar N, Bellomo R. Cardiorenal syndrome. J Am Coll Cardiol. 2008;52(19):1527-1539.
- Bock JS, Gottlieb SS. Cardiorenal syndrome: new perspectives. Circulation. 2010;121(23):2592-2600.
- Scirica BM, Mosenzon O, Bhatt DL, et al. Cardiovascular outcomes according to urinary albumin and kidney disease in patients with type 2 diabetes at high cardiovascular risk: observations from the SAVOR-TIMI 53 trial. JAMA Cardiol. 2018;3(2):155-163.
- Scirica BM, Bhatt DL, Braunwald E, et al. Prognostic implications of biomarker assessments in patients with type 2 diabetes at high cardiovascular risk: a secondary analysis of a randomized clinical trial. JAMA Cardiol. 2016;1(9):989-998.
- Scirica BM. Use of biomarkers in predicting the onset, monitoring the progression, and risk stratification for patients with type 2 diabetes mellitus. Clin Chem. 2017;63(1):186-195.
- Welsh P, Woodward M, Hillis GS, et al. Do cardiac biomarkers NT-proBNP and hsTnT predict microvascular events in patients with type 2 diabetes? Results from the ADVANCE trial. Diabetes Care. 2014;37(8):2202-2210.
- Dormandy JA, Charbonnel B, Eckland DJ, et al; PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279-1289.
- Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005;294(20):2581-2586.
- Nichols GA, Koro CE, Gullion CM, Ephross SA, Brown JB. The incidence of congestive heart failure associated with antidiabetic therapies. Diabetes Metab Res Rev. 2005;21(1):51-57.
- Home PD, Pocock SJ, Beck-Nielsen H, et al; RECORD Study Team. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009;373(9681):2125-2135.
- Scirica BM, Bhatt DL, Braunwald E, et al; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-1326.