1. Carina Signori, DO Journal Club August 2010 Macdonald, M. et al. Diabetes Care; Jun 2010; 33, 6. 1213-1218

2. Introduction Treatment guidelines for diabetes (DM) in heart failure (CHF) patients is controversial. Evidence is insufficient: CHF patients have been excluded from trials of glucose lowering drugs Safety of diabetic medications in CHF patients still unclear.

3. Introduction Several observational studies have shown prognostic differences between various diabetic meds in CHF patients However, no placebo group is available to compare prognosis Also, no data was available for potential confounders in CHF

4. Objective of Study To examine mortality risk in patients with diabetes and heart failure To examine whether outcomes were associated with a particular antidiabetic drug therapy.

5. Methods Case control study Using the U.K. General Practice Research Database Cohort with information on comorbidities and treatments Collected from >450 general practictioners in U.K. Often used for studies of benefits and harms for prescription medications. Includes patient demographics, physical and lab data, diagnoses, outpatient medications. Clinical diagnoses assigned by PCP.

6. Methods Clinical comorbidities were coded from the time patient entered into the database up until index date. Code selection for each diagnosis was done by 2 researchers independently and cross checked by a third.

7. Methods Study sample Inclusion criteria: >35yo with newly dx’d type 2 DM and CHF between January 1988-2007 with >1year of data Exclusion: Dx of DM or CHF <1988, type I DM, gestational DM, or drug induced DM All patients were followed until death, termination from database, or October 2007.

8. Methods Case subjects = patients in cohort with DM and CHF who died (all cause mortality) Control subjects: Matched to cohort patients on age (+-5 years), sex, general practice, calendar year, years of follow up within GPRD. Patient had to be alive on index date (date case subject had died).

9. Methods Definition of medication exposure: Current use = 1 prescription recorded in 90 days prior to index date. Classification of antidiabetic drug exposure No drug tx, sulfonylurea alone, metformin alone, TZD alone, insulin alone, combination therapy with insulin, combination oral without insulin. Evaluated any use of diabetic medication in a sensitivity analysis 90 days prior to index date. Adjusted for duration of DM, CHF and which developed first. Drug use was examined 6 months and 12 months prior to index date.

10. Statistical analysis Conditional logistic regression used to estimate crude and adjusted odds ratios. Numerous potential confounding variables were adjusted for. Analysis was conducted using SAS version 9.2 P value of 0.05 was used.

11. Results 8404 patients found to have DM and CHF dx’d between 1988 and 2007. 1633 patients who died were matched with 1633 control subjects. Mean living with DM and CHF was 2.8, 2.9 years in case subjects and control subjects respectively. DM diagnosed first in 54% of case patients and 41% of control subjects (mean time of dx: 3.9, 3.3). CHF diagnosed first in 44% of case subjects and 58% of control subjects (mean time of dx: 3.1, 3.2 respectively)

12. Results Mean age was 78 years at index date. 1738 male (53%) Average time followed in GPRD was 11 years. Case and control subjects matched well in age, sex and time within GPRD. Case subjects had higher rates of comorbidities and abnormal lab values Poor prognostic factors evaluated: hypotension, elevated cr, anemia, copd, cancer, dementia, cva, prior MI Elevated BMI was associated with lower mortality risk. 644 (18%) of patients received ACEI/ARB and beta blockers. 271 (12%) received ACEI/ARB, BB, ASA, statin. ACEI/ARBS, BB, ASA, Dig, statins all independently associated with reduced mortality risk in pts with CHF and DM.

13. Results Diabetes treatment Off medications 1306 patients (40%) were not exposed to antidiabetic meds in the 90 days prior to the index date. It was presumed they were using diet and lifestyle On medications Sulfonylurea was most common (n-753, 25%), then combination oral therapy without insulin (n=470, 14%), then metformin monotherapy (n=378, 12%)

14. Results All cause mortality Unadjusted analyses= compared to patients not on antidiabetic therapy, users of sulfonylureas, metformin, or combination antiDM meds exhibited lower mortality risk. Adjusted analysis = only current use of metformin monotherapy associated with covariates (adjusted OR 0.65 [0.48-0.87]

15. Results Metformin alone had lower mortality even when duration of DM and CHF were adjusted for (0.63 [0.47- 0.86], GFR was included as a continuous variable (0.68 [0.49- 0.93] If DM was adjusted for diagnosed first (0.65 [0.48-0.88]. No association between current use of other diabetic medications and all-cause morality

16. Results Outcomes for “any use” of drugs= Only metformin was associated with all-cause mortality reduction (OR.72 [-.59-0.9], p=0.003). No association seen for any of the other medications (p>0.2)

17. Conclusions Compared with individuals not exposed to antidiabetic drugs, metformin use is associated with lower mortality risk than other medications even after adjusting for other prognostic factors. This is consistent with other study findings suggesting metformin has a positive effect instead of harm from other agents. Metformin may improve heart failure based on improving insulin resistance. There was no association between A1C and mortality

18. Conclusions Mortality risk was improved in diabetic and heart failure patients on ACEI and BB. However only 18% of study patients were on both.

19. Conclusions Weaknesses: High amount of patients not on antidiabetic medications (40%). Authors presumed these patients were doing dietary or lifestyle modifications Data collected from UKGPRD depends on physician diagnoses or documentation of heart failure There could be a selection bias- metformin patients may have less severe diabetes Observational study so confounding variables may be present.

20. Conclusion The results suggest metformin has better outcomes (compared to other DM meds) in patients with DM and CHF. This is consistent with observational studies Metformin reduces mortality risk compared to age and sex matched diabetics on no antidiabetic medications Independent of glycemic control, BMI and other prognostic factors. Metformin can be used patients with heart failure to treat diabetes.