This K08 proposal will develop the career of Dr. James Floyd, a general internist with training and interests in cardiovascular disease epidemiology and pharmacoepidemiology. His goals are: 1) to evaluate the cardiovascular effects of various combinations of diabetes therapies;and 2) to become a successful independent investigator studying cardiovascular drug safety. These goals will be accomplished through an intensive mentored research experience in the design and conduct of cardiovascular drug safety studies and training in the use of several epidemiologic methods that can be used to address confounding and other forms of bias common in observational studies. These activities will take place under the supervision of primary mentor Dr. Bruce Psaty and co-mentors Dr. Barbara McKnight and Dr. Miguel Hernan, all of whom are accomplished investigators with expertise in cardiovascular disease, epidemiologic methods, and the design and conduct of drug safety studies. Insulin and oral glucose-lowering drugs are leading causes of hospitalizations for adverse drug effects in the U.S., and about 40% of persons with type 2 diabetes mellitus (DM) on insulin therapy use oral agents in combination. Concerns about the cardiovascular safety of oral diabetes therapies first emerged over forty years ago, when the first-generation sulfonylurea tolbutamide was found to increase the risk of cardiovascular death in the University Group Diabetes Program clinical trial. Sulfonylureas may cause adverse cardiovascular events as a consequence of hypoglycemia and through direct myocardial effects. We hypothesize that among persons with type 2 DM using long-acting insulin, the use of sulfonylureas compared with the use of long- acting insulin alone increases the risk of cardiovascular disease and death. In the setting of Group Health Cooperative, a large integrated healthcare delivery system, we have previously used electronic prescription records and health data obtained from medical records to conduct population-based studies of the cardiovascular safety of other classes of medications. Leveraging existing data from these studies, we propose to evaluate the cardiovascular safety of sulfonylureas and other glucose-lowering therapies in two linked epidemiologic studies: (1) an MI case-control study of long-acting insulin users with type 2 DM and no prior history of MI;and (2) an inception cohort study of survivors from the MI case group of the first study. Restriction to subjects without prevalent cardiovascular disease, adjustment for key potential confounding factors, analytic methods such as propensity score calibration, and sensitivity analyses will be used to address residual confounding, the most serious threat to the validity of these studies. Causal inference methods will be used to address time-varying selection bias that can occur in the cohort study. These studies may improve cardiovascular disease prevention for patients with type 2 DM, and this work will lead to proposals for other cardiovascular drug safety studies and launch the career of Dr. Floyd as a leading investigator in this area.

Public Health Relevance

The continued use of sulfonylureas after the initiation of insulin therapy is common, unsupported by evidence, and may increase the risk of adverse cardiovascular outcomes in persons with type 2 diabetes mellitus. The proposed epidemiologic cardiovascular safety studies will provide important information about these potential risks in both primary and secondary prevention populations. This work has the potential to have an immediate public health impact on the prevention of cardiovascular disease in diabetic patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL116640-01A1
Application #
8580532
Study Section
Special Emphasis Panel (ZHL1-CSR-K (M2))
Program Officer
Aviles-Santa, Larissa
Project Start
2013-08-01
Project End
2018-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$129,789
Indirect Cost
$9,614
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Ward-Caviness, Cavin K; Huffman, Jennifer E; Everett, Karl et al. (2018) DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis. Blood 132:1842-1850
Floyd, J S; Sitlani, C M; Avery, C L et al. (2018) Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group. Pharmacogenomics J 18:127-135
Marcum, Zachary A; Forsberg, Christopher W; Moore, Kathryn P et al. (2018) Mortality Associated with Metformin Versus Sulfonylurea Initiation: A Cohort Study of Veterans with Diabetes and Chronic Kidney Disease. J Gen Intern Med 33:155-165
Flory, James H; Ukena, Jenny K; Floyd, James S (2016) Novel Anti-glycemic Drugs and Reduction of Cardiovascular Risk in Diabetes: Expectations Realized, Promises Unmet. Curr Atheroscler Rep 18:79
Floyd, James S; Psaty, Bruce M (2016) The Application of Genomics in Diabetes: Barriers to Discovery and Implementation. Diabetes Care 39:1858-1869
Floyd, James S; Brody, Jennifer A; Tiniakou, Eleni et al. (2016) Absence of anti-HMG-CoA reductase autoantibodies in severe self-limited statin-related myopathy. Muscle Nerve 54:142-4
Floyd, James S; Wiggins, Kerri L; Christiansen, Mark et al. (2016) Case-control study of oral glucose-lowering drugs in combination with long-acting insulin and the risks of incident myocardial infarction and incident stroke. Pharmacoepidemiol Drug Saf 25:151-60
Floyd, James S; Wellman, Robert; Fuller, Sharon et al. (2016) Use of Electronic Health Data to Estimate Heart Failure Events in a Population-Based Cohort with CKD. Clin J Am Soc Nephrol 11:1954-1961
Floyd, James S; Blondon, Marc; Moore, Kathryn P et al. (2016) Validation of methods for assessing cardiovascular disease using electronic health data in a cohort of Veterans with diabetes. Pharmacoepidemiol Drug Saf 25:467-71
Floyd, J S; Wiggins, K L; Sitlani, C M et al. (2015) Case-control study of second-line therapies for type 2 diabetes in combination with metformin and the comparative risks of myocardial infarction and stroke. Diabetes Obes Metab 17:1194-7

Showing the most recent 10 out of 14 publications