Unmet needs and opportunities for optimal management of patients with type 2 diabetes and chronic kidney disease.

This brief report utilizes EHR data from a large US health system to summarize unmet needs in patients with type 2 diabetes and chronic kidney disease and identifies areas of opportunity to optimize management within this patient population from treatment, screening and monitoring, and health care resource use perspectives.

Descriptive study of the economic burden among patients with type 2 diabetes mellitus, chronic kidney disease, and chronic kidney disease and type 2 diabetes mellitus in a large US commercially insured population.

BACKGROUND: Chronic kidney disease (CKD) is a major public health concern that affects 37 million adults in the United States. It is well known that CKD presents a large economic burden, especially in the Medicare population. However, studies of the economic burden of CKD in younger populations are scarce. In particular, there is a gap in understanding how the presence of type 2 diabetes mellitus (T2DM) affects the burden of CKD in commercially insured populations. OBJECTIVE: To describe the economic and health care resource utilization (HCRU) burden of CKD within 3 patient groups (T2DM only, CKD only, and CKD and T2DM) aged 45-64 years overall and by Kidney Disease Improving Global Outcomes (KDIGO) CKD estimated glomerular filtration rate-based stage categories. METHODS: A descriptive, observational retrospective cohort study was conducted using administrative medical and pharmacy claims integrated with laboratory results data available in the HealthCore Integrated Research Database from January 1, 2017, to December 31, 2019. Three mutually exclusive groups of commercially insured patients aged 45-64 years were identified: T2DM only, CKD only, and CKD and T2DM. All-cause and disease-specific HCRU and costs in total, by medical and pharmacy benefits and across all places of service, were described for each of these groups 12 months after index date. For the CKD only and CKD and T2DM groups, costs were also described by KDIGO CKD stage. RESULTS: The CKD and T2DM group (n = 13,052) had numerically higher 12-month post-index all-cause and CKD/T2DM-related HCRU across all places of service. Mean 12-month all-cause costs for this group were $35,649, whereas costs for the CKD only group (n = 7,876) were $25,010 and costs for the T2DM only group (n = 120,364) were $16,121. Costs also tended to increase as CKD stage increased, with the greatest increases beginning at KDIGO stage 3b and higher. Mean 12-month all-cause costs for the CKD and T2DM group ranged from $29,993 to $41,222 for stages 1 to 3a and from $46,796 to $119,944 for stages 3b to 5. CONCLUSIONS: Commercially insured patients aged 45-64 years with CKD, especially those who also have T2DM, present a substantial burden in terms of elevated HCRU and costs. Costs tend to increase across KDIGO CKD stages and increase most rapidly at stage 3b and later. Therefore, there is an opportunity to reduce the burden of CKD in this population by investing in interventions to prevent or delay CKD disease progression. DISCLOSURES: HealthCore, Inc, received funding to perform this research, as well as funding from multiple pharmaceutical companies to perform various research studies outside of the submitted work. Mr Crowe and Dr Willey are employees of HealthCore, Inc., a wholly owned subsidiary of Elevance Health, Inc. Ms Chung was an employee of HealthCore, Inc., a wholly owned subsidiary of Elevance Health, Inc, at the time of study performance. Ms Chung and Dr Willey are shareholders of Elevance Health, Inc. Dr Kong, Dr Singh, Mr Farej, Dr Elliot, and Dr Williamson are employees of Bayer US, LLC. Dr Singh is a shareholder of Bayer US, LLC.

Geographical variation in kidney function testing and associations with health care costs among patients with chronic kidney disease and type 2 diabetes.

