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Objective: To characterize and compare glucose-lowering medication use in type 2 diabetes in the U.S., Sweden, and Israel, including adoption of newer medications and prescribing patterns.Research Design and Methods: We used data from the National Health and Nutrition Examination Survey (NHANES) from the U.S., the Stockholm CREAtinine Measurements (SCREAM) project from Sweden, and Maccabi Healthcare Services (Maccabi) from Israel. Specific pharmacotherapy for type 2 diabetes between 2007 and 2018 was examined.Results: Use of glucose-lowering medications among patients with type 2 diabetes was substantially lower in NHANES and SCREAM than in Maccabi (66.0% in NHANES, 68.4% in SCREAM, and 88.1% in Maccabi in 2017-2018). Among patients who took at least one glucose-lowering medication in 2017-2018, metformin use was also lower in NHANES and SCREAM (74.1% in NHANES, 75.9% in SCREAM, and 92.6% in Maccabi) whereas sulfonylureas use was greater in NHANES (31.5% in NHANES, 16.0% in SCREAM, and 14.9% in Maccabi). Adoption of dipeptidyl peptidase 4 inhibitors and sodium-glucose cotransporter 2 inhibitors (SGLT2i) was slower in NHANES and SCREAM than in Maccabi. History of atherosclerotic cardiovascular disease, heart failure, reduced kidney function, or albuminuria was not consistently associated with greater use of SGLT2i or glucagon-like peptide 1 receptor agonists (GLP1RA) across the three countries.Conclusions: There were substantial differences in real-world use of glucose-lowering medications across the U.S., Sweden, and Israel, with more optimal pharmacologic management in Israel. Variation in access to care and medication cost across countries may have contributed to these differences. SGLT2i and GLP1RA use in patients at high risk was limited in all three countries during this time period. [ABSTRACT FROM AUTHOR]

Background: The safety of restarting angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) after acute kidney injury (AKI) is unclear. There is concern that previous users do not restart ACEI/ARB despite ongoing indications. We sought to determine the risk of adverse events after an episode of AKI, comparing prior ACEI/ARB users who stop treatment to those who continue.Methods: We conducted two parallel cohort studies in English and Swedish primary and secondary care, 2006-2016. We used multivariable Cox regression to estimate hazard ratios (HR) for hospital admission with heart failure (primary analysis), AKI, stroke, or death within 2 years after hospital discharge following a first AKI episode. We compared risks of admission between people who stopped ACEI/ARB treatment to those who were prescribed ACEI/ARB within 30 days of AKI discharge. We undertook sensitivity analyses, including propensity score-matched samples, to explore the robustness of our results.Results: In England, we included 7303 people with AKI hospitalisation following recent ACEI/ARB therapy for the primary analysis. Four thousand three (55%) were classified as stopping ACEI/ARB based on no prescription within 30 days of discharge. In Sweden, we included 1790 people, of whom 1235 (69%) stopped treatment. In England, no differences were seen in subsequent risk of heart failure (HR 1.10; 95% confidence intervals (CI) 0.93-1.30), AKI (HR 0.90; 95% CI 0.77-1.05), or stroke (HR 0.99; 95% CI 0.71-1.38), but there was an increased risk of death (HR 1.27; 95% CI 1.15-1.41) in those who stopped ACEI/ARB compared to those who continued. Results were similar in Sweden: no differences were seen in risk of heart failure (HR 0.91; 95% CI 0.73-1.13) or AKI (HR 0.81; 95% CI 0.54-1.21). However, no increased risk of death was seen (HR 0.94; 95% CI 0.78-1.13) and stroke was less common in people who stopped ACEI/ARB (HR 0.56; 95% CI 0.34-0.93). Results were similar across all sensitivity analyses.Conclusions: Previous ACEI/ARB users who continued treatment after an episode of AKI did not have an increased risk of heart failure or subsequent AKI compared to those who stopped the drugs. [ABSTRACT FROM AUTHOR]

To assess adherence and persistence to sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1-RA), and dipeptidyl peptidase-4 inhibitors (DPP4i) in routine care. Using retrospective healthcare data from the Stockholm region, Sweden, we evaluated new-users of these agents during 2015–2020. We investigated adherence (≥80 % of days covered by an active supply), persistence (no treatment gap ≥ 60 days), and predictors for non-adherence and non-persistence. We identified 24,470 new-users of SGLT2i (10,743), GLP1-RA (10,315), and/or DPP4i (9,488). Over 2.8 years median follow-up, the proportion demonstrating adherence was higher for SGLT2i (57 %) than DPP4i (53 %, comparison p < 0.001), and for GLP1-RA than DPP4i (54 % vs 53 %, p < 0.001). Similarly, persistence was higher for both SGLT2i and GLP-RA than DPP4i (respectively, 50 % vs 44 %, p < 0.001; 49 % vs 44 %, p < 0.001). Overall adherence was better among users who were older, had a history of high blood pressure, used more non-diabetic medications, had lower Hba1c, had better kidney function, and had completed secondary schooling or university. Women had worse adherence to SGLT2i and GLP1-RA than DPP4i. We report adherence and persistence to SGLT2i, GLP1-RA and DPP4i in routine care, and identify prognostic factors that could inform implementation interventions to improve uptake of these important therapies. [ABSTRACT FROM AUTHOR]

