Serum potassium and adverse outcomes across the range of kidney function: a CKD Prognosis Consortium meta-analysis.

Aims: Both hypo- and hyperkalaemia can have immediate deleterious physiological effects, and less is known about long-term risks. The objective was to determine the risks of all-cause mortality, cardiovascular mortality, and end-stage renal disease associated with potassium levels across the range of kidney function and evaluate for consistency across cohorts in a global consortium. Methods and results: We performed an individual-level data meta-analysis of 27 international cohorts [10 general population, 7 high cardiovascular risk, and 10 chronic kidney disease (CKD)] in the CKD Prognosis Consortium. We used Cox regression followed by random-effects meta-analysis to assess the relationship between baseline potassium and adverse outcomes, adjusted for demographic and clinical characteristics, overall and across strata of estimated glomerular filtration rate (eGFR) and albuminuria. We included 1 217 986 participants followed up for a mean of 6.9 years. The average age was 55 ± 16 years, average eGFR was 83 ± 23 mL/min/1.73 m2, and 17% had moderate- to-severe increased albuminuria levels. The mean baseline potassium was 4.2 ± 0.4 mmol/L. The risk of serum potassium of >5.5 mmol/L was related to lower eGFR and higher albuminuria. The risk relationship between potassium levels and adverse outcomes was U-shaped, with the lowest risk at serum potassium of 4-4.5 mmol/L. Compared with a reference of 4.2 mmol/L, the adjusted hazard ratio for all-cause mortality was 1.22 [95% confidence interval (CI) 1.15-1.29] at 5.5 mmol/L and 1.49 (95% CI 1.26-1.76) at 3.0 mmol/L. Risks were similar by eGFR, albuminuria, renin-angiotensin-aldosterone system inhibitor use, and across cohorts. Conclusions: Outpatient potassium levels both above and below the normal range are consistently associated with adverse outcomes, with similar risk relationships across eGFR and albuminuria.

Within-class differences in cancer risk for sulfonylurea treatments in patients with type 2 diabetes (ZODIAC-55) - a study protocol.

BACKGROUND: Patients with type 2 diabetes (T2D) are at increased risk for developing cancer. As approximately 8% of the world's population is living with T2D, even a slight increase in cancer risk could result in an enormous impact on the number of persons developing cancer. In addition, several glucose lowering drug classes for treating patients with T2D have been associated with a difference in risk of cancer overall, and especially for obesity related cancers. In what way and to what degree cancer risk is modified by the use of different sulfonylureas (SU) is unclear. The primary aim of this study will be to evaluate within-class SU differences in obesity related cancer risk. Secondary aims will be to investigate within-class SU differences in risk for all cancers combined and site-specific cancers separately (i.e. breast, colorectal, prostate, bladder and lung cancer) and to account for duration-response relationships between individual SU use and cancer risk. METHODS: Patients will be selected from a Dutch primary care cohort of patients with T2D linked with the Dutch Cancer Registration (ZODIAC-NCR). Within this cohort study annually collected clinical data (e.g. blood pressure, weight, HbA1c) and nationwide data on cancer incidence are available. Time-dependent cox proportional hazard analyses will be performed to evaluate SU cancer risk, adjusted for potential confounders. DISCUSSION: This study will be the first prospective cohort study investigating within-class SU differences in cancer risk and could contribute to improved decision making regarding the individual drugs within the class of SUs, and possibly improve quality of life and result in an increased cost-effectiveness of healthcare in patients with T2D. TRIAL REGISTRATION: Nederlands Trialregister ( NTR6166 ), 6 Jan 2017.

High-sensitive troponin T is associated with all-cause and cardiovascular mortality in stable outpatients with type 2 diabetes (ZODIAC-37).

