The Intersection of SGLT2 Inhibitors, Cognitive Impairment, and CKD.

Impairment in cognition and decline in kidney function often converge in the aging individual with chronic kidney disease (CKD). Cognitive impairment (CI) may be preventable through modification of health behaviors and risk factors that contribute to the vascular disease burden. CKD patients often have multiple coexisting comorbid conditions contributing to vascular risk. These comorbidities include hypertension, diabetes, cerebrovascular disease, and cardiovascular disease. Emerging evidence suggests that the management and prevention of vascular risk factors and cardiovascular diseases may indirectly contribute to the prevention of CI in CKD. Sodium glucose transport protein 2 inhibitors (SGLT2i) are emerging as the standard of care for selected individuals with CKD, type 2 diabetes (T2DM), and heart failure with rapidly expanding indications being actively investigated. In this narrative review, we examine the intriguing hypothesis that SGLT2i demonstrate potential disease modifying properties in CI among individuals with CKD.

Opioids and the Risk of Motor Vehicle Collision: A Systematic Review.

Background: Opioid analgesics are among the most commonly prescribed medications, but questions remain regarding their impact on the day-to-day functioning of patients including driving. We set out to perform a systematic review on the risk of motor vehicle collision (MVC) associated with prescription opioid exposure. Method: We searched Medline, PubMed, EMBASE, Scopus, and TRID from January 1990 to August 31, 2021 for primary studies assessing prescribed opioid use and MVCs. Results: We identified 14 observational studies that met inclusion criteria. Among those, 8 studies found an increased risk of MVC among those participants who had a concomitant opioid prescription at the time of the MVC and 3 found no significant increase of culpability of fatal MVC. The 3 studies that evaluated the presence of a dose-response relationship between the dose of opioids taken and the effects on MVC risk reported the existence of a dose-response relationship. Due to the heterogeneity of the different studies, a quantitative meta-analysis to sum evidence was deemed unfeasible. Our review supports increasing evidence on the association between motor vehicle collisions and prescribed opioids. This research would guide policies regarding driving legislation worldwide. Conclusion: Our review indicates that opioid prescriptions are likely associated with an increased risk of MVCs. Further studies are warranted to strengthen this finding, and investigate additional factors such as individual opioid medications, opioid doses and dose adjustments, and opioid tolerance for their effect on MVC risk.

Safety of add-on sulfonylurea therapy in patients with type 2 diabetes using metformin: a population-based real-world study.

INTRODUCTION: Metformin is the initial oral antihyperglycemic agent (OHA) of choice for most patients with type 2 diabetes (T2D). However, more than one agent is often required for optimal glucose control. As the choice of preferred second OHAs is less well defined, we sought to compare the real-world safety of sulfonylureas to other OHAs as add-on therapy to metformin in patients with T2D. RESEARCH DESIGN AND METHODS: This retrospective cohort study included adults in Manitoba, Canada with T2D from 2006 to 2017. Using a new-user design, we divided patients who started on metformin into two groups: add-on therapy with a sulfonylurea and add-on therapy with a different OHA. Outcomes included all-cause mortality, cardiovascular events, and major hypoglycemic episodes. We calculated propensity scores and applied inverse probability of treatment weights to each individual. We compared groups using Cox proportional hazards regression and explored differences in HRs between pre-2008 (acarbose, meglitinides, and thiazolidinediones) and post-2008 (dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose linked transporter-2 inhibitors) OHAs. RESULTS: Our cohort included 32 576 individuals (28 077 metformin plus sulfonylurea and 4499 metformin plus 'other'). Patients newly prescribed a sulfonylurea in the setting of metformin had a higher risk of all-cause mortality (HR 1.44, 95% CI 1.12 to 1.84, p=0.005) and major hypoglycemic episodes (HR 2.78, 95% CI 1.66 to 4.66, p<0.001) than those prescribed an 'other' OHA. No differences in cardiovascular events were observed (HR 0.99, 95% CI 0.81 to 1.22, p=0.92). In subgroup analyses, mortality and cardiovascular event risk was higher in patients prescribed sulfonylureas versus post-2008 OHAs. CONCLUSIONS: Sulfonylureas as add-on therapy to metformin are associated with increased risk of all-cause mortality and major hypoglycemic episodes compared with 'other' OHAs. Post hoc analysis suggests newer OHAs may be preferred to sulfonylureas as second-line therapy for glycemic control.

Hyperkalemia and its Association With Mortality, Cardiovascular Events, Hospitalizations, and Intensive Care Unit Admissions in a Population-Based Retrospective Cohort.

