BACKGROUND/RATIONALE:
DM and its cardiovascular and renal complications represent an enormous healthcare burden, and result in nearly 200,000 US deaths per year. It is estimated that 69% of patients with DM are prescribed an oral antidiabetic drug (OAD). OADs have been licensed for use largely based on the evaluation of surrogate outcomes (e.g. A1C). However, these surrogates are only weakly correlated with serious cardiovascular outcomes. For both older OADs such as metformin and sulfonylureas and more recently licensed thiazolidinediones and meglitinides, information on their relative clinical effectiveness and safety over extended periods of use is limited. Thus, important questions about the optimal choices of OADs remain for patients and clinicians. A recent AHRQ-commissioned systematic review synthesized available information on the comparative effectiveness and safety of OADs. Although available data were sufficient to address many key questions, the review identified specific knowledge gaps. The following objsectives are funded by AHRQ for further evaluation.

OBJECTIVE(S):
Question: Does OAD drug choice influence the risk of serious cardiovascular morbidity and mortality?
SPECIFIC AIM: To measure the effects of specific OADs on incidence of a combined cardiovascular endpoint (acute myocardial infarction, stroke) or all cause death and to determine any difference in effects by age and co-morbidities.

METHODS:
This project will utilize national VA data (Corporate Data Warehouse- Vital Signs File; pharmacy, SAS Medical datasets, VIReC Medicare data and VA Vital status files) to construct a national cohort of veterans with DM. The study will be conducted as a retrospective cohort of over 411,000 incident veterans newly initating therapy for diabetes with an OAD. We will evaluated the use of one of 4 OAD classes: metformin(reference) , sulfonylureas, combination metformin+ sulfonylurea and thiazolidendiones. Persons included are aged >18 years, have utilization of VA healthcare system between 10/01/1999 to 09/31/2008, and no serious medical illness in the year prior to cohort entry. Baseline characteristics among exposure groups will be examined for important covariates (HbA1c, LDL, BP, GFR, use of high risk medications, demographics). We will examine the distal clinical outcomes including CVD (AMI, Stroke) as well as all cause mortality. Two analyses will be conducted; the first analysis will be based on time on drug regimen. The second analysis will be a first exposure carried forward analysis, similar to an intention to treat analysis in RCTs. The research team is poised to conduct a rigorous study on the safety and clinical effectiveness of pharmacologic therapies for DM.

FINDINGS/RESULTS:
We received 622 (46.4%) of 1341 mailed surveys containing complete and usable information. Respondents were 97.4% male and older than non responders (58.2% 65 years vs. 45.5% of non responders [p < 0.001]). The average PAM score was 54.4 (sd 11.4). Those who were 65 had higher activation scores than younger patients (55.3 vs. 53.1 p = 0.02). Those veterans who had 12th grade education scored 2 points higher on the PAM than those with 12th grade education (p = 0.004). PAM did not differ by race, gender, or number of co-morbidities. Activation levels were positively correlated to quality of life. A one unit increase in QOL corresponded to an average 7.8 point higher PAM score (95% CI 6.2, 9.5 p<0.001).

IMPACT:
Cardiovascular disease (CVD) accounts for approximately 65% of deaths in patients with diabetes mellitus (DM).1,2 Although randomized trials have evaluated risk of CVD associated with selected glycemic control thresholds,3,4 the role of specific antidiabetic drugs is less clear. Much controversy has surrounded the use of thiazolidinediones and the risk for cardiovascular disease,5-7 however, the comparative effectiveness of the two most commonly used drugs metformin and sulfonylurea, on CVD risk remains uncertain. More than 10.1 million Americans (~34% of patients with treated diabetes) use a sulfonylurea for their diabetes treatment.8

CVD remains the major complication of DM and leading cause of DM-related death. Since CVD risk is associated with glycemic control, several studies have evaluated the effects of achieving glycemic targets on CVD, without regard to the medications used. Whether risk of CVD varies by incident agent used is unclear. Our study included a national cohort of veterans initiating oral treatment for DM, and found that sulfonylurea use as first-line treatment for DM was associated with an increase in the risk of AMI, stroke or death compared with metformin. A recent comparative effectiveness review3 concluded that metformin had a slightly lower risk of all-cause mortality compared with sulfonylureas, but results were inconsistent and the evidence was rated imprecise. Our study strengthens these conclusions, and provides quantification of the differences in these outcomes for those initiating sulfonylureas versus metformin.


