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Comorbidity Affects the Relationship Between Glycemic Control and Cardiovascular Outcomes in Diabetes: A Cohort Study

Sheldon Greenfield, MD; John Billimek, PhD; Fabio Pellegrini, MS; Monica Franciosi, MSc; Giorgia De Berardis, MSc; Antonio Nicolucci, MD; and Sherrie H. Kaplan, PhD, MPH
[+] Article, Author, and Disclosure Information

From the University of California Irvine, Irvine, California, and Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy.

Grant Support: By Pfizer of Italy.

Potential Conflicts of Interest: None disclosed.

Reproducible Research Statement:Study protocol and statistical code: Available from Dr. Nicolucci (nicolucci@negrisud.it). Data set: Not available.

Requests for Single Reprints: Sheldon Greenfield, MD, Health Policy Research Institute, 100 Theory, Suite 110, Irvine, CA 92697; e-mail, sgreenfi@uci.edu.

Current Author Addresses: Drs. Greenfield, Billimek, and Kaplan: Health Policy Research Institute, 100 Theory, Suite 110, Irvine, CA 92697.

Mr. Pellegrini, Ms. Franciosi, Ms. De Berardis, and Dr. Nicolucci: Consorzio Mario Negro Sud, Via Nazionale, 8/A Santa Maria Imbaro, Italy.

Author Contributions: Conception and design: S. Greenfield, M. Franciosi, G. De Berardis, A. Nicolucci, S.H. Kaplan.

Analysis and interpretation of the data: S. Greenfield, J. Billimek, F. Pellegrini, M. Franciosi, G. De Berardis, A. Nicolucci, S.H. Kaplan.

Drafting of the article: S. Greenfield, J. Billimek, F. Pellegrini, M. Franciosi, G. De Berardis, A. Nicolucci, S.H. Kaplan.

Critical revision of the article for important intellectual content: S. Greenfield, J. Billimek, M. Franciosi, G. De Berardis, A. Nicolucci, S.H. Kaplan.

Final approval of the article: S. Greenfield, J. Billimek, F. Pellegrini, M. Franciosi, G. De Berardis, A. Nicolucci, S.H. Kaplan.

Provision of study materials or patients: M. Franciosi, G. De Berardis, A. Nicolucci, S. Greenfield.

Statistical expertise: J. Billimek, F. Pellegrini, A. Nicolucci, S.H. Kaplan.

Obtaining of funding: A. Nicolucci.

Administrative, technical, or logistic support: S. Greenfield, J. Billimek.

Collection and assembly of data: M. Franciosi, G. De Berardis, A. Nicolucci.

Ann Intern Med. 2009;151(12):854-860. doi:10.7326/0003-4819-151-12-200912150-00005
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Background: Recent studies have shown mixed results regarding the effectiveness of intensive glucose-lowering therapy in reducing risk for cardiovascular events.

Objective: To determine whether attaining hemoglobin A1c (HbA1c) targets of 6.5% or less or 7.0% or less for glycemic control at baseline provides differential benefits for patients with high versus low-to-moderate levels of comorbidity.

Design: 5-year longitudinal observational study of patients with type 2 diabetes. Patients were categorized into high and low-to-moderate comorbidity subgroups by using the Total Illness Burden Index (TIBI), a validated patient-reported measure of comorbidity.

Setting: 101 diabetes outpatient clinics and 103 general practitioners' clinics in Italy.

Patients: 2613 (83%) of 3074 patients with type 2 diabetes, sampled randomly from diabetes outpatient clinic rosters and recruited consecutively from general practitioners' clinics, who completed the baseline questionnaire.

Measurements: TIBI score, total mortality, and incident cardiovascular events. Hazard ratios (HRs) were adjusted for age and sex.

Results: Attaining an HbA1c level of 6.5% or less at baseline was associated with lower 5-year incidence of cardiovascular events in the low-to-moderate comorbidity subgroup (adjusted HR, 0.60 [95% CI, 0.42 to 0.85]; P = 0.005) but not in the high comorbidity subgroup (adjusted HR, 0.92 [CI, 0.68 to 1.25]; P = 0.61; P for subgroup by HbA1c interaction = 0.048). Similarly, attaining a baseline HbA1c level of 7.0% predicted fewer cardiovascular events in the low-to-moderate comorbidity subgroup (adjusted HR, 0.61 (CI, 0.44 to 0.83; P = 0.001) but not in the high comorbidity subgroup (adjusted HR, 0.88 [CI, 0.66 to 1.17]; P = 0.38; P for subgroup by HbA1c interaction = 0.093).