OBJECTIVES: Clinical practice guidelines recommend at least annual testing of estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (uACR) for patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). This study assessed the adequacy of eGFR and uACR testing in this patient population across the United States. STUDY DESIGN: Observational real-world study. METHODS: Adults with CKD and T2D were identified from the Optum Clinformatics database (2015-2019). The eGFR and uACR tests were assessed nationally and by state. The proportions of tested patients and patients receiving adequate monitoring per clinical practice guidelines were analyzed during the 1-year period after T2D and CKD diagnosis, along with all-cause health care costs. RESULTS: Among 101,057 adults with CKD and T2D, 94.1% had at least 1 eGFR test and 38.7% had at least 1 uACR test over 1 year. Only 20.3% of patients had adequate uACR monitoring; this was much lower than observed for adequate eGFR monitoring (86.6%). The eGFR testing rates were high across states (range, 79.5% [Colorado] to 97.3% [Alabama]); conversely, uACR testing rates were uniformly lower and showed wider variation (range, 14.0% [Maine] to 58.9% [Hawaii]). Mean annual all-cause health care costs were $28,636 and increased with CKD GFR stage. Lower uACR testing rates were associated with higher health care costs at the state level (Pearson r = -0.55; P < .01). CONCLUSIONS: In the United States, uACR testing is underutilized, with large geographical variations in testing rates noted between states. Lower uACR testing rates were associated with higher health care costs. The lack of sufficient uACR testing raises concerns about CKD management in patients with T2D.

Development of clinical prediction models for renal and cardiovascular outcomes and mortality in patients with type 2 diabetes and chronic kidney disease using time-varying predictors.

AIMS: To develop a set of prediction models for end-stage kidney disease (ESKD), cardiovascular outcomes, and mortality in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) using commonly measured clinical variables. METHODS: We studied 1432 participants with T2D and CKD enrolled in the Chronic Renal Insufficiency Cohort, followed for a median period of 7 years. We used Cox proportional-hazards models to model the six outcomes (ESKD, stroke, myocardial infarction (MI), congestive heart failure (CHF), death before ESKD, and all-cause mortality). We internally evaluated these models using concordance and calibration measures. RESULTS: The newly developed six prediction models included 15 predictors: age at diabetes diagnosis, sex, blood pressure, body mass index, hemoglobin A1c, high density lipoprotein cholesterol, urine protein-to-creatinine ratio, estimated glomerular filtration rate, smoking status, and history of stroke, MI, CHF, ESKD, and amputation. The resulting models demonstrated good/strong discrimination (cross-validation C-index range: 0.70 to 0.90) and calibration. CONCLUSIONS: This study provided an internally validated and useful tool for predicting individual adverse outcomes and mortality in patients with T2D and CKD. These models may inform optimal use of targeted health interventions.

CKD Prevalence Among Patients With and Without Type 2 Diabetes: Regional Differences in the United States.

RATIONALE & OBJECTIVE: Regional variation in chronic kidney disease (CKD) prevalence in patients with or without type 2 diabetes mellitus (T2DM) has not been well characterized. STUDY DESIGN: Spatial and temporal comparative analysis. SETTING & PARTICIPANTS: MarketScan databases were used to identify patients with CKD overall and subgroups of patients with CKD with and without T2DM in the United States. OUTCOMES: Spatial patterns in CKD prevalence based on year, regional clusters of CKD between years, and characteristics of patients in high-prevalence states. ANALYTICAL APPROACH: Geomapping was used to visualize the state-level data of CKD prevalence generated from 2013 to 2018. We used univariate local indicators of spatial association (LISA) to evaluate geographic differences in prevalence, differential LISA for changes in CKD prevalence over time, and the χ2 test to identify patient characteristics in the top-20th percentile states for the prevalence of CKD. RESULTS: In univariate LISA, low-low clusters, in which a state has a low CKD prevalence and the surrounding states have a below-average CKD prevalence, were observed in the northwest region throughout the study period, regardless of the T2DM status, indicating a consistently low prevalence of CKD clustered in these areas. High-high clusters were observed, regardless of the T2DM status, in the southeast region in more recent years, suggesting an increased CKD prevalence in this region. LIMITATIONS: Health care insurance enrollment might not have been representative of the United States; the estimates were based on claims data that likely underestimated the true prevalence. CONCLUSIONS: Geographic disparities in CKD prevalence appear increasingly magnified, with an increase in the southeastern region of the United States. This increase is especially problematic because patients with CKD in high-prevalence states experience a greater likelihood of chronic conditions than those in the rest of the United States.

The effect of genistein aglycone on cancer and cancer risk: a review of in vitro, preclinical, and clinical studies.

