HbA1c as an Early Serologic Marker for the Hemodynamic Progression of Stage A Heart Failure

Overview

In a retrospective community based cohort study from Pueblo County Colorado which has a higher population proportion of metabolic syndrome and diabetes mellitus,¹⁴ we hope to clarify and quantify an association of the AGE HBa1c elevation with the early subclinical hemodynamic changes of diabetic cardiomyopathy as measured by LAV, LVM, E/A ratio, E/e' ratio and BNP in patients with stage A heart failure.

Full Title of Study: “HbA1c as an Early Serologic Marker for the Hemodynamic Progression of Stage A Heart”

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Retrospective
  • Study Primary Completion Date: August 30, 2020

Detailed Description

The classic association of glycemic control, as represented by HBa1c, with progression¹ or improvement of microvascular²'³ and macrovascular⁴'⁵ clinical complications has been well documented. Additionally, while the association of HBa1c elevation with a syndrome described as diabetic cardiomyopathy has also been well documented⁶'⁷, the use of the advanced glycation end product axis (AGE/sRAGE/esRAGE which includes HBa1c) as markers for the early subclinical hemodynamic changes of diabetic cardiomyopathy has been suggested⁸ but less well characterized or utilized⁹. Stage A heart failure is defined as persons with normal cardiac structure and function who have predisposing subclinical risks for cardiovascular disease¹⁰. Estimates suggest that Stage A heart failure may comprise up to 56% of any community's patient population and are patients most commonly seen in non-specialty primary care clinics¹¹. In light of newer cardiometabolic agents which show promise in cardiovascular disease primary prevention,¹² these patients may be an important target for preventative cardiometabolic care.¹³ In a retrospective community based cohort study from Pueblo County Colorado which has a higher population proportion of metabolic syndrome and diabetes mellitus,¹⁴ we hope to clarify and quantify an association of the AGE HBa1c elevation with the early subclinical hemodynamic changes of diabetic cardiomyopathy as measured by LAV, LVM, E/A ratio, E/e' ratio and BNP in patients with stage A heart failure.

Methods: Retrospective cohort analysis by chart review of patients presenting to Parkview Medical Center's inpatient service and outpatient clinics who obtained a full resting echo characterized by normal cardiac structure and function in conjunction with HBa1c and BNP levels within a 3 month time window. Using multiple regression analysis of the dependent variables LAV, LVM, E/A ratio, E/e' ratio and BNP, powered to detect a 5% change in LAV in conjunction with rising HBa1c levels characterized as normal (<5.7), metabolic syndrome (5.7-6.4) or diabetic (>6.4) after controlling for the presence of hypertension and coronary artery disease.

Bibliography

1. Fowler MJ. Microvascular and macrovascular complications of diabetes. Clinical Diabetes. 2011;29(3):116-122.

2. The UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet. 1998;352(9131):837-853.

3. Diabetes Control and Complications Research Group, Nathan DM, Genuth S, Lachin J, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. NEJM. 1993;329(14):977-986.

4. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology and management. JAMA. 2002;287(19):2570-2581.

5. Fox CS, Coady S, Sorlie PD, et al. Trends in cardiovascular complications of diabetes. JAMA 2004;292(20):2495-2499.

6. Van Heerebeek L, Hamdani N, Handoko ML, et al. Diastolic Stiffness in the failing heart. Circulation 2008; 117:43-51.

7. Levelt E, Gulsin G, Neubauer S, et al. Mechanisms in endocrinology: Diabetic cardiomyopathy: pathophysiology and potential metabolic interventions state of the art. Eur J Endocrinol 2018; Apr, 178(4):R127-R139.

8. Singh VP, Bali A, Singh N, Jaggi SA. Advance glycation end products and diabetic complications. Korean J Physiol Pharmacol 2014; 18:1-14.

9. Jia G, DeMarco V, Sowers, JR. Insulin resistance and the hperinsulinaemia in diabetic cardiomyopathy. Nat Rev Endocrinol 2016; March; 12(3):144-153.

10. ACC/AHA 2005 Guideline update for the diagnosis and management of chronic heart failure in the adult-summary article. Circ 2005;112:1825-1852.

11. Ammar KA, Jacobsen SJ, Mahoney DW, Kors JA, Redfield MM, et al. Prevalence and prognostic significance of heart failure stages; application of the American College of Cardiology/American Heart Association heart failure staging criteria in the community. Circ 2007;155:1563-1570.

