Ines Bilic-Curcic

Impact of health policy and practice on finding the best fit for patients with type 2 diabetes after metformin failure: Croatian pilot study

AIM We assessed the impact of clinical practice and health policy on the choice and efficacy of different second-line therapies for the treatment of type 2 diabetes (T2DM) after failure of metformin. METHODS This retrospective database analysis included 200 patients with a follow-up period of 6 months. The primary end-point was achievement of HbA1c <7% and fasting (FBG) and postprandial glucose levels (PPG) <7.2mmol/L and <10mmol/L, respectively after three and six months of different add-on treatments. Secondary end-points were weight change during treatment and incidence of hypoglycemia. RESULTS All second-line therapeutic options, except human basal insulin (BHI) and thiazolidendions (TZD) significantly increased the proportion of patients reaching target HbA1c after 6 months (p<0.01). Only sulfonylurea (SU) and dipeptidyl peptidase-4 (DPP-4) inhibitors significantly reduced all monitored parameters of glucoregulation without changing body weight and BMI after 3 and 6 months as opposed to insulin agents. However, there were no statistically significant differences between the groups when adjusting for starting HbA1c, FBG and PPG (F=1.16, p=NS), although a statistically significant difference in HbA1c levels (F=3.35, p<0.01) persisted in DPP-4 inhibitor users. The incidence of hypoglycemia was significantly higher in patients treated with NPH insulin and premixed insulin than in patients treated with other agents. CONCLUSION A more aggressive approach is needed with early treatment intensification using available agents.

Plasminogen activator inhibitor-1 concentrations and bone mineral density in postmenopausal women with type 2 diabetes mellitus

BackgroundWomen with type 2 diabetes mellitus (T2DM) have a higher risk of fractures despite increased bone mineral density (BMD). In experimental studies a potential role of plasminogen activator inhibitor-1 (PAI-1) in bone remodeling is suggested but studies in humans are lacking. This is a first study in humans investigating whether circulated levels of PAI-1 in postmenopausal women with T2DM are related to BMD and adiposity.MethodsAnthropometric variables, PAI-1 and insulin levels, serum lipids and bone turnover markers were measured in 127 postmenopausal women with T2DM. A total of 117 female patients were divided according to lumbar spine BMD measurements via dual-energy x-ray absorptiometry in three groups: 47 with osteopenia, 21 with osteoporosis and 49 with normal BMD.ResultsDiabetic patients with normal BMD had significantly higher BMI, greater waist circumference and lower bone turnover markers than diabetics with osteopenia and osteoporosis. PAI-1 was lower in diabetics with osteoporosis and osteopenia compared with diabetics with normal BMD. Multiple regression analysis revealed insulin, triglycerides levels, pyrilinks and beta blocker therapy to be the strongest predictors of PAI-1 levels. PAI-1 levels correlated with both L-BMD and hip BMD, but after adjustment for age and BMI association was no longer significant.ConclusionOur findings suggest that elevated PAI-1 levels are associated with higher BMD in obese diabetic patients but the possible implications of this finding and underlying mechanisms still remain unclear. Obviously, metabolic parameters, may affect both BMD and PAI-levels, and association of PAI-1 and BMD could be indirect. However, as pyrilinks is also independently and significantly negatively correlated to PAI-1 its direct involvement in bone metabolism is also plausible. Further investigations are needed to elucidate the nature of interaction of this matrix modulator in relation to energy and bone metabolism in humans.

Sex-dependent association between coronary vessel dominance and cardiac syndrome X: a case-control study

BackgroundPrevious studies have demonstrated the relevance of left coronary artery dominance in the outcome and prognosis of obstructive coronary artery disease (CAD). However, no studies have investigated the influence of coronary vessel dominance on non obstructive CAD. The aim of this study was to establish the association of left and mixed dominance of the major epicardial arteries with the development of non obstructive CAD and evaluate potential sex-dependent differences in the coronary artery supply.MethodsA total of 484 patients underwent the same diagnostic procedures. The patients were divided into two groups based on their coronary angiogram results: the control group (242 patients with obstructive CAD; coronary artery stenosis of ≥50%) and the experimental group (242 patients with non obstructive CAD; coronary artery stenosis of <50%).ResultsSignificantly more women than men were affected by non obstructive CAD (P = 0.005). Left dominance was more frequent in the non obstructive CAD group than in the control group (P = 0.018) and was more pronounced in women than in men (P = 0.013). Among men with non obstructive CAD, a left supply was more frequent than a mixed supply (P = 0.012). Women with non obstructive CAD had a higher frequency of a left supply, whereas a mixed supply was less frequent in men than in patients with obstructive CAD (P = 0.013 and 0.018, respectively).ConclusionThese results suggest that left dominance (particularly in women) and the absence of a mixed supply in men could cause regional ischemia, thus affecting the development of non obstructive CAD. Furthermore, sex may determine the incidence of specific coronary artery supply types, therefore influencing disease development and prognosis.