Importance: Hyperkalemia is a common complication in people with type 2 diabetes (T2D) that may limit the use of guideline-recommended renin-angiotensin system inhibitors (RASis). Emerging evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase urinary potassium excretion, which may translate into reduced hyperkalemia risk., Objective: To compare rates of hyperkalemia and RASi persistence among new users of GLP-1RAs vs dipeptidyl peptidase-4 inhibitors (DPP-4is)., Design, Setting, and Participants: This cohort study included all adults with T2D in the region of Stockholm, Sweden, who initiated GLP-1RA or DPP-4i treatment between January 1, 2008, and December 31, 2021. Analyses were conducted between October 1, 2023, and April 29, 2024., Exposures: GLP-1RAs or DPP-4is., Main Outcomes and Measures: The primary study outcome was time to any hyperkalemia (potassium level >5.0 mEq/L) and moderate to severe (potassium level >5.5 mEq/L) hyperkalemia. Time to discontinuation of RASi use among individuals using RASis at baseline was assessed. Inverse probability of treatment weights served to balance more than 70 identified confounders. Marginal structure models were used to estimate per-protocol hazard ratios (HRs)., Results: A total of 33 280 individuals (13 633 using GLP-1RAs and 19 647 using DPP-4is; mean [SD] age, 63.7 [12.6] years; 19 853 [59.7%] male) were included. The median (IQR) time receiving treatment was 3.9 (1.0-10.9) months. Compared with DPP-4i use, GLP-1RA use was associated with a lower rate of any hyperkalemia (HR, 0.61; 95% CI, 0.50-0.76) and moderate to severe (HR, 0.52; 95% CI, 0.28-0.84) hyperkalemia. Of 21 751 participants who were using RASis, 1381 discontinued this therapy. The use of GLP-1RAs vs DPP-4is was associated with a lower rate of RASi discontinuation (HR, 0.89; 95% CI, 0.82-0.97). Results were consistent in intention-to-treat analyses and across strata of age, sex, cardiovascular comorbidity, and baseline kidney function., Conclusions: In this study of patients with T2D managed in routine clinical care, the use of GLP-1RAs was associated with lower rates of hyperkalemia and sustained RASi use compared with DPP-4i use. These findings suggest that GLP-1RA treatment may enable wider use of guideline-recommended medications and contribute to clinical outcomes in this population.

Background: The pharmacological management of hyperkalemia traditionally considered calcium or sodium polystyrene sulfonate and, since recently, the novel binders patiromer and sodium zirconium cyclosilicate. We evaluated their patterns of use, duration of treatment and relative effectiveness/safety in Swedish routine care., Methods: Observational study of adults initiating therapy with sodium polystyrene sulfonate or a novel binder (sodium zirconium cyclosilicate or patiromer) in Stockholm 2019-2021. We quantified treatment duration by repeated dispensations, compared mean achieved potassium concentration within 60 days, and potential adverse events between treatments., Results: A total of 1879 adults started treatment with sodium polystyrene sulfonate, and 147 with novel binders (n = 41 patiromer and n = 106 sodium zirconium cyclosilicate). Potassium at baseline for all treatments was 5.7 mmol/L. Sodium polystyrene sulfonate patients stayed on treatment a mean of 61 days (14% filled ≥3 consecutive prescriptions) compared to 109 days on treatment (49% filled ≥3 prescriptions) for novel binders. After 15 days of treatment, potassium similarly decreased to 4.6 (SD 0.6) and 4.8 (SD 0.6) mmol/L in the sodium polystyrene sulfonate and novel binder groups, respectively, and was maintained over the 60 days post-treatment. In multivariable regression, the odds ratio for novel binders (vs sodium polystyrene sulfonate) in reaching potassium ≤ 5.0 mmol/L after 15 days was 0.65 (95% CI 0.38-1.10) and after 60 days 0.89 (95% CI 0.45-1.76). Hypocalcemia, hypokalemia, and initiation of anti-diarrheal/constipation medications were the most-commonly detected adverse events. In multivariable analyses, the OR for these events did not differ between groups., Conclusion: We observed similar short-term effectiveness and safety for all potassium binders. However, treatment duration was longer for novel binders than for sodium polystyrene sulfonate., (© 2024. The Author(s).)