INTRODUCTION: Hyperkalemia is a common, potentially life-threatening condition in patients with chronic kidney disease (CKD). We studied the association between hyperkalemia and mortality, cardiovascular events, hospitalizations, and intensive care unit (ICU) admissions. METHODS: We performed a retrospective cohort study using administrative databases in Manitoba, Canada. All adults (≥18 years of age) with potassium tests between January 2007 and December 2016 were included, with follow-up until March 31, 2017. Propensity score matching was performed among patients with de novo hyperkalemia (serum potassium ≥ 5.0 mmol/l) and patients who were nonhyperkalemic. The association between hyperkalemia and normokalemia and mortality was assessed using multivariate Cox proportional hazards regression models, adjusting for patient characteristics in a 1:1 propensity score-matched sample. Secondary outcomes included cardiovascular events, hospitalizations, and ICU admissions. A sensitivity analysis was performed with hyperkalemia defined as serum potassium ≥ 5.5 mmol/l. RESULTS: Of 93,667 patients with de novo hyperkalemia, 36% had diabetes mellitus (DM), 28% had CKD, and 21% had heart failure (HF). In the propensity score-matched sample of 177,082 individuals, hyperkalemia was associated with an increased risk for all-cause mortality (hazard ratio [HR] 1.15 [95% confidence interval {CI} 1.13-1.18], P < 0.001), cardiovascular events (HR 1.20 [95% CI 1.14-1.26], P < 0.001), short-term mortality (odds ratio [OR] 1.29 [95% CI 1.24-1.34], P < 0.001), hospitalizations (OR 1.71 [95% CI 1.68-1.74]), and ICU admissions (OR 3.48 [95% CI 3.34-3.62], P < 0.001). Findings were unchanged when a threshold of serum potassium ≥ 5.5 mmol/l was used. CONCLUSION: Hyperkalemia was an independent risk factor for all-cause mortality, cardiovascular events, hospitalizations, and ICU admissions. This finding expands our understanding of important clinical outcomes associated with hyperkalemia.

A Safety Comparison of Metformin vs Sulfonylurea Initiation in Patients With Type 2 Diabetes and Chronic Kidney Disease: A Retrospective Cohort Study.

OBJECTIVE: To compare the safety of metformin vs sulfonylureas in patients with type 2 diabetes by chronic kidney disease (CKD) stage. PATIENTS AND METHODS: This retrospective cohort study included adults in Manitoba, Canada, with type 2 diabetes, an incident monotherapy prescription for metformin or a sulfonylurea, and a serum creatinine measurement from April 1, 2006, to March 31, 2017. Patients were stratified by estimated glomerular filtration rate (eGFR) into the following groups: eGFR of 90 or greater, 60 to 89, 45 to 59, 30 to 44, or less than 30 mL/min/1.73 m2. Outcomes included all-cause mortality, cardiovascular events, and major hypoglycemic episodes. Baseline characteristics were used to calculate propensity scores and perform inverse probability of treatment weights analysis, and eGFR group was examined as an effect modifier for each outcome. RESULTS: The cohort consisted of 21,996 individuals (19,990 metformin users and 2006 sulfonylurea users). Metformin use was associated with lower risk for all-cause mortality (hazard ratio [HR], 0.48; 95% CI, 0.40-0.58; P<.001), cardiovascular events (HR, 0.67; 95% CI, 0.52-0.86; P=.002), and major hypoglycemic episodes (HR, 0.14; 95% CI, 0.09-0.20; P<.001) when compared with sulfonylureas. CKD was a significant effect modifier for all-cause mortality (P=.002), but not for cardiovascular events or major hypoglycemic episodes. CONCLUSION: Sulfonylurea monotherapy is associated with higher risk for all-cause mortality, major hypoglycemic episodes, and cardiovascular events compared with metformin. Although the presence of CKD attenuated the mortality benefit, metformin may be a safer alternative to sulfonylureas in patients with CKD.

