Sorin Ioacara

Cancer Specific Mortality in Insulin-Treated Type 2 Diabetes Patients

Aims To test the hypothesis that cumulative exposure to insulin and long-acting insulin analogs might be associated with cancer mortality in diabetes patients. Methods All consecutive diabetes patients aged over 40 years, residing in a major urban area were screened at their first diabetes outpatient visit between 01/01/2001-12/31/2008 (n = 79869). Exclusion criteria were insulin treatment at screening, no insulin treatment until 12/31/2008, less than 6 months of glucose-lowering treatment alone before insulin initiation, insulin prescription before glargine became available, age <40/≥80 years at first insulin prescription, and <6 months of insulin exposure. A total 4990 subjects were followed-up for death based on death certificate, until 12/31/2011. Adjusted time-dependent competing risk regression analysis, with daily updates of treatment modalities was performed. Results are expressed for every 10,000 IU of cumulative dose or one year of cumulative time exposure to insulin. Results Mean baseline age was 62±9 years, and follow-up 4.7±1.9 years. Glargine cumulative dose was associated with lower cancer mortality risk (subhazard ratio, SHR: 0.94 (95%CI 0.89–0.99, p = 0.033)). Cumulative exposure limited to that attained one year prior to death revealed lower SHRs for cumulative time (0.94 (95%CI 0.89–0.99, p = 0.018)) and cumulative dose of glargine (0.92 (95%CI 0.86–0.98, p = 0.014)). Glargine cumulative time and cumulative dose were significant predictors for lower pancreatic and breast cancer mortality, but not for deaths from lung, colorectal, female genital, liver, and urinary tract cancer. No increased hazards were found for any other subtypes of insulins. Conclusions The cumulative dose exposure to insulin glargine was associated with a lower risk of cancer mortality in general, and of breast and pancreatic cancer in particular. This effect remained even after additional “fixed” cohort or propensity score analyses.

A pathophysiological approach to metabolic syndrome using factor analysis in an adult Romanian population

Abstract The aim of the study was to examine the role of insulin resistance in etiopathogenesis of metabolic syndrome in an adult Romanian population using exploratory factor analysis. We analyzed 228 non-diabetic subjects randomized in respect to the age and sex distribution of the general population. For each patient, age, sex, body mass index (BMI), systolic and diastolic blood pressure (SBP, DBP), HDL-cholesterol (HDL), plasma triglycerides (TG), fasting plasma glucose (FPG) and fasting insulin were obtained. Factor analysis was performed using principal component analysis, with Varimax rotation of the major determinants of metabolic syndrome. Mean age was 48.9 ± 12.7 years; 107 (46.9%) were men and 121 (53.1%) women. We found three major factors, which are correlated with metabolic syndrome and may explain its variance. Factor 1 comprises SBP and DBP in men and SBP, DBP and BMI in women. Factor 2 comprises BMI, HDL, TG and FPG in men and BMI, TG and FPG in women. Factor 3 comprises fasting insulin in men and fasting insulin, TG and HDL in women. The finding of more than one factor suggests that insulin resistance is not the only pathophysiological mechanism involved. These factors appear to work independently of each other in men, but they intersect in women, suggesting that the pathophysiology of metabolic syndrome may be different in women compared with men.

The dynamics of life expectancy over the last six decades in elderly people with diabetes

AIM To investigate the historical changes in survival with diabetes in elderly people with diabetes. RESEARCH DESIGN AND METHODS We analyzed 6504 deaths (44.5% males) registered in a large urban population, aged ≥65 years, and deceased between 1943 and 2009. We split the analysis into three time periods according to year of death: 1943-1965, 1966-1988 and 1989-2009. The parallel changes in the corresponding general population were available. RESULTS The mean age at diabetes onset was 70.8 ± 4.7 years, with mean disease duration at death 7.5 ± 5 years, and mean age at death 78.3 ± 5.9 years. The mean survival loss due to diabetes (expected minus observed survival) was 4.5 ± 5.1 years (4.9 ± 5.1 years for females versus 4.1 ± 5.2 years for males, p<0.001). The mean disease duration at death was 6.4 ± 5.7 years in the period 1943-1965, followed by a significant (p=0.019) rise to 7 ± 5 years in 1966-1988, and 8.3 ± 4.9 years (p<0.001) in 1989-2009. There was a significant increase in coronary heart disease and stroke, and a significant decrease in infections and end-stage renal disease as causes of death. CONCLUSIONS We found a significant increase in age at onset and survival with diabetes leading to a significant increase in age at death. Females had a higher survival loss due to diabetes compared with males.

First case of neonatal diabetes with KCNJ11 Q52R mutation successfully switched from insulin to sulphonylurea treatment

In this report, we present the first known case of intermediate developmental delay, epilepsy and permanent neonatal diabetes (DEND) syndrome caused by a Q52R mutation in the KCNJ11 gene who was successfully switched (at age 1.3 years) to sulphonylurea monotherapy, namely glibenclamide. The most recent evaluation, after 2 years, showed a glycated hemoglobin level of 6.0% (42 mmol/mol). This mutation is so severe that none of the previously reported four cases were able to switch from insulin to sulphonylurea monotherapy. The Q52R mutation seems to have a chance of positive response to glibenclamide administered every 3–6 h instead of the classical 8–12 h, in doses around or above 2.5 mg/kg/day.

To diet or not to diet in neonatal diabetes responding to sulfonylurea treatment.