Importance: Among patients with bipolar disorder, discordant findings have been published on the nephrotoxic effects of lithium therapy., Objective: To quantify absolute and relative risks of chronic kidney disease (CKD) progression and acute kidney injury (AKI) in people who initiated lithium compared with valproate therapy and to investigate the association between cumulative use and elevated lithium levels and kidney outcomes., Design, Setting, and Participants: This cohort study had a new-user active-comparator design and used inverse probability of treatment weights to minimize confounding. Included patients initiated therapy with lithium or valproate from January 1, 2007, to December 31, 2018, and had a median follow-up of 4.5 years (IQR, 1.9-8.0 years). Data analysis began in September 2021, using routine health care data from the period 2006 to 2019 from the Stockholm Creatinine Measurements project, a recurrent health care use cohort of all adult residents in Stockholm, Sweden., Exposures: New use of lithium vs new use of valproate and high (>1.0 mmol/L) vs low serum lithium levels., Main Outcomes and Measures: Progression of CKD (composite of >30% decrease relative to baseline estimated glomerular filtration rate [eGFR] and kidney failure), AKI (by diagnosis or transient creatinine elevations), new albuminuria, and annual eGFR decrease. Outcomes by attained lithium levels were also compared in lithium users., Results: The study included 10 946 people (median [IQR] age, 45 [32-59] years; 6227 female [56.9%]), of whom 5308 initiated lithium therapy and 5638 valproate therapy. During follow-up, 421 CKD progression events and 770 AKI events were identified. Compared with patients who received valproate, those who received lithium did not have increased risk of CKD (hazard ratio [HR], 1.11 [95% CI, 0.86-1.45]) or AKI (HR, 0.88 [95% CI, 0.70-1.10]). Absolute 10-year CKD risks were low and similar: 8.4% in the lithium group and 8.2% in the valproate group. No difference in the risk of developing albuminuria or the annual rate of eGFR decrease was found between groups. Among more than 35 000 routine lithium tests, only 3% of results were in the toxic range (>1.0 mmol/L). Lithium values greater than 1.0 mmol/L, compared with lithium values of 1.0 mmol/L or less, were associated with increased risk of CKD progression (HR, 2.86; 95% CI, 0.97-8.45) and AKI (HR, 3.51; 95% CI, 1.41-8.76)., Conclusions and Relevance: In this cohort study, compared with new use of valproate, new use of lithium was meaningfully associated with adverse kidney outcomes, with low absolute risks that did not differ between therapies. However, elevated serum lithium levels were associated with future kidney risks, particularly AKI, emphasizing the need for close monitoring and lithium dose adjustment.

