Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia: Data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers.

INTRODUCTION: People with type 2 diabetes have increased risk of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are among the promising therapies for repurposing as a treatment for Alzheimer's disease; a key unanswered question is whether they reduce dementia incidence in people with type 2 diabetes. METHODS: We assessed exposure to GLP-1 RAs in patients with type 2 diabetes and subsequent diagnosis of dementia in two large data sources with long-term follow-up: pooled data from three randomized double-blind placebo-controlled cardiovascular outcome trials (15,820 patients) and a nationwide Danish registry-based cohort (120,054 patients). RESULTS: Dementia rate was lower both in patients randomized to GLP-1 RAs versus placebo (hazard ratio [HR]: 0.47 (95% confidence interval [CI]: 0.25-0.86) and in the nationwide cohort (HR: 0.89; 95% CI: 0.86-0.93 with yearly increased exposure to GLP-1 RAs). DISCUSSION: Treatment with GLP-1 RAs may provide a new opportunity to reduce the incidence of dementia in patients with type 2 diabetes.

Type 2 Diabetes Mellitus and Impact of Heart Failure on Prognosis Compared to Other Cardiovascular Diseases: A Nationwide Study.

BACKGROUND: Heart failure (HF) in patients with type 2 diabetes mellitus (T2D) has received growing attention. We examined the effect of HF development on prognosis compared with other cardiovascular or renal diagnoses in patients with T2D. METHODS AND RESULTS: Patients with new T2D diagnosis patients were identified between 1998 and 2015 through Danish nationwide registers. At yearly landmark timepoints after T2D diagnosis, we estimated the 5-year risks of death, 5-year risk ratios, and decrease in lifespan within 5 years associated with the development of HF, ischemic heart disease, stroke, peripheral artery disease, and chronic kidney disease. A total of 153 403 patients with newly diagnosed T2D were followed for a median of 9.7 years (interquartile range, 5.8-13.9) during which 48 087 patients died. The 5-year risk ratio of death associated with HF development 5 years after T2D diagnosis was 3 times higher (CI, 2.9-3.1) than patients free of diagnoses (CI, 2.9-3.1). Five-year risk ratios were lower for ischemic heart disease (1.3 [1.3-1.4]), stroke (2.2 [2.1-2.2]), chronic kidney disease (1.7 [1.7-1.8]), and peripheral artery disease (2.3 [2.3-2.4]). The corresponding decrease in lifespan within 5 years when compared with patients free of diagnoses (in months) was HF 11.7 (11.6-11.8), ischemic heart disease 1.6 (1.5-1.7), stroke 6.4 (6.3-6.5), chronic kidney disease 4.4 (4.3-4.6), and peripheral artery disease 6.9 (6.8-7.0). HF in combination with any other diagnosis imposed the greatest risk of death and decrease in life span compared with other combinations. Supplemental analysis led to similar results when stratified according to age, sex, and comorbidity status, and inclusion period. CONCLUSIONS: HF development, at any year since T2D diagnosis, was associated with the highest 5-year absolute and relative risk of death, and decrease in lifespan within 5 years, when compared with development of other cardiovascular or renal diagnoses.

Risk of diabetes among related and unrelated family members.

AIMS: The aim was to explore familial aggregation of diabetes in genetically related and unrelated individuals. METHODS: We included citizens from Danish nationwide registries between 1995 and 2018 and calculated rate ratios (RR) of diabetes based on family relation using Poisson regression. RESULTS: Of 7.3 million individuals eligible for inclusion, we identified 343,237 (4.7%) with diabetes. The RR of diabetes was 2.02 (95% CI: 1.99-2.05; p < 0.0001) if any relative had diabetes, 1.79 (95% CI: 1.76-1.83) if a father had diabetes, and 2.06 (95% CI: 2.02-2.10) if a mother had diabetes. If both parents had diabetes, the RR was 3.40 (95% CI: 3.24-3.56). Among full siblings, the RR for developing diabetes was 2.77 (95% CI: 2.71-2.84) and 5.76 (95% CI: 5.00-6.63) for twins. For second-degree relatives, half siblings with a common mother had a RR of 2.35 (95% CI: 2.15-2.56), and with a common father 1.99 (95% CI: 1.81-2.17). Furthermore, the RR was 1.60 (95% CI: 1.56-1.64) if a wife had diabetes, and 1.41 (95% CI: 1.38-1.44) if a husband had diabetes. A subgroup analysis of individuals receiving insulin only treatment (N = 23,054) demonstrated a similar risk pattern, although with slightly higher risk estimates. CONCLUSIONS/INTERPRETATION: Family aggregation of diabetes is associated with genetic disposition with maternal status being the predominant factor. Furthermore, we observed increased risk of diabetes in second-degree relatives, and between unrelated spouses, indicating that environmental factors influence diabetes risk substantially.

The Importance and Role of Multiple Risk Factor Control in Type 2 Diabetes.