BACKGROUND: We aimed to investigate whether high-sensitive cardiac troponin T (hs-cTnT) is associated with all-cause and cardiovascular mortality in stable type 2 diabetes (T2D) outpatients treated in primary care. METHODS: Cardiac troponin T was measured with a high-sensitive assay at baseline in patients with T2D participating in the observational ZODIAC study. Cox proportional hazards models were used to investigate the relationship between hs-cTnT and mortality with adjustment for selected confounders. Risk prediction capabilities of hs-cTnT were assessed with Harrell C statistics. RESULTS: Complete baseline data were available for 1,133 patients. During median follow-up of 11 (7-14) years, 513 (45%) patients died, of which 218 (42%) died of cardiovascular causes. Of the patients with undetectable hs-cTnT levels (<3 ng/L), only 23% died, compared with 58% with low detectable levels (3-14 ng/L) and 84% with raised levels (≥14 ng/L). Natural log hs-cTnT was significantly associated with all-cause mortality (hazard ratio 1.30, 95% CI 1.19-1.42) and cardiovascular mortality (hazard ratio 1.33, 95% CI 1.15-1.53), independent of potential confounders. The Harrell C statistic for the crude model of hs-cTnT was 0.72 (95% CI 0.70-0.75) for all-cause mortality and 0.74 (95% CI 0.71-0.77) for cardiovascular mortality. CONCLUSIONS: Higher levels of hs-cTnT are associated with mortality in stable outpatients with T2D. The high crude Harrell C values and the excellent prognosis of patients with undetectable levels illustrate the strength of hs-cTnT as a potential marker for mortality.

Addition of sulphonylurea to metformin does not relevantly change body weight: a prospective observational cohort study (ZODIAC-39).

AIM: To investigate changes in body weight trajectories after the addition of individual sulphonylureas (SUs) to metformin in patients with type 2 diabetes. MATERIALS AND METHODS: We conducted a retrospective observational cohort study, in a primary care setting in the Netherlands. Patients aged ≥18 years with type 2 diabetes who were included in the ZODIAC cohort between 1998 and 2012 and who received metformin monotherapy at inclusion (n = 29 195), and had used metformin as monotherapy for at least 1 year before receiving dual therapy through the addition of an SU for at least 1 year were eligible for inclusion. The primary outcome was within-drug yearly change in body weight after receiving add-on therapy with individual SUs during 5 years of follow-up. The secondary outcome was within-drug yearly change in glycated haemoglobin (HbA1c). Annual changes in weight and HbA1c were estimated with linear mixed models, adjusted for age, gender and diabetes duration. RESULTS: A total of 2958 patients were included. No significant weight changes were observed within and between any of the individual SUs after treatment intensification (p = 0.24). In addition, no significant difference in weight between the add-on therapy combinations was observed (p = 0.26). The average HbA1c the year before intensification was 7.2% (55 mmol/mol) and dropped below 7.0% (53 mmol/mol) the year after. CONCLUSIONS: In patients with type 2 diabetes treated in primary care, strict glycaemic control can be maintained with SUs used as add-on therapy to metformin, without the offset of relevant weight changes.

Alanine aminotransferase and mortality in patients with type 2 diabetes (ZODIAC-38).

INTRODUCTION: Combined data suggest a bimodal association of alanine aminotransferase (ALT) with mortality in the general population. Little is known about the association of ALT with mortality in patients with type 2 diabetes. We therefore investigated the association of ALT with all-cause, cardiovascular and noncardiovascular mortality in patients with type 2 diabetes. DESIGN: A prospective study was performed in patients with type 2 diabetes, treated in primary care, participating in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study. Cox regression analyses were performed to determine the associations of log2 -transformed baseline ALT with all-cause, cardiovascular and noncardiovascular mortality. RESULTS: In 1187 patients with type 2 diabetes (67 ± 12 years, 45% female), ALT levels were 11 (8-16) U/L. During median follow-up for 11.1 (6.1-14.0) years, 553 (47%) patients died, with 238 (20%) attributable to cardiovascular causes. Overall, ALT was inversely associated with all-cause mortality (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.72-0.92), independently of potential confounders. This was less attributable to cardiovascular mortality (HR 0.87; 95% CI 0.72-1.05), than to noncardiovascular mortality (HR 0.77; 95% CI 0.65-0.90). Despite the overall inverse association of ALT with mortality, it appeared that a bimodal association with all-cause mortality was present with increasing risk for levels of ALT above normal (P = 0.003). DISCUSSION: In patients with type 2 diabetes, low levels of ALT are associated with an increased risk of all-cause mortality, in particular noncardiovascular mortality, compared to normal levels of ALT, while risk again starts to increase when levels are above normal.

The relationship between N-terminal prosomatostatin, all-cause and cardiovascular mortality in patients with type 2 diabetes mellitus (ZODIAC-35).