In Asian epidemiological studies, health benefits, including reduced incidence of breast and prostate cancers, are attributed to soy food and isoflavone consumption. The recent increased intake of soy foods and supplements in the American diet has raised concerns about the possible estrogen-like effects of natural isoflavones and possible promotion or propagation of estrogen-sensitive cancers. These concerns are primarily based on in vitro and rodent data which suggest that genistein aglycone can stimulate tumor cell proliferation and growth in mice having deficient immune systems. In contrast, a recent nested case-control study and meta-analysis of numerous epidemiological studies show an inverse correlation between genistein intake and breast cancer risk. Furthermore, clinical studies in osteopenic and osteoporotic, postmenopausal women support the breast and uterine safety of purified naturally derived genistein administered for up to 3 years. In this review, we summarize the in vitro, preclinical and clinical evidence for the safety of natural genistein.

Cocaine disrupts pup-induced maternal behavior in juvenile and adult rats.

Impaired onset of maternal behavior in first generation rat dams was previously correlated with rearing by cocaine-treated dams and prenatal cocaine exposure. Pup-induced maternal behavior in non-lactating rats has not been examined with regard to cocaine exposure and rearing conditions. First generation male and female juveniles and young adult males reared by cocaine-treated or control dams and prenatally exposed to either cocaine or control conditions were tested for pup-induced maternal behavior at postnatal days 28 and 60. We now report disruptions in pup-induced maternal behavior in both 28 and 60 day old first generation offspring attributable to rearing condition and prenatal cocaine exposure.

Neurokinin 1 receptor signaling mediates sex differences in mu and kappa opioid-induced enhancement of contact hypersensitivity.

Contact hypersensitivity (CHS) is a type of cutaneous inflammation that is exacerbated by neurogenic factors. Both mu- and kappa-opioids enhance CHS to a greater extent in females than males. It was hypothesized that potentiated neurokinin 1 (NK1) receptor signaling following opioid treatment accounts for sex differences in the magnitude of CHS. Following morphine or spiradoline treatment the NK1 receptor antagonist SR140,333 significantly attenuated the magnitude of CHS in females but not males. By contrast, the NK2 antagonist SR48968 had no effect on morphine modulation of CHS. Taken together, these data indicate that NK1 receptor signaling is a key mediator of sex differences in opioid-induced enhancement of CHS.

Dissociation between sex differences in the immunological, behavioral, and physiological effects of kappa- and delta-opioids in Fischer rats.

RATIONALE: The sex of the individual can have a profound effect on sensitivity to the effects of opioids. Recently, our laboratory provided the first evidence that females may be more sensitive to the immune-altering effects of mu-opioids than males. However, it remains unknown whether kappa- and delta-opioids produce sexually dimorphic effects on immune responses. OBJECTIVE: The present study sought to determine whether kappa- and delta-opioids produce differential immunological effects in males and females using the memory-T-cell-dependent in vivo inflammatory response contact hypersensitivity (CHS). As sex differences in the magnitude of opioid effects can be outcome-specific, additional experiments were conducted to compare the immunological effects of kappa- and delta-opioids with other behavioral and physiological effects. MATERIALS AND METHODS: Contact hypersensitivity was induced in male and female Fischer rats. Prior to elicitation of CHS, animals were administered selected doses of the kappa-opioid spiradoline (0.2-20 mg/kg), delta-opioid SNC80 (1-10 mg/kg), or vehicle. The antinociceptive and diuretic effects of spiradoline were also assessed in males and females, as were the locomotor effects of SNC80. RESULTS: Spiradoline produced significantly greater enhancement of CHS in females than males, but produced comparable antinociceptive and diuretic effects in both sexes. By contrast, SNC80 did not significantly affect the course of CHS in either sex, but females were significantly more sensitive to its locomotor stimulatory effects. CONCLUSIONS: These results demonstrate that females are more sensitive than males to the CHS-altering effects of spiradoline and that sex differences in the magnitude and direction of opioid-induced sex differences are outcome dependent.

Cocaine treatment and prenatal environment interact to disrupt intergenerational maternal behavior in rats.

