Management of Diabetes With Metformin In Patients With Chronic Heart Failure

Heart failure (HF) affects 5 million individuals in the United States including over 10% of
elderly persons >75 years. HF mortality is high, with approximately 20% 1-year risk of death
(1). Diabetes is a common co-morbidity in patients with HF, present in approximately 25% of
stable outpatients and 40% of hospitalized patients with HF (2). Diabetes in HF patients is
associated with higher mortality (3,4). Hyperglycemia is independently associated with
hospitalization for HF, longer length of stay during HF hospitalization, as well as higher
in-hospital HF mortality (5-7). Furthermore, HF patients with more symptoms and worse
functional status are more likely to have insulin resistance (8,9).

Despite the abundance of evidence linking diabetes, insulin resistance, and hyperglycemia to
impaired functional status and worse outcomes in patients with HF, there is lack of data and
guidelines on optimal strategies to manage diabetes in patients with chronic HF. In
retrospective studies, many diabetes medications in HF have been associated with harm
including insulin, thiazolidinediones, and sulfonylureas (10). The only anti-hyperglycemic
medication that has been associated in retrospective studies with benefit in patients with
HF and diabetes is metformin, which recently had its "black box warning" in HF lifted by the
FDA, although most physicians are unaware of the change in labeling (10-12). Our analysis of
data on 401 advanced, systolic HF patients with DM followed at the Ahmanson-UCLA
Cardiomyopathy Center also found metformin therapy to be associated with improvement of LVEF
as well as decreased 1-year mortality (figure 1)(13).

Glycemic control in HF patients has not been prospectively studied; however, improved
glycemic control has potential benefits in HF, including improvement of myocardial glucose
utilization, decrease of potentially cardiotoxic free fatty acids, and reduced accumulation
of myocardial collagen and advanced glycation end-products (14,15). Metformin therapy,
compared to insulin and other antidiabetic medications, has potentially beneficial
mechanisms of action in HF including insulin sensitization, improvement in lipid profiles,
and more efficient myocardial metabolism (16,17). The purpose of this study is to gather
pilot data for an anticipated comprehensive study DM management in HF, with the goal of NIH
funding.

References

1. Heart Disease and Stroke Statistics - 2005 update. American Heart Association.

2. Horwich TB, Fonarow GC. Impact and Treatment of Comorbidities in Heart Failure. In:
Hosenspud JD, Greenberg BH, eds. Congestive Heart Failure Third ed. Philadelphia:
Lippincott Williams and Wilkins, 2007:670-681.

3. Gustafsson I, Brendorp B, Seibaek M, et al. Influence of diabetes and diabetes-gender
interaction on the risk of death in patients hospitalized with congestive heart
failure. J Am Coll Cardiol 2004;43:771-7.

4. Smooke S, Horwich TB, Fonarow GC. Insulin-treated diabetes is associated with a marked
increase in mortality in patients with advanced heart failure. Am Heart J
2005;149:168-74.

5. Held C, Gerstein HC, Yusuf S, et al. Glucose Levels Predict Hospitalization for
Congestive Heart Failure in Patients at High Cardiovascular Risk. Circulation
2007;115:1371-1375.

6. Gebreegziabher Y, McCullough PA, Bubb C, et al. Admission hyperglycemia and length of
hospital stay in patients with diabetes and heart failure: a prospective cohort study.
Congest Heart Fail 2008;14:117-20.

7. Berry C, Brett M, Stevenson K, McMurray JJV, Norrie J. Nature and prognostic importance
of abnormal glucose tolerance and diabetes in acute heart failure. Heart
2008;94:296-304.

8. Swan JW, Anker SD, Walton C, et al. Insulin resistance in chronic heart failure:
relation to severity and etiology of heart failure. J Am Coll Cardiol 1997;30:527-32.

9. Suskin N, McKelvie RS, Burns RJ, et al. Glucose and insulin abnormalities relate to
functional capacity in patients with congestive heart failure. Eur Heart J
2000;21:1368-1375.

10. Eurich DT, McAlister FA, Blackburn DF, et al. Benefits and harms of antidiabetic agents
in patients with diabetes and heart failure: systematic review. Bmj 2007;335:497.

11. Inzucchi SE, Masoudi FA, McGuire DK. Metformin in Heart Failure. Diabetes Care
2007;30:e129-.

12. Masoudi FA, Wang Y, Inzucchi SE, et al. Metformin and thiazolidinedione use in Medicare
patients with heart failure. Jama 2003;290:81-5.

13. Shah DD FG, Horwich TB. Metformin therapy in advanced, systolic heart failure patients
with diabetes is associated with improved survival and improved cardiac function.
Circulation 2008;118:S717.

14. Bell DS. Heart failure: the frequent, forgotten, and often fatal complication of
diabetes. Diabetes Care 2003;26:2433-41.

15. Kostis JB, Sanders M. The Association of Heart Failure With Insulin Resistance and the
Development of Type 2 Diabetes[ast]. Am J Hypertens 2005;18:731.

16. Grant PJ. The effects of high- and medium-dose metformin therapy on cardiovascular risk
factors in patients with type II diabetes. Diabetes Care 1996;19:64-6.

17. Kawabata H, Ishikawa K. Cardioprotection by metformin is abolished by a nitric oxide
synthase inhibitor in ischemic rabbit hearts. Hypertens Res 2003;26:107-10.