Objective: To identify the optimal estimated glomerular filtration rate (eGFR) at which to initiate dialysis in people with advanced chronic kidney disease., Design: Nationwide observational cohort study., Setting: National Swedish Renal Registry of patients referred to nephrologists., Participants: Patients had a baseline eGFR between 10 and 20 mL/min/1.73 m 2 and were included between 1 January 2007 and 31 December 2016, with follow-up until 1 June 2017., Main Outcome Measures: The strict design criteria of a clinical trial were mimicked by using the cloning, censoring, and weighting method to eliminate immortal time bias, lead time bias, and survivor bias. A dynamic marginal structural model was used to estimate adjusted hazard ratios and absolute risks for five year all cause mortality and major adverse cardiovascular events (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) for 15 dialysis initiation strategies with eGFR values between 4 and 19 mL/min/1.73 m 2 in increments of 1 mL/min/1.73 m 2 . An eGFR between 6 and 7 mL/min/1.73 m 2 (eGFR 6-7 ) was taken as the reference., Results: Among 10 290 incident patients with advanced chronic kidney disease (median age 73 years; 3739 (36%) women; median eGFR 16.8 mL/min/1.73 m 2 ), 3822 started dialysis, 4160 died, and 2446 had a major adverse cardiovascular event. A parabolic relation was observed for mortality, with the lowest risk for eGFR 15-16 . Compared with dialysis initiation at eGFR 6-7 , initiation at eGFR 15-16 was associated with a 5.1% (95% confidence interval 2.5% to 6.9%) lower absolute five year mortality risk and 2.9% (0.2% to 5.5%) lower risk of a major adverse cardiovascular event, corresponding to hazard ratios of 0.89 (95% confidence interval 0.87 to 0.92) and 0.94 (0.91 to 0.98), respectively. This 5.1% absolute risk difference corresponded to a mean postponement of death of 1.6 months over five years of follow-up. However, dialysis would need to be started four years earlier. When emulating the intended strategies of the Initiating Dialysis Early and Late (IDEAL) trial (eGFR 10-14 v eGFR 5-7 ) and the achieved eGFRs in IDEAL (eGFR 7-10 v eGFR 5-7 ), hazard ratios for all cause mortality were 0.96 (0.94 to 0.99) and 0.97 (0.94 to 1.00), respectively, which are congruent with the findings of the randomised IDEAL trial., Conclusions: Very early initiation of dialysis was associated with a modest reduction in mortality and cardiovascular events. For most patients, such a reduction may not outweigh the burden of a substantially longer period spent on dialysis., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Swedish Research Council, Center of Innovative Medicine Karolinska, and Stockholm City Council. JJC has consulted for Baxter and AstraZeneca and received grant support from AstraZeneca, Viforpharma, and Astellas, all outside the submitted work; CMC has received consultation, advisory board membership, or research funding from the Ontario Ministry of Health, Sanofi, Johnson and Johnson, Pfizer, Leo Pharma, Astellas, Janssen, Amgen, Boehringer-Ingelheim, and Baxter, all outside the submitted work; CW has received consultation and advisory board membership honorariums from AstraZeneca, Akebia, Bayer, Boehringer-Ingelheim, Gilead, GSK, MSD, Sanofi-Genzyme, and Tricida, outside the present work. KJJ has received grant support from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and speaker honorariums from Fresenius Medical Care, outside the submitted work. FJC has received grant support from the National Institute for Health Research and Kidney Research UK and honorariums from Baxter. ME has received payment for advisory boards and lectures and research funding from Astellas Pharma, Astra Zeneca, Vifor Pharma, and Fresenius, all outside the submitted work; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: It is unknown whether stopping renin-angiotensin system (RAS) inhibitor therapy in patients with advanced CKD affects outcomes., Methods: We studied patients referred to nephrologist care, listed on the Swedish Renal Registry during 2007-2017, who developed advanced CKD (eGFR<30 ml/min per 1.73 m 2 ) while on RAS inhibitor therapy. Using target trial emulation techniques on the basis of cloning, censoring, and weighting, we compared the risks of stopping within 6 months and remaining off treatment versus continuing RAS inhibitor therapy. These included risks of subsequent 5-year all-cause mortality, major adverse cardiovascular events, and initiation of kidney replacement therapy (KRT)., Results: Of 10,254 prevalent RAS inhibitor users (median age 72 years, 36% female) with new-onset eGFR <30 ml/min per 1.73 m 2 , 1553 (15%) stopped RAS inhibitor therapy within 6 months. Median eGFR was 23 ml/min per 1.73 m 2 . Compared with continuing RAS inhibition, stopping this therapy was associated with a higher absolute 5-year risk of death (40.9% versus 54.5%) and major adverse cardiovascular events (47.6% versus 59.5%), but with a lower risk of KRT (36.1% versus 27.9%); these corresponded to absolute risk differences of 13.6 events per 100 patients, 11.9 events per 100 patients, and -8.3 events per 100 patients, respectively. Results were consistent whether patients stopped RAS inhibition at higher or lower eGFR, across prespecified subgroups, after adjustment and stratification for albuminuria and potassium, and when modeling RAS inhibition as a time-dependent exposure using a marginal structural model., Conclusions: In this nationwide observational study of people with advanced CKD, stopping RAS inhibition was associated with higher absolute risks of mortality and major adverse cardiovascular events, but also with a lower absolute risk of initiating KRT., (Copyright © 2021 by the American Society of Nephrology.)