BACKGROUND: The hormone somatostatin inhibits growth hormone release from the pituitary gland and is theoretically linked to diabetes and diabetes related complications. This study aimed to investigate the relationship between levels of the stable somatostatin precursor, N-terminal prosomatostatin (NT-proSST), with mortality in type 2 diabetes (T2DM) patients. METHODS: In 1,326 T2DM outpatients, participating in this ZODIAC prospective cohort study, Cox proportional hazards models were used to investigate the independent relationship between plasma NT-proSST concentrations with all-cause and cardiovascular mortality. RESULTS: Median concentration of NT-proSST was 592 [IQR 450-783] pmol/L. During follow-up for 6 [3-10] years, 413 (31%) patients died, of which 176 deaths (43%) were attributable to cardiovascular causes. The age and sex adjusted hazard ratios (HRs) for all-cause and cardiovascular mortality were 1.48 (95%CI 1.14 - 1.93) and 2.21 (95%CI 1.49 - 3.28). However, after further adjustment for cardiovascular risk factors there was no independent association of log NT-proSST with mortality, which was almost entirely attributable to adjustment for serum creatinine. There were no significant differences in Harrell's C statistics to predict mortality for the models with and without NT-proSST: both 0.79 (95%CI 0.77 - 0.82) and 0.81 (95%CI 0.77 - 0.84). CONCLUSIONS: NT-proSST is unsuitable as a biomarker for cardiovascular and all-cause mortality in stable outpatients with T2DM.

The Value of Glycemic Control Prior to Cancer Diagnosis on All-Cause Mortality among Patients with Type 2 Diabetes in Dutch Primary Care.

BACKGROUND: Poor glycemic control prior to cancer diagnosis for patients with preexisting type 2 diabetes (T2DM) may predict a worse cancer diagnosis. We investigated the association between pre-diagnosis glycemic control and all-cause mortality in patients with T2DM who develop cancer. METHODS: This prospective cohort study linked data from three sources covering 1989 to 2019: a T2DM benchmarking database, the Netherlands Cancer Registry, and the Personal Records Database. We included patients with T2DM and incident primary breast, colorectal, or prostate cancer (stage 0-III), with target glycemic control defined according to Dutch guidelines. Analysis involved estimating the association between glycemic control and all-cause mortality with Cox proportional hazard models, accounting for individual expected survival relative to the general population and relevant disease (e.g., diabetes duration and medications) and individual (e.g., age and gender) characteristics. RESULTS: Of the 71,648 linked cases, 620 had breast cancer, 774 had colorectal cancer, and 438 had prostate cancer, with follow-up data available for 6.4 (4.2-8.4), 5.6 (2.7-7.6), and 6.3 (4.5-8.2) years, respectively. Compared with patients with pre-diagnosis glycemic control at target, the HRs and 95% confidence intervals for mortality among those with pre-diagnosis glycemic control not at target were 1.40 (1.00-1.96) for breast cancer, 1.45 (1.12-1.88) for colorectal cancer, and 1.39 (0.98-1.98) for prostate cancer. CONCLUSIONS: Among patients with T2DM in Dutch primary care, poor glycemic control before diagnosis with breast and colorectal cancer can increase mortality compared with good control. IMPACT: Glycemic control prior to cancer diagnosis is of prognostic value.

Association between 9p21 genetic variants and mortality risk in a prospective cohort of patients with type 2 diabetes (ZODIAC-15).

The genomic region at 9p21 chromosome near the CDKN2A/CDKN2B genes is associated with type 2 diabetes(T2D) and cardiovascular disease(CVD). The effect of the 9p21 locus on long-term mortality in patients with T2D has yet to be determined.We examined three single nucleotide polymorphisms (SNPs) on 9p21, consistently and independently associated with T2D (rs10811661) or CVD (rs10757278, rs2383206), in relation to the risk of total and cardiovascular mortality in diabetic patients. We also aimed to replicate the previously observed interaction between rs2383206 and glycemic control on mortality.Genotypes for three SNPs were determined in 914 individuals from a prospective cohort of T2D patients of Dutch origin. Associations with mortality were assessed using Cox proportional hazard analyses.After a median follow-up of 9.5 years, 358 out of 914 patients had died. The hazard ratio (HR) for total mortality among individuals homozygous for the T2D-risk allele of rs10811661 compared to non-homozygous individuals was 0.74(95%CI 0.59-0.93). For the carriers of both CVD-risk alleles of rs10757278, the HR for total mortality was 1.31(95%CI 1.01-1.70). We found a significant interaction between rs2383206 and HbA1c on mortality, which was higher among patients with two CVD-risk alleles in the two lowest HbA1c tertiles (HR 1.68(95%CI 1.08-2.63); HR 1.48(95%CI 1.01-2.18).In conclusion, common variants on 9p21 were associated with mortality in patients with T2D in a Dutch population. The T2D SNP was inversely associated with mortality, while the CVD SNP increased the risk for mortality. We confirmed a possible, although different, synergistic relationship between HbA1c and rs2383206 on total mortality.