The link between impaired maternal behavior (MB) and cocaine treatment could result from drug-induced decreases in maternal reactivity to offspring, prenatal drug exposure (PDE) in offspring that could alter their ability to elicit MB, or the interaction of both, which could subsequently impair MB of the 1st-generation dams. Following chronic or intermittent cocaine or saline treatment during gestation, rat dams rearing natural or cross-fostered litters were compared along with untreated dams for MB. Untreated 1st-generation females with differentially treated rearing dams and PDE were tested for MB with their natural litters. The authors report disruptions in MB in dams and their 1st-generation offspring, attributable to main and interaction effects of maternal treatment, litter PDE, and rearing experience.

Cocaine increases inducible nitric oxide synthase expression in rats: effects of acute and binge administration.

The present studies assessed the effects of acute and binge cocaine administration on the in vivo production of inducible nitric oxide synthase in a rat model of endotoxemia. Inducible nitric oxide synthase is a key enzyme involved in host defense and inflammatory responses consequent to infection through its production of nitric oxide. Male Lewis rats received subcutaneous injections of saline or selected doses of cocaine (7.5-30 mg/kg) at the same time as a 50 microg/kg dose of lipopolysaccharide (LPS). Animals in the binge cocaine experiments received two additional injections of cocaine or saline at 2 and 4 h after the initial injections. All animals were sacrificed 6 h after initial drug administration and tissues harvested for determination of iNOS protein levels. Plasma nitrite/nitrate levels were also assayed to assess any treatment-related differences in the degradative by-products of nitric oxide metabolism. Western blot analyses of iNOS expression indicated that both acute and binge cocaine treatment resulted in significant increases in iNOS expression in all tissues assayed. Furthermore, acute and binge cocaine treatment also dose-dependently increased plasma nitrite levels. These data suggest that cocaine may impact resistance to gram-negative infections and severity of these infections via modulation of nitric oxide parameters.

An oxytocin antagonist infused into the central nucleus of the amygdala increases maternal aggressive behavior.

Decreased oxytocin levels in the amygdalas of rat dams following chronic gestational cocaine exposure have been correlated with heightened maternal aggressive behavior. In this experiment, drug-naive dams were implanted with bilateral cannulas into the central nucleus of the amygdala (CNA) or control area and infused with 1,000 or 500 ng of an oxytocin antagonist (OTA) or buffer, 4 hr before testing. Behavior was compared among dams infused with OTA into target areas just outside the CNA and cocaine-treated dams (infused with buffer). Dams infused with 1,000 ng OTA attacked intruders significantly more often than buffer-infused dams. OTA did not affect other behaviors, suggesting that disruption of oxytocin activity in the CNA may be sufficient to selectively alter maternal aggressive behavior.

Sex differences in opioid-induced enhancement of contact hypersensitivity.

Previous research has demonstrated that, in male rats, the magnitude of contact hypersensitivity (CHS) can be enhanced by morphine treatment. The present experiments test the hypothesis that the mu-opioids morphine, etorphine, and buprenorphine would produce significant sex differences in the magnitude of 2,4-dinitrofluorobenzene-induced CHS. During tests conducted over a 192-h period, morphine, etorphine, and buprenorphine administered before elicitation of CHS on the external surface of the ear (pinna) potentiated the CHS response, and the magnitude of this enhancement was significantly greater in females than males. By contrast, morphine had no effect on croton oil-induced irritant contact dermatitis, indicating that morphine's effects on CHS do not generalize to immunologically nonspecific forms of contact dermatitis. Activation of brain mu-opioid receptors is responsible for the effects of morphine on CHS, because intracerebroventricular treatment with the mu-opioid receptor antagonist beta-funaltrexamine blocked morphine potentiation of CHS in females and males. The sex differences in morphine potentiation of CHS appear to be a result of the gonadal hormonal milieu, because castration enhanced the CHS response following vehicle and morphine treatment, whereas ovariectomy significantly attenuated the enhancement of CHS by morphine. Because ovariectomy had no effect on the CHS response following vehicle treatment, the presence of female gonadal hormones may underlie the sex differences in morphine potentiation of CHS in gonadally intact animals. Overall, these results support an increased sensitivity to the modulatory effects of opioids on the CHS response in females that depends on the interaction between gonadal hormones and the central mu-opioid system.