Abstract Background Neonatal diabetes mellitus (NDM) is defined as a monogenic form of diabetes that occurs in the first 6 months of life. As information on diet in NDM patients successfully treated with sulfonylurea is not yet available, we aimed to investigate the hypothesis that a carb-restricted diet is not needed in such cases. Case presentation In this case report, we present a successful implementation of a completely liberalized diet in a young patient with NDM, developmental delay and epilepsy (DEND syndrome), who was also switched to sulfonylurea treatment. The excellent metabolic control during follow-up despite completely ignoring any diet suggests that at least in some patients this approach might work. Conclusions If our proposed hypothesis is also confirmed by other reports, it might add significantly to the quality of life of these patients and broaden the knowledge in this medical field.

All-cause and cardiovascular mortality associated with sulphonylurea and metformin therapy in type 2 diabetes

ABSTRACT Purpose: To test the hypothesis that cumulative exposure to sulphonylurea (SU) or metformin (MET) have different effects on mortality when taken as a replacement or add-on of one for the other. Methods: All consecutive diabetes patients aged over 20 years were screened at their first diabetes outpatient visit between 2001 and 2008 (n = 79869). Only patients on MET (n = 11374) or SU (n = 18502) monotherapy were retained. All patients were followed up for death until December 31, 2011, but censored at first exposure to anything else besides MET/SU. Adjusted time-dependent Cox regression and competing risk regression analysis, with daily updates of treatment modalities were performed. Results: Mean age was 62.1 ± 11.2 years and follow-up was 4.6 ± 3.2 years (138496 person-years). Adjusted all-cause and cardiovascular mortality rates were significantly higher in MET as compared with SU group. All-cause mortality hazard ratios (HR) for cumulative time exposure were as follows: HR 0.956 (95%CI 0.951–0.962, p < 0.001) for SU added to MET, HR 1.092 (95%CI 1.087–1.096, p < 0.001) for SU replacing MET, HR 0.979 (95%CI 0.975–0.983, p < 0.001) for MET added to SU, and HR 1.127 (95%CI 1.118–1.136, p < 0.001) for MET replacing SU. Conclusion(s): The effect on all-cause mortality was beneficial for MET+SU combined therapy, but deleterious for either SU replacing MET, or MET replacing SU. There were no major outcome differences when analyzing individual SU, or specific mortality.

Recent diabetes-related mortality trends in Romania

AimsAs there are no published articles on country-level diabetes-related mortality in Romania, we aimed to investigate this aspect for the 1998–2015 period.MethodsAnonymized demographic and diabetes-related mortality data (underlying or first secondary cause of death) were retrospectively obtained from the National Institute of Statistics/Eurostat microdata. Age-standardized mortality rates (ASMR) and their annual percentage change (APC) were analysed.ResultsDuring 1998–2015, 4,567,899 persons died in Romania, among whom, diabetes was responsible for 168,854 cases. The ASMR for diabetes was 39.34 per 100,000 person-years (p-y) (95% CI 39.32–39.35). There was an increase in ASMR from 27.10 per 100,000 p-y (95% CI 27.01–27.19) in women and 30.88 per 100,000 p-y (95% CI 30.77–30.99) in men in 1998 to 35.42 per 100,000 p-y (95% CI 35.34–35.51) in women and 48.41 per 100,000 p-y (95% CI 48.29–48.52) in men, in 2015. The mean APC in women was 3.8% per year (95% CI 3.5–4.0, p < 0.001) during 1998–2010 and − 1.9% per year (95% CI − 2.7 to − 1.1, p < 0.001) during 2010–2015. The mean APC in men was 5.3% per year (95% CI 5.0–5.5, p < 0.001) during 1998–2010 and − 1.5% per year (95% CI − 2.2 to − 0.8, p < 0.001) during 2010–2015. Diabetes-related mortality rates increased with age, with men experiencing higher mortality rates than women for most age groups and calendar years.ConclusionsDiabetes-related mortality rates increased significantly in Romania during 1998–2010, followed by a steady decline during 2010–2015.

Cardiovascular Mortality in Type 2 Diabetes Patients with Incident Exposure to Insulin Glargine

The study investigated the impact of insulin glargine exposure on cardiovascular mortality in type 2 diabetes patients with incident insulin initiation. All consecutive diabetes patients aged >40 years were screened at their first diabetes outpatient visit between 01/01/2001 and 12/31/2008 (n = 79869). Exclusion criteria restricted the cohort to 4990 incident insulin users, aged 40–79 years, who were followed up for death until 12/31/2011. Baseline was defined 6 months after insulin initiation. Adjusted time-dependent competing risk regression analysis was performed. Mean baseline age was 62 ± 9 years, with mean follow-up of 4.7 ± 1.9 years. During 23179 person-years of exposure time, there were 887 deaths (521 cardiovascular). Glargine cumulative time exposure significantly lowered overall cardiovascular, subhazard ratio (SHR) 0.963 (CI 95% 0.944–0.981, p < 0.001), and myocardial infarction mortality, SHR 0.945 (CI 95% 0.899–0.994, p = 0.028), but not stroke mortality. Glargine cumulative dose exposure (10,000 IU increments) significantly lowered cardiovascular mortality, SHR 0.977 (CI 95% 0.960–0.993, p = 0.006), but not for myocardial infarction and stroke. Both cumulative dose and time exposure to insulin glargine were associated with lower cardiovascular mortality. The effect was mostly driven by myocardial infarction end point, supporting the concept of macrovascular benefit for basal analogue insulin use in type 2 diabetes.