Safety of Intravenous Iron in Dialysis: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: The safety of intravenous iron dosing in dialysis is uncertain. Higher-dose intravenous iron may be associated with a higher risk of infections, cardiovascular events, hospitalizations, and mortality. This systematic review aimed to determine the safety of higher-dose versus lower-dose intravenous iron, oral iron, or no iron supplementation in adult patients treated with dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We searched Medline, EMBASE, Cochrane library, and CINAHL from inception to January 6, 2017 for randomized, controlled trials and observational studies comparing higher-dose intravenous iron with lower-dose intravenous iron, oral iron, or no iron in patients treated with dialysis that had all-cause mortality, infection, cardiovascular events, or hospitalizations as outcomes. RESULTS: Of the 2231 eligible studies, seven randomized, controlled trials and 15 observational studies met inclusion criteria. The randomized, controlled trials showed no association between higher-dose intravenous iron (>400 mg/mo for most studies) and mortality (six studies; n=970; pooled relative risk, 0.93; 95% confidence interval, 0.47 to 1.84; follow-up ranging from 35 days to 26 months) or infection (four studies; n=743; relative risk, 1.02; 95% confidence interval, 0.74 to 1.41). The observational studies showed no association between higher-dose intravenous iron (>200 mg/mo for most studies) and mortality (eight studies; n=241,408; hazard ratio, 1.09; 95% confidence interval, 0.98 to 1.21; follow-up ranging from 3 to 24 months), infection (eight studies; n=135,532; pooled hazard ratio, 1.13; 95% confidence interval, 0.99 to 1.28), cardiovascular events (seven studies; n=135,675; hazard ratio, 1.18; 95% confidence interval, 0.90 to 1.56), or hospitalizations (five studies; n=134,324; hazard ratio, 1.08; 95% confidence interval, 0.97 to 1.19). CONCLUSIONS: Higher-dose intravenous iron does not seem to be associated with higher risk of mortality, infection, cardiovascular events, or hospitalizations in adult patients on dialysis. Strength of this finding is limited by small numbers of participants and events in the randomized, controlled trials and statistical heterogeneity in observational studies.

Total Kidney Volume as a Biomarker of Disease Progression in Autosomal Dominant Polycystic Kidney Disease.

PURPOSE OF REVIEW: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by the formation of kidney cysts and kidney enlargement, which progresses to kidney failure by the fifth to seventh decade of life in a majority of patients. Disease progression is evaluated primarily through serum creatinine and estimated glomerular filtration rate (eGFR) measurements; however, it is known that serum creatinine and eGFR values typically do not change until the fourth or fifth decade of life. Until recently, therapy only existed to target complications of ADPKD. As therapeutic agents continue to be investigated for use in ADPKD, a suitable biomarker of disease progression in place of serum creatinine is needed. SOURCES OF INFORMATION: This review summarizes recent research regarding the use of total kidney volume as a biomarker in ADPKD, as presented at the Canadian Society of Nephrology symposium held in April 2015. FINDINGS: Measurement of patients' total kidney volume made using ultrasound (US) or magnetic resonance imaging (MRI) has been shown by the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study to be directly correlated with both increases in cyst volume and change in glomerular filtration rate (GFR). Additional studies have shown total kidney volume to have an association with complications of ADPKD as well. LIMITATIONS: Areas for further study continue to exist in comparison of methods of measuring total kidney volume. IMPLICATIONS: We believe that the evidence suggests that total kidney volume may be an appropriate surrogate marker for ADPKD disease progression.

MISE EN CONTEXTE ET OBJECTIF DE LA REVUE: La polykystose rénale autosomique dominante (PKD) est une maladie héréditaire caractérisée par la formation de kystes aux reins et par l'hypertrophie des reins. Chez la majorité des patients atteints, la PKD évolue vers l'insuffisance rénale entre l'âge de 50 et de 70 ans. La progression de la maladie est essentiellement évaluée par la mesure de la créatinine sérique et du débit de filtration glomérulaire estimé (DFGe). Toutefois, règle générale, ce n'est que vers l'âge de 40 à 50 ans que l'on observe des changements dans ces paramètres. Jusqu'à tout récemment, les traitements ne ciblaient que les complications de la PKD. Bien que des médicaments fassent l'objet d'études en vue de leur utilisation pour traiter la PKD, on constate l'importance d'identifier un biomarqueur qui remplacerait le dosage de la créatinine sérique et qui faciliterait le suivi de la progression de la maladie. SOURCES: La revue fait la synthèse des recherches menées récemment au sujet de l'utilisation de la mesure du volume total des reins comme biomarqueur de la PKD, comme présenté lors du symposium de la Société canadienne de néphrologie qui s'est tenu en avril 2015. CONSTATATIONS: L'étude CRISP (Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease) a démontré que les mesures du volume rénal total des patients, effectuées par ultrasons (US) ou par imagerie par résonance magnétique (MRI), sont directement corrélées à une augmentation du volume des kystes de même qu'à des variations du débit de filtration glomérulaire (DFG). LIMITES DE L'ÉTUDE: Plusieurs domaines de comparaison entre les différentes méthodes de mesure du volume total des reins sont encore à explorer. CONCLUSION: Nous sommes d'avis que les données probantes suggèrent que la mesure du volume total des reins pourrait s'avérer un marqueur substitut adéquat pour suivre la progression de la PKD.