Purpose

To evaluate pharmacists’ impact on diabetes outcomes in kidney transplant recipients (KTRs) after implementation of a collaborative practice agreement (CPA) under which pharmacists performed diabetes management.

Methods

In this single-center, retrospective cohort study, adult patients who received a kidney transplant at the institution during the study period were followed for at least 3 months. The primary endpoint was the percentage of KTRs with at least 1 hospitalization due to hyperglycemia within 3 months of transplant. The secondary endpoints included the number of post-transplant hospitalizations, and emergency department (ED) visits due to uncontrolled diabetes and the characterization of drug class utilization within 3 months of transplant.

Results

The pre- and post-CPA cohorts included 88 and 85 patients, respectively. The percentage of KTRs with at least 1 hospitalization due to hyperglycemia in the pre-CPA cohort was 0% (n = 0) vs. 1% (n = 1) in the post-CPA cohort (P = 0.49). There were no ED visits due to uncontrolled diabetes in either cohort. Overall, 32% of KTRs were receiving sulfonylureas, 3% were on dipeptidyl peptidase-4 (DPP-4) inhibitors, and 55% were taking insulin in the pre-CPA cohort versus 9% on sulfonylureas, 31% on DPP-4 inhibitors, 87% on insulin in the post-CPA cohort.

Conclusion

The patients included in this study had a low frequency of hospitalizations and ED visits due to hyperglycemia. Guideline-directed medications were initiated and continued in greater percentages of patients after implementation of the CPA.

Kidney transplant recipients (KTRs) are at risk of developing hyperglycemia during the immediate post-transplant phase.1  KTRs experience this increased risk due to physiological changes after renal transplant, such as impaired insulin secretion.2  The risk for hyperglycemia is heightened by immunosuppressant maintenance therapy with steroids, calcineurin inhibitors, and other medications that complicate glycemic control.3,4  Therefore, close glucose monitoring and management is necessary in the early post-transplant period. The American Diabetes Association (ADA) recommends close follow-up with a primary care provider (PCP) or endocrinologist after discharge5 ; however, establishing care for diabetes management after discharge in a timely manner can pose a great challenge for KTRs. This challenge is amplified in KTRs who have a new diagnosis of diabetes after transplant or whose diabetes appeared to be controlled before transplant due to end-stage renal disease. This subset of patients may lack close care with a PCP or endocrinologist for diabetes management before transplant.

Diabetic management in KTRs by pharmacists has resulted in positive diabetic and cardiovascular outcomes, including a reduction in hemoglobin A1C from baseline.6,7  In addition, a small study demonstrated a pharmacist-managed post-transplant hyperglycemia program minimized rehospitalizations due to hyperglycemia (9 hospitalizations in the pre-transplant phase vs. 1 hospitalization afterward).8 

Pharmacists’ impact on glycemic control in this patient population should be further investigated given the heightened risk of glycemic complications during the immediate post-transplant phase and challenges to establishing care with PCP or endocrinologist in a timely manner. A pharmacist-driven collaborative practice agreement (CPA) was initiated for inpatients at our institution in April 2019 to assist transplant nephrologists with diabetes management. Before this study, the impact of the CPA implementation on diabetic outcomes in KTRs at this institution had not been studied. Additionally, the type of antihyperglycemic agents used in the immediate post-transplant period for KTRs had not been characterized.

The objective of this study was to evaluate the impact on hospitalizations and emergency department (ED) visits due to uncontrolled diabetes in KTRs after implementation of a pharmacist CPA. In addition, this study aimed to characterize the utilization of guideline-directed oral antiglycemic agents during the immediate post-transplant period after implementation of a pharmacist CPA.

This study was a single-center, retrospective cohort study. The study cohorts were determined based on whether the time of transplant was before or after the implementation of the CPA for diabetic management in KTRs. Participants were identified through the SlicerDicer tool in the Epic electronic medical record (EMR) using procedure codes for kidney transplantation and ICD-10 codes (E10, E11, diabetes registry concept grouper) to account for previously diagnosed and newly diagnosed diabetes type 1 and type 2 as well pharmacy referral order for the post-pharmacy CPA group.

Participants were screened for eligibility through EMR chart review. The inclusion criteria included adult patients (≥ 18 years of age) who received a kidney transplant at this academic medical center. Patients who were lost to follow-up (no follow-up with the institution's transplant clinic for at least 3 months post-transplantation) and vulnerable patients, as defined by the Institutional Review Board (IRB), were excluded from this study. The IRB defined vulnerable patients as children, neonates, prisoners, and cognitively impaired adults. This study was approved by the organization's IRB.

The study period included eligible patients transplanted between August 1, 2018, to December 31, 2019, for the pre-pharmacist CPA cohort and between May 1, 2020, to April 30, 2021, for post-pharmacist CPA cohort.