Background: It is unknown if β-blockers reduce mortality/morbidity in patients with heart failure (HF) and advanced chronic kidney disease (CKD), a population underrepresented in HF trials., Methods: Observational cohort of HF patients with advanced CKD (estimated glomerular filtration rate <30 mL/min per 1.73 m 2 ) from the Swedish Heart Failure Registry between 2001 and 2016. We first explored associations between β-blocker use, 5-year death, and the composite of cardiovascular death/HF hospitalization among 3775 patients with HF with reduced ejection fraction (HFrEF) and advanced CKD. We compared observed hazards with those from a control cohort of 15 346 patients with HFrEF and moderate CKD (estimated glomerular filtration rate <60-30 mL/min per 1.73 m 2 ), for whom β-blocker trials demonstrate benefit. Second, we explored outcomes associated to β-blocker among advanced CKD participants with preserved (HFpEF; N=2009) and midrange ejection fraction (HFmrEF; N=1514)., Results: During a median follow-up of 1.3 years, 2012 patients had a subsequent HF hospitalization, and 2849 died in the HFrEF cohort, of which 2016 died due to cardiovascular causes. Among patients with HFrEF, β-blocker use was associated with lower risk of death (adjusted hazard ratio 0.85 [95% CI, 0.75-0.96]) and cardiovascular mortality/HF hospitalization (0.87 [0.77-0.98]) compared with nonuse. The magnitude of the associations was similar to that observed for HFrEF patients with moderate CKD. Conversely, no significant association was observed for β-blocker users in advanced CKD with HFpEF (death: 0.88 [0.77-1.02], cardiovascular mortality/HF hospitalization: 1.05 [0.90-1.23]) or HFmrEF (death: 0.95 [0.79-1.14], cardiovascular mortality/HF hospitalization: 1.09 [0.90-1.31])., Conclusions: In HFrEF patients with advanced CKD, the use of β-blockers was associated with lower morbidity and mortality. Although inconclusive due to limited power, these benefits were not observed in similar patients with HFpEF or HFmrEF.

Background: Persistent, low-grade inflammation likely participates in the pathophysiology of both atherosclerosis and kidney disease. Although high-sensitivity C-reactive protein (hsCRP) predicts future cardiovascular risk in patients with chronic kidney disease (CKD), it is unknown whether hsCRP levels predict adverse renal outcomes in patients with cardiovascular disease., Methods: We studied all myocardial infarction (MI) survivors undergoing hsCRP testing >30 days after their MI during routine health care in Stockholm, Sweden (2006-2011), with available information on estimated glomerular filtration rate (eGFR). HsCRP tests measured during hospitalization/emergency room visits, followed by antibiotics or indicative of acute illness, were excluded, together with patients with ongoing/recent cancer, chronic infections, or immunosuppression. Inflammation was defined over a 3-month baseline window. Study outcomes were CKD progression (composite of doubling plasma creatinine, renal replacement therapy, or renal death) and acute kidney injury (AKI, acute creatinine peaks according to Kidney Disease: Improving Global Outcomes criteria). Multivariable Cox regression was used to adjust for age, sex, eGFR, hemoglobin, time since MI, comorbidities, undertaken procedures, and medications., Results: A total of 12,905 patients (62% men, mean age 73 years and 3 years since MI) were included, of whom 35% had an eGFR<60 mL/min/1.73 m 2 . The mean (SD) hsCRP was 3.0 (4.4) mg/L. Baseline hsCRP levels were increasingly higher across lower eGFR categories. During a median follow-up of 3.2 years, 1,019 CKD progressions and 1,481 AKI events were recorded. Patients with hsCRP ≥2 mg/L were at higher risk of both CKD progression (adjusted hazard ratio 1.42; 95% CI 1.21-1.66) and AKI (1.29; 1.13-1.47) compared to those with hsCRP <2 mg/L. This association persisted across single CKD severity stages and after further hsCRP categorization into 4 groups (≤1, 1-3, 3-10, >10 mg/L). Results were robust across subgroups of patients and after exclusion of events occurring during the first 6-12 months., Conclusions: In post-MI patients undergoing routine health care, elevated hsCRP was associated with subsequent risk of AKI and progression of CKD, irrespective of baseline kidney function., (Copyright © 2019 Elsevier Inc. All rights reserved.)