Type 2 Diabetes Mellitus and Clinicopathological Tumor Characteristics in Women Diagnosed with Breast Cancer: A Systematic Review and Meta-Analysis.

Poor prognosis caused by type 2 diabetes mellitus (T2DM) in women with breast cancer is conferred, while the association between T2DM and breast tumor aggressiveness is still a matter of debate. This study aimed to clarify the differences in breast cancer characteristics, including stage, size, lymph node status, grade, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (Her2), between patients with and without pre-existing T2DM. PubMed, Embase, and Web of Science were searched for studies from 1 January 2010 to 2 July 2021. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were pooled by using a random effects model. T2DM was significantly associated with tumor stages III/IV versus cancers in situ and stages I/II (pooled ORs (pOR), 95% CI: 1.19; 1.04-1.36, p = 0.012), tumor size >20 versus ≤20 mm (pOR, 95% CI: 1.18; 1.04-1.35, p = 0.013), and lymph node invasion versus no involvement (pOR, 95% CI: 1.26; 1.05-1.51, p = 0.013). These findings suggest that women with T2DM are at a higher risk of late-stage tumors, large tumor sizes, and invasive lymph nodes at breast cancer diagnosis.

The Risk of Cutaneous Squamous Cell Carcinoma Among Patients with Type 2 Diabetes Receiving Hydrochlorothiazide: A Cohort Study.

BACKGROUND: Because of continuous hyperglycemia and hyperinsulinemia and the use of photosensitizing drug, hydrochlorothiazide (HCTZ), the risk of cutaneous squamous cell carcinoma (cSCC) might be increased among patients with diabetes. This study aimed to estimate the risk of cSCC among HCTZ users with type 2 diabetes, and to determine whether thiazide-like diuretics, another drug in the same class with HCTZ, would be safer. METHODS: We linked the benchmarking database in Dutch primary care, the Netherlands Cancer Registry, and the Dutch Personal Records Database (1998-2019). All 71,648 patients were included, except for those who had a history of skin cancer prior to cohort entry. We used Cox modeling to estimate the HRs and 95% confidence intervals for cSCC. The model was adjusted by cumulative exposure to each antihypertensive, age, sex, smoking, body mass index, blood pressure, serum creatinine, other confounding drug use at cohort entry, and cohort entry year. RESULTS: There were 1,409 cSCC events (23 among thiazide-like diuretics users), during a follow-up of 679,789 person-years. Compared with no HCTZ use, the adjusted HRs for HCTZ use were 1.18 (1.00-1.40) for ≤2 years, 1.57 (1.32-1.88) for 2 to 4 years, and 2.09 (1.73-2.52) for >4 years. The HR was 0.90 (0.79-1.03) for an additional year of thiazide-like diuretic use. CONCLUSIONS: In patients with diabetes, exposure to HCTZ for >2 years is associated with an increased risk of cSCC, whereas no increased risk associated with thiazide-like diuretics was observed. IMPACT: The potential increased risk of cSCC should be a consideration when prescribing HCTZ, with thiazide-like diuretics offering a safer alternative.

Glycemic Control for Colorectal Cancer Survivors Compared to Those without Cancer in the Dutch Primary Care for Type 2 Diabetes: A Prospective Cohort Study.