The primary endpoint was the percentage of KTRs with at least 1 hyperglycemia-related hospitalization within 3 months of the transplant date. The secondary endpoints included the total number of post-transplant hyperglycemia-related hospitalizations and the total number of ED visits due to either hypoglycemia or hyperglycemia within 3 months of the transplant date.

The total number of pharmacist visits within 3 months of the transplant date for the post-pharmacist CPA cohort was also collected. Pharmacist encounters were defined as telephone, video, or in-person visits. The medication drug classes prescribed at the time of transplant and within 3 months post-transplant were collected to characterize drug-class utilization. These endpoints were collected via EMR chart review.

The power calculation, with an alpha of 0.05 and beta of 0.2, was performed using a 2-arm binomial test. Using estimates from Do et al. showing an 18% reduction in the incidence of hospitalizations due to hyperglycemia in KTR after pharmacist CPA implementation, the power calculation indicated that 49 participants were needed in each cohort.

The statistical analysis of the baseline characteristics, primary endpoint, and secondary endpoints was completed using a chi-square test or Fisher's exact test for proportional data and a 2-sample t-test for numeric data. Hypothesis tests were 2-sided and evaluated at a significance level of 0.05 using the SAS version 9.4 (SAS Institute, Cary, North Carolina).

A total of 212 participants met eligibility criteria based on SlicerDicer criteria, including 120 patients identified for the pre-CPA study cohort. Upon chart review, 1 patient had undergone transplant before the study period, 1 patient had a failed transplant, and 30 had no history of diabetes or new-onset diabetes after transplantation (NODAT) within the 3 months post-transplant therefore were excluded. A total of 88 patients were included for analysis in the pre-CPA cohort.

Based on review of charts for the 92 patients in the post-CPA cohort, 7 patients were excluded because their diabetes was managed by their PCP or endocrinologist instead of the transplant pharmacist. Thus, a total of 85 patients were included for analysis (Figure 1).

Figure 1

Flow Chart of Participant Enrollment, Assignments, and Outcomes

Figure 1

Flow Chart of Participant Enrollment, Assignments, and Outcomes

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Some baseline characteristics differed between cohorts (Table 1). The cohorts differed significantly in their mean age (56.7 in pre-CPA vs. 60.0 in post-CPA cohorts, P = .03), graft function (good 50%, slow 19%, delayed 31% in pre-CPA vs. good 20%, slow 33%, delayed 47% in post-CPA, P = <.001), and dialysis requirement (20% in pre-CPA vs. 41% in post-CPA, P = .0031).

Table 1

Baseline Characteristics of Study Participants

Baseline Characteristics of Study Participants
Baseline Characteristics of Study Participants

The rates of hospitalization due to hyperglycemia were low in both cohorts, with none in pre-CPA cohort versus 1 in post-CPA cohort (P = .49). There were no hospitalizations due to hypoglycemia or ED visits due to hyperglycemia or hypoglycemia in either cohort.

Transplant pharmacists had a mean (SD) of 5.2 (2.82) encounters per patient per 90 days. Drug-class utilization differed between cohorts both before transplant and within 3 months of transplant. Before transplant, fewer patients were on sulfonylureas in the pre-CPA cohort versus in the post-CPA cohort (16% vs. 29%, P = .03). After transplantation, in the pre-CPA cohort, more patients were on no medications for diabetes (25% vs. 5% P = .0002), fewer patients were on insulin (55% vs. 87%, glycemia P < .0001), more patients were on sulfonylureas (32% vs. 9%, P = .0003), and fewer patients were on dipeptidyl peptidase-4 (DPP-4) inhibitors (3% vs. 31%, P < .0001) compared with the post-CPA cohort (Figure 2 and Table 2).

Figure 2

Medication Use Trends Before and After Implementation of the Pharmacist-Driven Collaborative Practice Agreement

Figure 2

Medication Use Trends Before and After Implementation of the Pharmacist-Driven Collaborative Practice Agreement

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Table 2

Medication Drug Class Utilization Before Transplant and Within 3 Months Post-Transplant

Medication Drug Class Utilization Before Transplant and Within 3 Months Post-Transplant
Medication Drug Class Utilization Before Transplant and Within 3 Months Post-Transplant

Overall, the frequency of hospitalizations due to hyperglycemic events was low in both cohorts. Given the low event rate, we were unable to conclude the absence of a difference in the primary outcome. There were no negative events for the secondary outcomes, demonstrating the safety of pharmacists managing diabetes under a CPA in this patient population.

The baseline characteristics showed the post-CPA cohort has more risk factors for complications than the pre-CPA cohort, and this can complicate glycemic management. The patients in post-CPA cohort were older compared with the pre-CPA cohort. Older age can complicate medication management and increase the risk for severe adverse drug events with high-risk medications such as insulin. In addition, patients in post-CPA cohort had more uncontrolled diabetes and worse renal function. The mean hemoglobin A1c was higher in the pharmacist-managed cohort. However, this was not statistically significant.