12. Mahaffey KW, Jardine MJ, Bompoint S, Cannon CP, Neal B, et al. Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups. Circ 2019 Aug 27;140(9):739-750.

13. From AM, Scott CG, Chen HH. The development of heart failure in patients with diabetes mellitus and pre-clinical diastolic dysfunction. A population based study. Jacc 2010; 55(4):300-305.

14. Pueblo County 2016 Community Health Status report.

Interventions

  • Diagnostic Test: Glycosylated hemoglobin
    • Glycosylated hemoglobin levels associated with correlative measures of diastolic cardiac function

Clinical Trial Outcome Measures

Primary Measures

  • Left Atrial volume
    • Time Frame: 3 months
    • Echocardiogram

Secondary Measures

  • BNP
    • Time Frame: 3 months
    • Serum
  • E/e’
    • Time Frame: 3 months
    • Echocardiogram

Participating in This Clinical Trial

Inclusion Criteria

  • Stage A heart failure on basis of metabolic criteria

Exclusion Criteria

  • LV dysfunction, valvular heart disease, hypertension and CAD

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: N/A

Investigator Details

  • Lead Sponsor
    • Parkview Medical Center
  • Provider of Information About this Clinical Study
    • Sponsor

References

1. Fowler MJ. Microvascular and macrovascular complications of diabetes. Clinical Diabetes. 2011;29(3):116-122.

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837-53. Erratum in: Lancet 1999 Aug 14;354(9178):602.

Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993 Sep 30;329(14):977-86.

Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002 May 15;287(19):2570-81. Review.

Fox CS, Coady S, Sorlie PD, Levy D, Meigs JB, D'Agostino RB Sr, Wilson PW, Savage PJ. Trends in cardiovascular complications of diabetes. JAMA. 2004 Nov 24;292(20):2495-9.

van Heerebeek L, Hamdani N, Handoko ML, Falcao-Pires I, Musters RJ, Kupreishvili K, Ijsselmuiden AJ, Schalkwijk CG, Bronzwaer JG, Diamant M, Borbély A, van der Velden J, Stienen GJ, Laarman GJ, Niessen HW, Paulus WJ. Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation. 2008 Jan 1;117(1):43-51. Epub 2007 Dec 10.

Levelt E, Gulsin G, Neubauer S, McCann GP. MECHANISMS IN ENDOCRINOLOGY: Diabetic cardiomyopathy: pathophysiology and potential metabolic interventions state of the art review. Eur J Endocrinol. 2018 Apr;178(4):R127-R139. doi: 10.1530/EJE-17-0724. Epub 2018 Feb 12. Review.

Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol. 2014 Feb;18(1):1-14. doi: 10.4196/kjpp.2014.18.1.1. Epub 2014 Feb 13. Review.

Jia G, DeMarco VG, Sowers JR. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat Rev Endocrinol. 2016 Mar;12(3):144-53. doi: 10.1038/nrendo.2015.216. Epub 2015 Dec 18. Review.

Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005 Sep 20;112(12):e154-235. Epub 2005 Sep 13.

Ammar KA, Jacobsen SJ, Mahoney DW, Kors JA, Redfield MM, Burnett JC Jr, Rodeheffer RJ. Prevalence and prognostic significance of heart failure stages: application of the American College of Cardiology/American Heart Association heart failure staging criteria in the community. Circulation. 2007 Mar 27;115(12):1563-70. Epub 2007 Mar 12.

Mahaffey KW, Jardine MJ, Bompoint S, Cannon CP, Neal B, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Capuano G, de Zeeuw D, Greene T, Levin A, Pollock C, Sun T, Wheeler DC, Yavin Y, Zhang H, Zinman B, Rosenthal N, Brenner BM, Perkovic V. Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups. Circulation. 2019 Aug 27;140(9):739-750. doi: 10.1161/CIRCULATIONAHA.119.042007. Epub 2019 Jul 11.

From AM, Scott CG, Chen HH. The development of heart failure in patients with diabetes mellitus and pre-clinical diastolic dysfunction a population-based study. J Am Coll Cardiol. 2010 Jan 26;55(4):300-5. doi: 10.1016/j.jacc.2009.12.003. Erratum in: J Am Coll Cardiol. 2010 Nov 2;56(19):1612.

Pueblo County 2016 Community Health Status report.

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