Genome-wide association study of hospitalized patients and acute kidney injury.

Acute kidney injury (AKI) is a common and devastating complication of hospitalization. Here, we identified genetic loci associated with AKI in patients hospitalized between 2002-2019 in the Million Veteran Program and data from Vanderbilt University Medical Center's BioVU. AKI was defined as meeting a modified KDIGO Stage1 or more for two or more consecutive days or kidney replacement therapy. Control individuals were required to have one or more qualifying hospitalizations without AKI and no evidence of AKI during any other observed hospitalizations. Genome-wide association studies (GWAS), stratified by race, adjusting for sex, age, baseline estimated glomerular filtration rate (eGFR), and the top ten principal components of ancestry were conducted. Results were meta-analyzed using fixed effects models. In total, there were 54,488 patients with AKI and 138,051 non-AKI individuals included in the study. Two novel loci reached genome-wide significance in the meta-analysis: rs11642015 near the FTO locus on chromosome 16 (obesity traits) (odds ratio 1.07 (95% confidence interval, 1.05-1.09)) and rs4859682 near the SHROOM3 locus on chromosome 4 (glomerular filtration barrier integrity) (odds ratio 0.95 (95% confidence interval, 0.93-0.96)). These loci colocalized with previous studies of kidney function, and genetic correlation indicated significant shared genetic architecture between AKI and eGFR. Notably, the association at the FTO locus was attenuated after adjustment for BMI and diabetes, suggesting that this association may be partially driven by obesity. Both FTO and the SHROOM3 loci showed nominal evidence of replication from diagnostic-code-based summary statistics from UK Biobank, FinnGen, and Biobank Japan. Thus, our large GWA meta-analysis found two loci significantly associated with AKI suggesting genetics may explain some risk for AKI.

Recent metformin adherence and the risk of hypoglycaemia in the year following intensification with a sulfonylurea.

AIM: To evaluate whether recent low adherence to metformin monotherapy is associated with hypoglycaemia after addition of a sulfonylurea. METHODS: We assembled a retrospective cohort of veterans who filled a new prescription for metformin between 2001 and 2011 and intensified treatment with a sulfonylurea after ≥1 year of metformin use. We calculated metformin adherence from pharmacy data using the proportion of days covered in the 180-day period before intensification. The primary outcome was hypoglycaemia, defined as a hospitalization or emergency department visit for hypoglycaemia or an outpatient blood glucose measurement <3.3 mmol/l in the year following intensification. Cox proportional hazards models were used to compare the risk of hypoglycaemia between participants with low (<80%) and high (≥80%) adherence. Adherence was also modelled as a continuous variable using restricted cubic splines. RESULTS: Of 187 267 participants who initiated metformin monotherapy, 49 424 added a sulfonylurea after ≥1 year. The median (interquartile range) rate of treatment adherence was 87 (50-100)% and 43% had adherence <80%. Hypoglycaemia rates per 1000 person-years were 23.1 (95% CI 21.1-25.4) and 24.5 (95% CI 22.7-26.4) in participants with low and high adherence, respectively (adjusted hazard ratio 0.95, 95% CI 0.84-1.08). The risk of hypoglycaemia was similar across all levels of adherence when adherence was modelled as a continuous variable. CONCLUSIONS: We found no evidence that past low adherence to metformin monotherapy was associated with hypoglycaemia after intensification with a sulfonylurea.

Blood pressure control among patients with hypertension and newly diagnosed diabetes.

AIMS: To determine the proportion of patients who achieved blood pressure control during the 2 years following new diabetes diagnosis. METHODS: A retrospective cohort of veterans ≥ 18 years with hypertension who initiated a diabetes medication from 2000 to 2007 in the Veterans Administration Mid-South Network was assembled. Blood pressure control at diabetes treatment initiation (baseline) was compared with blood pressure control 6, 12, 18 and 24 months later. The Veterans Affairs and American Diabetes Association definitions of control, ≤ 140/90 and ≤ 130/80 mmHg, respectively, were primary and secondary outcomes. RESULTS: At baseline, 59.5% of 16,182 patients had controlled blood pressure according to the Veterans Affairs guideline (31.5% using American Diabetes Association definition). Six months following initiation of diabetes treatment, 65.7% had their blood pressure controlled (P < 0.001). Blood pressure control was sustained but not further improved between 6 months and 2 years, with 66.5% controlled at 2 years following baseline. Higher initial systolic blood pressure, black race and hospitalization in the previous year were associated with higher likelihood of uncontrolled blood pressure at 6 months; whereas baseline cardiovascular disease, baseline dementia and later year of cohort entry were associated with lower likelihood of uncontrolled blood pressure. CONCLUSION: We found an increase in blood pressure control in the 6 months following initiation of diabetes treatment. However, overall blood pressure control remained suboptimal and with no further improvement over the next 18 months.

Comparisons of persistence and durability among three oral antidiabetic therapies using electronic prescription-fill data: the impact of adherence requirements and stockpiling.

Two important challenges are inherent in the design of studies using prescription data from electronic health records: how to define the minimum level of adherence that would qualify as "continuous drug use" and how to handle stockpiling of medications. Generally, the sensitivity of a study's conclusions to these design choices is not analyzed. In our study, covariate adjusted Cox models were used to compare persistence and durability with respect to three common oral antidiabetic therapies in a cohort of 12,697 incident users. Assuming 50% stockpiling, sulfonylurea therapy, as compared with metformin, showed a significantly lower risk of nonpersistence (changing or stopping therapy) when no gap days were allowed (HR 0.95, P = 0.032), no significant difference when 14 gap days were allowed (HR 0.99, P = 0.536), and significantly greater risk of nonpersistence when 30 gap days were allowed (HR 1.05, P = 0.046). All the drug comparisons showed statistically significant effects in both directions, the risk of nonpersistence increasing or decreasing depending on the design parameters.