More patients in the pharmacist-managed cohort required antihyperglycemic agents for diabetes control, implying poorer diabetes control in these patients. There was a larger percentage of patients with slow or delayed graft function after transplant in the pharmacist-managed cohort, further complicating diabetes management due to the potential for fluctuating insulin secretion and impairment.9  This difference may have been due to the organs allocated to the site during the study period and/or other factors not assessed in this study.

This study demonstrated positive trends in drug utilization during pharmacist-driven medication management during the immediate post-transplant phase. The recommendation from the American Diabetes Association guidelines throughout the study period included adding an oral agent based on drug-specific and patient-specific factors. Non-insulin antihyperglycemic agents are often limited during the immediate post-transplant phase.9,10  Oral antihyperglycemic agents are limited because of fluctuating renal function and adverse effects such as the increased risk of urinary tract infection with sodium-glucose co-transporter-2 (SGLT2) inhibitors or fluid retention with thiazolidinediones. Data are limited on the use of glucagon-like peptide (GLP-1) agonists and SGLT2 inhibitors during the immediate post-transplant phase.11  Therefore, diabetes is commonly managed with agents such as sulfonylureas or DPP-4 inhibitors.

DPP-4 inhibitors are a favorable choice in KTRs because of their limited risk of hypoglycemia and their protective effects on the beta islet cell.12  1n addition, DPP-4 inhibitors target postprandial glucose reduction, which is an added benefit for KTRs who are taking steroids.13  In comparison, sulfonylureas are a less preferred choice given the elevated risk for hypoglycemia and the adverse effect of weight gain. The study results demonstrated a positive increase in DPP-4 inhibitor use and a decrease in the use of sulfonylureas in the pharmacist-managed cohort. In contrast, before the implementation of the pharmacist CPAs, use of sulfonylureas was greater and DPP-4 inhibitor use was lower.

Aside from initiating more favorable medications, the patients in the pharmacy-managed cohort were initiated on medications for diabetes control sooner, as evidenced by only 5% of patients not being on an antihyperglycemic agent within 3 months of transplant compared to 35% in the pre-CPA cohort (P = .0002). In addition, there was a statistically significant higher percentage of insulin use in post-CPA cohort without an increase in hypoglycemic events. Therefore, insulin therapy was initiated more quickly and was safely managed in the pharmacist CPA period.

The retrospective design of this study limited data to those available in EMRs. This could have potentially contributed to missing a hospitalization or ED visit at another institution; however, our institution's EMR has the capability of linking outside records, reducing the risk of missed data.

Additionally, the availability of data limited the types of outcomes that could be collected. Self-monitored blood glucose data were available in pharmacist chart notes for the post-CPA cohort, but these were not consistently documented for the pre-CPA cohort. Additionally, hemoglobin A1c data were not consistently available, as the institution did not have a standard protocol to collect these at the time of transplant and 3 months post-transplant for all patients. Therefore, hospitalizations due to hyperglycemia were selected as the primary endpoint as this outcome was objective and available.

Furthermore, data collection for baseline characteristics and outcomes relied on manual chart review by 2 researchers working independently. To alleviate discrepancies, each data point was collected using the same method by the researchers and data validation was completed.

This study included a diverse patient population, as evidenced by age, hemoglobin A1c values, and renal function. An additional strength was the use of measures that are easily replicated. Based on the initial power calculation, this study met power to detect a difference. However, given the low event rate, we were unable to draw conclusions for the primary outcome.

This study adds to the literature supporting the use of newer antihyperglycemic agents in KTRs. While multiple studies have demonstrated the safe and effective use of DPP-4 inhibitors in this population, most either excluded patients with unstable renal function or who were in the immediate post-transplant period, or did not clarify the time since transplant for their study population.11,14 

One study included patients within 24 hours of kidney transplantation; however, they focused on the use of linagliptin in the 5 days immediately post-transplant during the hospitalization, not long-term in the outpatient setting.15  This study also had a limited sample size, with only 14 patients receiving linagliptin. While tolerability of DPP-4 inhibitors was not an outcome of this study, the results show patients were on the agent at the 3-month post-transplant timepoint, suggesting they were able to tolerate the medication and therefore supports the use of DPP-4 inhibitors immediately post-transplantation in the outpatient setting.

The percentage of KTRs with a hospitalization or ED visit due to uncontrolled diabetes was low before the implementation of a pharmacist CPA and remained low afterwards. Transplant pharmacist–optimized medication management was evidenced by more rapid initiation of guideline-directed therapies during the immediate post-transplant phase. This study demonstrated that transplant pharmacists working under a CPA can effectively provide diabetes management for this high-risk patient population. Additional studies are needed to demonstrate further the safety and efficacy of newer antihyperglycemic agents in the immediate post-transplant period.

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