Our study results are consistent with those of the UKPDS and extend them by inclusion of non-overweight persons. Our results are also consistent with several observational studies in diabetic patients. In a propensity score-matched cohort (n= 8,977), McAfee et al38 demonstrated a 23% decrease in AMI or revascularization with metformin compared to sulfonylurea initiators (aHR 0.77, 95% CI: 0.62, 0.96). Using the UK general practice research database (n=91,000), Tzoulaki and colleagues39 found sulfonylurea compared to metformin use was associated with an increase in all-cause mortality (aHR 1.24, 95% CI 1.14, 1.35), but not first AMI (aHR 1.09, 95% CI 0.94, 1.27). Finally, the VHA Diabetes Epidemiology Cohort reported all-cause mortality of 2.7% in 2,988 metformin users compared to 5.3% among 19,053 sulfonylureas users (adjusted odds ratio 0.87, 95% CI 0.68, 1.10).40


Our study of more than 250,000 patients is consistent with UKPDS and these three observational studies and also has multiple strengths. First, it includes the largest number of initiators of metformin and sulfonylureas to date. We included clinical variables, such as HbA1c, cholesterol, BP, creatinine and BMI lacking in the McAfee study38 that relied on administrative data alone. Although two observational studies included these variables,39, 40 they were often missing and reduced the patient sample available for analysis. We used multiple imputation techniques to preserve our sample size for those with missing covariates. Notably, our sensitivity analyses demonstrated that our findings were not sensitive to the imputation strategy.41-43

Second, our prior studies evaluating intermediate outcomes in a regional VHA cohort reported results similar to those reported in the comparative effectiveness review and determined to be "high quality evidence." In the comparative effectiveness review, metformin compared to sulfonylureas resulted in 2.7 kg lower weight; 10 mg/dL lower LDL; 8.6 mg/dL lower triglycerides, and no difference in HbA1c.3 Our group estimated that after one year, compared with sulfonylurea use, metformin initiators had 3.2 kg lower weight; a non-significant 5 mg/dL lower LDL, 8.7 mg/dL lower triglycerides; and no difference in HbA1c.18, 19 Our prior studies also found metformin to be associated with 1.2 mmHg lower systolic blood pressure and a modest advantage on changes in kidney function.44 These results are similar to those from clinical trials and suggest a lack of systematic bias in our cohort. Whether the minor advantages in cholesterol, weight and BP among metformin users could account for the differences observed in CVD and death or whether there is another mechanism accounting for the risk difference observed, such as ischemic preconditioning45 is currently unknown.

Third, our large cohort allowed quantification of the excess risk associated with choice of therapy. Finally, a number of planned sensitivity analyses gave consistent results highlighting the robustness of our main findings.34-37


Despite these strengths, our findings must be interpreted in light of limitations. First, confounding by indication could occur if patients with certain characteristics which increase CVD risk were also more likely to use metformin or sulfonylureas. We collected an extensive list of covariates, and accounted for them in our regression models. Furthermore, since sulfonylurea prescribing declined over time,8, 46 we accounted for this secular trend in all analyses. The large sample size of our cohorts and the number of events allowed us to control for covariates directly, and the use of alternate summary scores (propensity scores or disease risk scores) was not necessary. Second, refill data were used as a proxy for medication taking, and may result in exposure misclassification. Nevertheless, prescription fills appear to be a good proxy for medication use.47 Finally, if individuals were admitted to non-VHA facilities for outcomes, those events could be missed by our definitions and outcome misclassification could occur. Nevertheless, we supplemented our VHA data with national Medicaid/Medicare data to minimize this concern. Furthermore, the use of non-VHA facilities is unlikely to be differential by exposure group. The analysis restricted to patients aged 65 years, in which missing events are less likely, yielded similar results.

In conclusion, our study suggests a modest, but clinically important 16-25% increased risk of AMI, stroke or death associated with initiation of sulfonylureas, compared with metformin. This translates into an excess of 1 and 4 events per 1000 person-years in patients without and with CVD history. These observations support the use of metformin for first line diabetes therapy, and strengthen the evidence regarding the cardiovascular advantages of metformin compared with sulfonylureas.

---

External Links for this Project

---

PUBLICATIONS:

Journal Articles

1. Munson GW, Wallston KA, Dittus RS, Speroff T, Roumie CL. Activation and perceived expectancies: correlations with health outcomes among veterans with inflammatory bowel disease. Journal of general internal medicine. 2009 Jul 1; 24(7):809-15. [view]
2. Choma NN, Griffin MR, Huang RL, Mitchel EF, Kaltenbach LA, Gideon P, Stratton SM, Roumie CL. An algorithm to identify incident myocardial infarction using Medicaid data. Pharmacoepidemiology and drug safety. 2009 Nov 1; 18(11):1064-71. [view]
3. Salanitro AH, Roumie CL. Blood pressure management in patients with diabetes. Clinical diabetes : a publication of the American Diabetes Association. 2010 Jul 1; 28(3):107-114 . [view]
4. Roumie CL, Elasy TA, Wallston KA, Pratt S, Greevy RA, Liu X, Alvarez V, Dittus RS, Speroff T. Clinical inertia: a common barrier to changing provider prescribing behavior. Joint Commission Journal on Quality and Patient Safety. 2007 May 1; 33(5):277-85. [view]
5. Schuberth JL, Elasy TA, Butler J, Greevy R, Speroff T, Dittus RS, Roumie CL. Effect of short call admission on length of stay and quality of care for acute decompensated heart failure. Circulation. 2008 May 20; 117(20):2637-44. [view]
6. Huizinga MM, Roumie CL, Greevy RA, Liu X, Murff HJ, Hung AM, Grijalva CG, Griffin MR. Glycemic and weight changes after persistent use of incident oral diabetes therapy: a Veterans Administration retrospective cohort study. Pharmacoepidemiology and drug safety. 2010 Nov 1; 19(11):1108-12. [view]
7. Ikard RW, Vavra D, Forbes RC, Richman JC, Roumie CL. Management of senescent gynecomastia in the Veterans Health Administration. The Breast Journal. 2011 Mar 1; 17(2):160-6. [view]
8. Roumie CL, Mitchel EF, Kaltenbach L, Arbogast PG, Gideon P, Griffin MR. Nonaspirin NSAIDs, cyclooxygenase 2 inhibitors, and the risk for stroke. Stroke. 2008 Jul 1; 39(7):2037-45. [view]
9. Roumie CL, Choma NN, Kaltenbach L, Mitchel EF, Arbogast PG, Griffin MR. Non-aspirin NSAIDs, cyclooxygenase-2 inhibitors and risk for cardiovascular events-stroke, acute myocardial infarction, and death from coronary heart disease. Pharmacoepidemiology and drug safety. 2009 Nov 1; 18(11):1053-63. [view]
10. Roumie CL, Greevy R, Wallston KA, Elasy TA, Kaltenbach L, Kotter K, Dittus RS, Speroff T. Patient centered primary care is associated with patient hypertension medication adherence. Journal of behavioral medicine. 2011 Aug 1; 34(4):244-53. [view]
11. Choma NN, Huang RL, Dittus RS, Burnham KE, Roumie CL. Quality improvement initiatives improve hypertension care among veterans. Circulation. Cardiovascular quality and outcomes. 2009 Jul 1; 2(4):392-8. [view]
12. Schnipper JL, Roumie CL, Cawthon C, Businger A, Dalal AK, Mugalla I, Eden S, Jacobson TA, Rask KJ, Vaccarino V, Gandhi TK, Bates DW, Johnson DC, Labonville S, Gregory D, Kripalani S, PILL-CVD Study Group. Rationale and design of the Pharmacist Intervention for Low Literacy in Cardiovascular Disease (PILL-CVD) study. Circulation. Cardiovascular quality and outcomes. 2010 Mar 1; 3(2):212-9. [view]
13. Bosworth HB, Almirall D, Weiner BJ, Maciejewski M, Kaufman MA, Powers BJ, Oddone EZ, Lee SY, Damush TM, Smith V, Olsen MK, Anderson D, Roumie CL, Rakley S, Del Monte PS, Bowen ME, Kravetz JD, Jackson GL. The implementation of a translational study involving a primary care based behavioral program to improve blood pressure control: The HTN-IMPROVE study protocol (01295). Implementation science : IS. 2010 Jul 16; 5:54. [view]
14. Pini TM, Griffin MR, Roumie CL, Huizinga MM, Fowke JH, Greevy R, Liu X, Murff HJ. Use of thiazolidinediones does not affect prostate-specific antigen levels in men with diabetes. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2009 Jun 1; 18(6):1937-8. [view]
15. Huang RL, Donelli A, Byrd J, Mickiewicz MA, Slovis C, Roumie C, Elasy TA, Dittus RS, Speroff T, Disalvo T, Zhao D. Using quality improvement methods to improve door-to-balloon time at an academic medical center. The Journal of invasive cardiology. 2008 Feb 1; 20(2):46-52. [view]
16. Roumie CL, Mitchel E, Gideon PS, Varas-Lorenzo C, Castellsague J, Griffin MR. Validation of ICD-9 codes with a high positive predictive value for incident strokes resulting in hospitalization using Medicaid health data. Pharmacoepidemiology and drug safety. 2008 Jan 1; 17(1):20-6. [view]

Journal Other

1. Huizinga MM, Roumie CL, Elasy TA, Murff HJ, Greevy R, Liu X, Speroff T, Griffin M. Changing incident diabetes regimens: a Veterans Administration cohort study from 2000 to 2005. [Letter to the Editor]. Diabetes Care. 2007 Aug 1; 30(8):e85. [view]