PURPOSE OF REVIEW: The importance of composite risk factor control for reducing CVD risk in type 2 diabetes (T2DM) has gained increased attention and here we review the latest findings in the field. RECENT FINDINGS: The Steno-2 study was the first to show that early intensive risk factor control could improve risk factor status and halve the CVD risk in patients with diabetes with lasting impact. A range of observational studies have added further insight to the importance of multiple risk factor control showing an incremental association between number of risk factors controlled and reduction in CVD risk. Noteworthy, a Swedish population-based study recently showed that optimal risk factor status in patients with T2DM was associated with a CVD risk similar to the general population. Early intensive intervention to achieve optimal risk factor control reduces CVD risk and should be of principal focus in T2DM management.

Limited value of routine follow-up visits in chronic lymphocytic leukemia managed initially by watch and wait: A North Denmark population-based study.

INTRODUCTION: The majority of newly diagnosed chronic lymphocytic leukemia (CLL) patients are followed initially by watch and wait (WAW). Clinical practice varies and the value of frequent follow-up visits remains unclear. Thus, in this study we investigated the clinical value of follow-up visits for patients with CLL. METHODS: We collected data from diagnosis and follow-up visits for patients diagnosed with CLL and managed by WAW in the North Denmark Region between 2007-2014. High- and low-risk group patients were determined by Binet stage, IgVH status, and cytogenetics at diagnosis. The effect of risk group allocation on the probability of receiving CLL-directed treatment within two years was included in a multivariable logistic regression model adjusted for age and blood test results. RESULTS: 273 patients were included in the study with a median follow-up of 3 years (IQR: 1.6-5.4). Overall, the median interval between follow-up visits was 98 days (95% CI: 96-100) (high-risk patients: 91 days [95% CI: 86-95] vs. low-risk patients: 105 days [95% CI: 100-110]). Among 2,312 follow-up visits, only 387 (17%) were associated with interventions. At the following time points: 6 months, 1 year, and 1.5 years, patients with low-risk CLL had significantly lower odds of initiating treatment compared to patients with high-risk CLL. CONCLUSION: WAW plays an important role in managing CLL. Interventions at follow-up visits were infrequent and low-risk patients had significantly lower risk of treatment initiation. We question the value of routine follow-up in CLL in the absence of changes in symptoms and/or blood test results.

A multiple myeloma classification system that associates normal B-cell subset phenotypes with prognosis.

Despite the recent progress in treatment of multiple myeloma (MM), it is still an incurable malignant disease, and we are therefore in need of new risk stratification tools that can help us to understand the disease and optimize therapy. Here we propose a new subtyping of myeloma plasma cells (PCs) from diagnostic samples, assigned by normal B-cell subset associated gene signatures (BAGS). For this purpose, we combined fluorescence-activated cell sorting and gene expression profiles from normal bone marrow (BM) Pre-BI, Pre-BII, immature, naïve, memory, and PC subsets to generate BAGS for assignment of normal BM subtypes in diagnostic samples. The impact of the subtypes was analyzed in 8 available data sets from 1772 patients' myeloma PC samples. The resulting tumor assignments in available clinical data sets exhibited similar BAGS subtype frequencies in 4 cohorts from de novo MM patients across 1296 individual cases. The BAGS subtypes were significantly associated with progression-free and overall survival in a meta-analysis of 916 patients from 3 prospective clinical trials. The major impact was observed within the Pre-BII and memory subtypes, which had a significantly inferior prognosis compared with other subtypes. A multiple Cox proportional hazard analysis documented that BAGS subtypes added significant, independent prognostic information to the translocations and cyclin D classification. BAGS subtype analysis of patient cases identified transcriptional differences, including a number of differentially spliced genes. We identified subtype differences in myeloma at diagnosis, with prognostic impact and predictive potential, supporting an acquired B-cell trait and phenotypic plasticity as a pathogenetic hallmark of MM.

Subtype assignment of CLL based on B-cell subset associated gene signatures from normal bone marrow - A proof of concept study.

Diagnostic and prognostic evaluation of chronic lymphocytic leukemia (CLL) involves blood cell counts, immunophenotyping, IgVH mutation status, and cytogenetic analyses. We generated B-cell associated gene-signatures (BAGS) based on six naturally occurring B-cell subsets within normal bone marrow. Our hypothesis is that by segregating CLL according to BAGS, we can identify subtypes with prognostic implications in support of pathogenetic value of BAGS. Microarray-based gene-expression samples from eight independent CLL cohorts (1,024 untreated patients) were BAGS-stratified into pre-BI, pre-BII, immature, naïve, memory, or plasma cell subtypes; the majority falling within the memory (24.5-45.8%) or naïve (14.5-32.3%) categories. For a subset of CLL patients (n = 296), time to treatment (TTT) was shorter amongst early differentiation subtypes (pre-BI/pre-BII/immature) compared to late subtypes (memory/plasma cell, HR: 0.53 [0.35-0.78]). Particularly, pre-BII subtype patients had the shortest TTT among all subtypes. Correlates derived for BAGS subtype and IgVH mutation (n = 405) revealed an elevated mutation frequency in late vs. early subtypes (71% vs. 45%, P < .001). Predictions for BAGS subtype resistance towards rituximab and cyclophosphamide varied for rituximab, whereas all subtypes were sensitive to cyclophosphamide. This study supports our hypothesis that BAGS-subtyping may be of tangible prognostic and pathogenetic value for CLL patients.