|Year : 2015 | Volume
| Issue : 2 | Page : 196-197
Can cardiac autonomic neuropathy be a predictor of cardiovascular outcomes in diabetes?
Sanjay Kalra1, Yashdeep Gupta2, Manash Baruah3
1 Department of Endocrinology, Bharti Hospital and B.R.I.D.E., Karnal, Haryana, India
2 Department of Medicine, Government Medical College, Chandigarh, India
3 Department of Endocrinology, Excel Hospitals, Guwahati, Assam, India
|Date of Web Publication||14-Jan-2015|
Department of Endocrinology, Bharti Hospital and B.R.I.D.E., Karnal, Haryana
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Kalra S, Gupta Y, Baruah M. Can cardiac autonomic neuropathy be a predictor of cardiovascular outcomes in diabetes?. Indian J Endocr Metab 2015;19:196-7
|How to cite this URL:|
Kalra S, Gupta Y, Baruah M. Can cardiac autonomic neuropathy be a predictor of cardiovascular outcomes in diabetes?. Indian J Endocr Metab [serial online] 2015 [cited 2020 Feb 26];19:196-7. Available from: http://www.ijem.in/text.asp?2015/19/2/196/145795
| Unexpected Results|| |
As various cardiovascular outcome trials conducted in persons with type 2 diabetes reach publication, scientific debate arises as to the interpretation of their results. Outcomes that follow expected lines are easily understood, while findings that are unusual have to be explained to a discerning audience of information-savvy patients and knowledgeable physicians.
A recent example is the finding of increased risk of hospitalization in patients randomized to saxagliptin, as reported by the saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus-thrombolysis in myocardial infarction (SAVOR-TIMI) 53 trial.  This unexpected result, which stemmed from analysis of one component of a secondary endpoint, has attracted more debate than the primary end point results, which showed that saxagliptin neither increased nor decreased the rate of ischemic events in persons with type 2 diabetes. No reason has been found so far to explain the association between saxagliptin and hospitalization. Results from the Vildagliptin in Ventricular Dysfunction Diabetes (VIVIDD) study regarding the effect of vildagliptin on cardiac function are also open to interpretation. 
Modern cardiovascular outcomes trials follow strict guidance for industry, as laid down by the United States Food and Drug Administration.  Thus, they represent a marked improvement over earlier generation trials such as the University Diabetes Group Programme study,  which attracted considerable criticism for methodological flaws. 
Trial design specialists take multiple factors into consideration while writing protocols, and try to ensure that as many variables as possible are captured in data collection. The SAVOR-TIMI trial, for example, assessed various parameters at baseline including hypertension; dyslipidemia; history of prior myocardial infarction, heart failure, and coronary revascularization, and the presence of established atherosclerotic diabetes.  All these variables, however, have not been able to predict or explain the occurrence of increased hospitalization for heart failure.
| Unheralded Predictor|| |
One important comorbid condition, which has not been assessed in these trials, though, is cardiovascular autonomic neuropathy (CAN). We hereby highlight the importance of assessing CAN as a determinant of cardiovascular outcomes in diabetes, and propose inclusion of CAN measurement in all cardiovascular outcome trials being conducted on antidiabetic drugs.
| Rationale of Assessment|| |
Cardiovascular autonomic neuropathy is a frequently encountered chronic complication of diabetes, defined as the impairment of autonomic control of the cardiovascular system in the setting of diabetes after exclusion of other causes.  CAN has been found to be a better predictor of major cardiac events than assessment of silent myocardial ischemia.  A meta-analysis of 15 studies showed that CAN is associated with increased risk of mortality, and this association is stronger if 2 or more abnormalities are used to define CAN.  The presence of CAN suggests a grave prognosis, with the risk of sudden death.  The higher mortality is observed in patients with CAN even in the absence of other clinically detectable microvascular and macro vascular complications.