Cancer survivors with diabetes tend to have worse glycemic control after their cancer diagnosis, which may increase the risk of cardiovascular diseases. We aimed to investigate whether glycemic control differs between colorectal cancer (CRC) survivors and those without cancer, among patients with type 2 diabetes being treated in the Dutch primary care. The Zwolle Outpatient Diabetes project Integrating Available Care database was linked with the Dutch Cancer Registry (n = 71,648, 1998-2014). The cases were those with stage 0-III CRC, and the controls were those without cancer history. The primary and secondary outcomes were the probability of reaching the glycated hemoglobin (HbA1c) target and the mean of HbA1c during follow-up, respectively. Mixed linear modeling was applied, where the status of CRC was a time-varying variable. Among the 57,330 patients included, 705 developed CRC during follow-up. The mean probability of reaching the HbA1c target during follow-up was 73% versus 74% (p = 0.157) for CRC survivors versus those without cancer, respectively. The mean HbA1c was 51.1 versus 50.8 mmol/mol (p = 0.045) among CRC survivors versus those without cancer, respectively. We observed a clinically comparable glycemic control among the CRC survivors without cancer, indicating that glycemic control for CRC survivors can be delegated to primary care professionals.

Lower blood pressure associated with higher mortality in elderly diabetic patients (ZODIAC-12).

OBJECTIVE: to investigate the relationship between blood pressure over time and mortality in elderly patients with type 2 diabetes mellitus (T2DM). DESIGN: prospective observational cohort study. SETTING: primary care, Zwolle, The Netherlands. SUBJECTS: patients with T2DM aged 60 years and older (n = 881). The cohort was divided into two age categories: 60-75 years and older than 75 years. METHODS: updated means for systolic, diastolic and pulse pressures were calculated after a median follow-up time of 9.8 years. These values were used as time-dependent covariates in a Cox proportional hazard model. Main outcome measures were all-cause and cardiovascular mortality. RESULTS: all of the blood pressure measures were inversely related to all-cause mortality in elderly diabetic patients (>75 years). Furthermore, these relationships were specifically found in elderly patients treated with antihypertensive medication at baseline. A decrease of 10 mm Hg in systolic blood pressure, diastolic blood pressure and pulse pressure led to a mortality increase of 22% [95% confidence interval (95% CI): 13-31%], 30% [95% CI: 13%-46%] and 22% [95% CI: 11%-33%], respectively. In the low age group (60-75 years), no relationship was found between blood pressure and mortality. CONCLUSIONS: blood pressure is a marker for mortality in elderly T2DM patients; however, the relationship is inverse.

Is Gliclazide Associated with a Lower Obesity-Related Cancer Risk Compared to Other Sulfonylureas? A Long-term Prospective Cohort Study.

BACKGROUND: Gliclazide has been suspected to be associated with a lower obesity-related cancer risk; however, current evidence is limited by important methodologic shortcomings. This study aimed to evaluate whether gliclazide is preferred over other sulfonylureas regarding obesity-related cancer risk. METHODS: In this prospective cohort study, an annual benchmarking database in Dutch primary care (Zwolle Outpatient Diabetes project Integrating Available CareZODIAC, 1998-2014) was linked to the Netherlands Cancer Registry and the Dutch Personal Record Database. Of the 71,648 patients with type 2 diabetes, we included 26,207 who used sulfonylureas and had no history of cancer or insulin use at baseline. Obesity-related cancer was defined using the latest definition of the World Cancer Research Fund. Cox regression analyses were used to estimate HRs, with both baseline sulfonylurea and cumulative exposure modeled and corrected for baseline covariates. RESULTS: During follow-up for 167,692 person-years, there were 1,111 obesity-related cancer events. For males, the adjusted HRs [95% confidence interval (CI)] for baseline sulfonylurea compared with gliclazide were as follows: glibenclamide, 1.10 (0.92-2.69); glimepiride, 1.13 (0.68-1.84); and tolbutamide, 0.93 (0.59-1.48). For females, these were as follows: glibenclamide, 1.49 (0.72-3.13); glimepiride, 0.96 (0.59-1.54); and tolbutamide, 0.84 (0.54-1.28). The adjusted HRs (95% CI) for one more year of cumulative exposure compared with gliclazide were as follows: glibenclamide, 0.90 (0.71-1.14); glimepiride, 0.96 (0.87-1.06); and tolbutamide, 1.00 (0.92-1.09). For females, these were as follows: glibenclamide, 0.93 (0.77-1.13); glimepiride, 0.99 (0.90-1.10); and tolbutamide, 1.04 (0.96-1.13). CONCLUSIONS: Obesity-related cancer risk was comparable between gliclazide and other sulfonylureas. IMPACT: Gliclazide is not preferred over other sulfonylureas regarding obesity-related cancer risk.