Conference Presentations

1. Munson GW, Wallston KA, Dittus RS, Speroff T, Roumie CL. Activation and adaptability: Correlations with healthcare outcomes among veterans with inflammatory bowel disease (IBD). Poster session presented at: Society of General Internal Medicine Annual Meeting; 2009 May 1; Miami, FL. [view]
2. Munson GW, Wallston KA, Dittus RS, Speroff T, Roumie CL. Activation and adaptability: Correlations with healthcare outcomes among veterans with inflammatory bowel disease (IBD). Poster session presented at: VA HSR&D National Meeting; 2008 Feb 1; Baltimore, MD. [view]
3. Choma NN, Huang RL, Mitchel EF, Kaltenbach L, Gideon P, Dyer S, Roumie CL. An algorithm to identify incident myocardial infarction using Medicaid data. Poster session presented at: Society of General Internal Medicine Annual Meeting; 2009 May 1; Miami, FL. [view]
4. Choma NN, Griffin MR, Greevy R, Kaltenbach L, Roumie CL. Blood Pressure Control among Patients with Hypertension and Newly Diagnosed Diabetes. Presented at: American Diabetes Association Annual Scientific Session; 2010 Jun 25; Orlando, FL. [view]
5. Choma NN, Huang RL, Dittus RS, Roumie CL. CL Local Quality Improvement Initiative Improves Hypertension Care among Veterans. Poster session presented at: American Heart Association Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke Annual Scientific Sessions; 2008 May 1; Baltimore, MD. [view]
6. Bravata DM, Williams LS, Ross JS, Arling G, Ofner S, Roumie CL, Keyhani S, Ordin D. Correlation between inpatient and outpatient measures of stroke care quality within Veterans Health Administration Hospitals. Paper presented at: American Heart Association Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke Annual Scientific Sessions; 2010 May 12; Washington, DC. [view]
7. Choma NN, Huang RL, Dittus RS, Burnham K, Roumie CL. Local Quality Improvement Initiative Improves Hypertension Care among Veterans. Poster session presented at: VA Career Development Award Program Annual Conference; 2009 Feb 1; Baltimore, MD. [view]
8. Choma NN, Roumie CL, Kaltenbach L, Mitchel EF, Arbogast PG, Griffin MR. Non Aspirin NSAIDs, Cyclo-Oxygenase 2 Inhibitors and the Risk for cardiovascular events—stroke, acute myocardial infarction, and sudden cardiac death. Poster session presented at: Society of General Internal Medicine Annual Meeting; 2008 Apr 8; Pittsburgh, PA. [view]
9. Roumie. Non Aspirin NSAID's, Cyclo-Oxygenase 2 Inhibitors and the Risk for Stroke. Paper presented at: Society of General Internal Medicine Annual Meeting; 2007 Apr 26; Toronto, Canada. [view]
10. Roumie, Huizinga MM, Elasy TA, et al.. Patterns and Persistence of Incident Diabetes prescriptions. Poster session presented at: Society of General Internal Medicine Annual Meeting; 2007 Apr 27; Toronto, Canada. [view]
11. Roumie C, Greevy R, Maney M, Findley TW. Prevalence of inadequate hypertension control among veterans after a major cardiovascular event. Presented at: Society of General Internal Medicine Annual Meeting; 2007 Apr 27; Toronto, Canada. [view]
12. Roumie CL, Huizinga MM, Murff HJ. The effect of incident diabetes regimens on lipid profiles in veterans with Type 2 Diabetes. Presented at: American Diabetes Association Annual Scientific Session; 2010 Jun 25; Orlando, FL. [view]
13. Roumie CL, Ross JS, Ofner S. The quality of hypertension care among veterans after hospitalization for an acute ischemic stroke. Poster session presented at: VA HSR&D National Meeting; 2011 Feb 16; National Harbor, MD. [view]
14. Huang , Huizinga , Roumie, Elasy, Dittus. Using Statistical Process Control to drive Improvement in door to balloon time. Poster session presented at: Society of General Internal Medicine Annual Meeting; 2007 Apr 27; Toronto, Canada. [view]
15. Roumie CL, Greevy R, Elasy TA. Veteran Self reports of activation and patient centered care predicts medication adherence among veterans with hypertension. Poster session presented at: American Heart Association Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke Annual Scientific Sessions; 2008 May 1; Baltimore, MD. [view]
16. Roumie CL, Greevy R, Elasy TA. Veteran Self reports of activation and patient centered care predicts medication adherence among veterans with hypertension. Poster session presented at: Society of General Internal Medicine Annual Meeting; 2008 Apr 9; Pittsburgh, PA. [view]
17. Roumie CL, Greevy R, Elasy TA. Veteran Self reports of activation and patient centered care predicts medication adherence among veterans with hypertension. Poster session presented at: VA HSR&D National Meeting; 2008 Feb 1; Baltimore, MD. [view]

DRA: Cardiovascular Disease, Diabetes and Other Endocrine Disorders
DRE: Epidemiology
Keywords: Comparative Effectiveness, Pharmaceuticals
MeSH Terms: none