Cardiovascular autonomic neuropathy is also directly linked with left ventricular dysfunction. Analysis of a large cohort of type 1 diabetes patients has shown that persons with CAN have significantly higher left ventricular mass, mass-to volume ratio, and cardiac output, independent of other factors.  Thus, CAN is certainly a predictor of cardiovascular outcomes in persons with diabetes.
| Feasibility of Assessment|| |
The assessment and quantification of CAN have been standardized to a great extent, and validated methods of assessment are available.  The American Diabetes Association suggests that screening for signs and symptoms of CAN should begin at diagnosis in type 2 diabetes, thus highlighting its importance.  It suggests CAN assessment as a means of cardiovascular risk stratification in persons with diabetes. Cardiovascular reflex tests are considered the gold standard for diagnosis. 
| The Cinderella of Cardiology|| |
Unfortunately, however, CAN seems to have been neglected by cardiology researchers and policy makers alike. The European Society of Cardiology (ESC) guidelines on diabetes, prediabetes, and cardiovascular diseases developed in collaboration with the European Association for the Study of Diabetes, for example, are an extremely comprehensive and exhaustive review of the subject.  They too, fail to mention the role of CAN in the pathogenesis of cardiovascular morbidity in diabetes
| Summary|| |
Assessment of CAN in diabetes clinical trials is both rational, and feasible. It is possible that the cardiac autonomic health, which was not considered during randomization, may have modified the response of subjects to therapy in the SAVOR-TIMI and VIVIDD trials. Keeping this in mind CAN should be, and must be, considered as a significant factor while designing randomization strategies in future cardiovascular outcome trials. This is especially true for trials involving incretin-based therapies, as their mechanism of action and response is closely linked with the autonomic nervous system.  This conjecture, however, is open to debate.
| References|| |
Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P, et al
. Heart failure, saxagliptin and diabetes mellitus: Observations from the SAVOR-TIMI 53 Randomized Trial. Circulation 2014.
Krum H, Skiba M, Wu S, Hopper I. Heart failure and dipeptidyl peptidase-4 inhibitors. Eur J Heart Fail 2014;16:603-7.
Food and Drug Administration, Center for Drug Evalution and Research. Guidance for Industry: Diabetes mellitus-evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes; 2008.
Goldner MG, Knatterud GL, Prout TE. Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. 3. Clinical implications of UGDP results. JAMA 1971;218:1400-10.
Seltzer HS. A summary of criticisms of the findings and conclusions of the University Group Diabetes Program (UGDP). Diabetes 1972;21:976-9.
Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al.
The design and rationale of the saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus-thrombolysis in myocardial infarction (SAVOR-TIMI) 53 study. Am Heart J 2011;162:818-25.e6.
Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, et al
. And on behalf of the Toronto consensus panel on diabetic neuropathy. Cardiovascular autonomic neuropathy in diabetes: Clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 2011;27:639-53.
Maser RE, Mitchell BD, Vinik AI, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: A meta-analysis. Diabetes Care 2003;26:1895-901.
Valensi P, Sachs RN, Harfouche B, Lormeau B, Paries J, Cosson E, et al.
Predictive value of cardiac autonomic neuropathy in diabetic patients with or without silent myocardial ischemia. Diabetes Care 2001;24:339-43.
Ewing DJ, Campbell IW, Clarke BF. Assessment of cardiovascular effects in diabetic autonomic neuropathy and prognostic implications. Ann Intern Med 1980;92:308-11.
Ziegler D, Zentai CP, Perz S, Rathmann W, Haastert B, Döring A, et al.
Prediction of mortality using measures of cardiac autonomic dysfunction in the diabetic and nondiabetic population: The MONICA/KORA Augsburg Cohort Study. Diabetes Care 2008;31:556-61.
Pop-Busui R, Cleary PA, Braffett BH, Martin CL, Herman WH, Low PA, et al.
Association between cardiovascular autonomic neuropathy and left ventricular dysfunction: DCCT/EDIC study (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications). J Am Coll Cardiol 2013;61:447-54.
American Diabetes Association. Executive summary: Standards of medical care in diabetes - 2014. Diabetes Care 2014;37 Suppl 1:S5-13.
Assessment: Clinical autonomic testing report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 1996;46:873-80.
Authors/Task Force Members, Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, et al
. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: The Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J 2013;34:3035-87.
Kalra S, Kalra B, Sahay R, Agrawal N. Predicting response to incretin-based therapy. Res Rep Endocr Disord 2011;1:11-9.