Limitations: The observational nature of the study does not allow causal inference. The length of the data collection period was limited. Information on clinical management was not available.

Conclusion: Patients with the high levels of comorbidity common in type 2 diabetes may receive diminished cardiovascular benefit from intensive blood glucose control. Comorbidity should be considered when tailoring glucose-lowering therapy in patients with type 2 diabetes.

Primary Funding Source: Pfizer of Italy.





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Comorbidity, Glycemic Control and Cardiovascular Outcomes in Diabetes
Posted on January 13, 2010
Leonard Pogach
VA New Jersey Health Care System
Conflict of Interest: None Declared

TO THE EDITOR: Greenfield et al. reported that a baseline A1C of less than 6.5% or 7% predicted fewer cardiovascular events in a low to moderate co-morbidity group than in a high comorbidity group over a 5 year clinical observational study (1). The authors speculate that tight glycemic control may not have a cardio-protective effect in the presence of comorbid illness. We suggest an alternative explanation, which is that the competing demands of non-cardiovascular illnesses in the high comorbidity group may have interfered with cardiovascular risk factor and glycemic management (2). We believe this explanation, although not investigated, is plausible for the following reasons:

First, effective blood pressure management and combined risk management is beneficial in decreasing cardiovascular events and mortality even in the absence of sustained tight glycemic control over a similar a 5.5 year observational period (3). In addition, a marked cardiovascular and mortality benefit of statins and blood pressure control have been demonstrated in multiple populations with comorbid illness. Although blood pressures and cholesterol levels were comparable among the groups at baseline in the current study, the baseline mean systolic pressure of 143 mm/Hg cannot be characterized as well controlled. Furthermore, we do not know if there were subsequent differences in the rates of initiation, adherence, or persistence to effective lipid and blood pressure management between the comorbidity groups during the 5 year follow-up. However, there is evidence indicating that patients with more unrelated comorbid conditions are less likely to have treatment intensification for uncontrolled blood pressure at a primary care visit than patients without such conditions (4).

In addition, serious hypoglycemia requiring third party assistance is now known to be associated with cardiovascular events and morality (5). Since the average duration of diabetes was 10 years or more in both the low-moderate and high comorbidity groups, it is likely that a significant number of individuals were receiving insulin in order to achieve A1c values <7%. It is therefore reasonable to speculate that individuals with a greater illness burden had more frequent serious hypoglycemic reactions, and thus could have incurred excess morbidity.

While the current study supports findings from the ACCORD and VA Diabetes Trial that comorbid conditions are a reason not to intensify glycemic control, we believe that a more important clinical recommendation is that blood pressure and lipid management should continue to be appropriately managed despite the presence of such conditions.


(1) Greenfield S, Billimek J, Pellegrini F, Franciosi M, De Berardis G, Nicolucci A et al. Comorbidity affects the relationship between glycemic control and cardiovascular outcomes in diabetes: a cohort study. Ann Intern Med. 2009; 151:854-60.PMID: 20008761

(2) Gaede P, Lund-Andersen H, Parving H. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580- 591. PMID: 18256393

(3) Piette, J D. and Kerr EA. The impact of comorbid chronic conditions on diabetes care. Diabetes Care 2006; 29: 725-31. PMID: 16505540

(4) Turner BJ, Hollenbeak CS, Weiner M, Ten Have T, Tang SS. Effect of unrelated comorbid conditions on hypertension management. Ann Intern Med 148(8): 578-86. PMID: 18413619

(5) Davis SJ. Effects of Severe Hypoglycemia on Primary Outcomes, Death and Myocardial Infarction in VADT. New Analyses from ACCORD and VADT. Presented at: American Diabetes Association's 69th Scientific Sessions; June 5-9, 2009; New Orleans. Accessed at http://diabetesconnect.org/storetemplate/Webcast_list.aspx?ses=1812 on December 22, 2009.

Conflict of Interest:

None declared

Submit a Comment/Letter

Summary for Patients

Chronic Health Problems Seem to Influence the Relationship of Blood Sugar Control and Cardiovascular Events in Patients With Type 2 Diabetes

The summary below is from the full report titled “Comorbidity Affects the Relationship Between Glycemic Control and Cardiovascular Outcomes in Diabetes. A Cohort Study.” It is in the 15 December 2009 issue of Annals of Internal Medicine (volume 151, pages 854-860). The authors are S. Greenfield, J. Billimek, F. Pellegrini, M. Franciosi, G. De Berardis, A. Nicolucci, and S.H. Kaplan.


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