Changes in HbA1c and hypoglycemic episodes in type 1 diabetes patients after switching to insulin glargine U300: Pilot study

We included diabetes type 1 (T1DM) patients with suboptimal glycemic control on morning application glargine (I-Glar) U100, switching them to U300. After six months improvement in HbA1c was observed, while hypoglycemic episodes decreased. Switch from I-Glar U100 to U300 could be a good therapeutic option for that subset of patients.

Bone mineral density in relation to metabolic syndrome components in postmenopausal women with diabetes mellitus type 2

Diabetes mellitus type 2 is associated with greater bone mineral density (BMD) due to obesity, although rapid bone loss observed over time could be explained by elevated chronic inflammation. The objective of this study was to investigate the relationship between central adiposity and hyperinsulinemia, as well as inflammation markers with vertebral and femoral BMD and bone turnover markers in postmenopausal women with type 2 diabetes. Femoral and vertebral BMD, osteocalcin, pyrilinks D, beta-CrossLaps (B-CTx), insulin, C-reactive protein (CRP), fibrinogen and plasminogen activator inhibitor-1 (PAI-1) were measured in 114 postmenopausal female patients with diabetes type 2. The patients of similar age, HbA1c levels and diabetes duration were divided into 2 groups based on their body mass index (BMI) values: lower or equal to 27 kg/m(2) (31 patients) and higher than 27 kg/m(2) (83 patients). Lower levels of osteocalcin (p=0.001), B-CTx (p=0.000007) and pyrilinks D (p=0.0365), and higher femoral BMD (p=0.00006), insulin level (p=0.0002), PAI-1 (p=0.00000) and CRP (p=0.002) were found in the overweight group. There were no signifi cant differences in vertebral BMD and fibrinogen. Osteocalcin and B-CTx showed inverse correlation, and femoral BMD positive correlation with waist circumference, insulin level and PAI-1. This suggests that abdominal obesity and hyperinsulinemia as components of the metabolic syndrome could increase femoral BMD by lowering bone rate. In addition, the only inflammation marker linked with femoral BMD was PAI-1, which is associated with increased mineralization of cortical bone in mouse.

Gastrin—A Potential Predictor of Glucoregulation in Newly Diagnosed Type 2 Diabetes Patients

Background and Aims: Experimental data demonstrated that activation of GLP-1 and gastrin signaling induces beta cell neogenesis, resulting in a promotion of glucose-induced insulin secretion. In addition, treatment with proton pump inhibitors is associated with greater glycemic control in patients with type 2 diabetes (T2DM), particularly in those on insulin- or GLP-1-based therapy. The aim of this study was to assess gastrin as a potential predictor of beta cell function and glucoregulation in newly diagnosed T2DM patients. Materials and Methods: In this cross sectional study 190 patients (64 males and 126 females) with new onset T2DM were included. Patients treated with IPPs were excluded. Fasting plasma glucose (FPG), postprandial PG, HbA1c, fasting insulin, pancreatic B cell function (HOMA-B), insulin resistance index (HOMA-IR), fasting c-peptide and gastrin levels were measured at the time of diagnosis. Results: Baseline HbA1c was 7.53±2.08%, average age of patients was 61.8±10.years and body mass index (BMI) was 31.25±5.73 kg/m2. Parameters of glucoregulation were not significantly correlated with gastrin (all p>0.05), while there was moderate negative correlation with HOMA-B (HbA1c, FPG and PPG ; p 0.05) or HOMA-IR. Furthermore, no association was established between c-peptide, insulin levels and gastrin (p>0.05). Conclusion: Baseline gastrin levels are not sufficient to have a significant effect on glucoregulation or HOMA-B and HOMA-IR in newly diagnosed T2DM, therefore it could be postulated that further stimulation of gastrin secretion (e.g., with IPPs or GLP-1 based therapy) is needed in order to influence beta cell function and glycemic control.

Are We Compensating for the Lack of Physical Activity in Our Diabetic Patients with Treatment Intensification

Background: We studied the association between leisure time physical activity (LTPA) and glycemic control, body mass index (BMI), and hypoglycemic incidents in type 1 (T1DM) and type 2 diabetes patients (T2DM). Methods: This is a cross-sectional study of 198 diabetic patients (60 with type 1 diabetes, 138 with type 2 diabetes). LTPA was assessed by a validated 12-month questionnaire. Patients were grouped as sedentary and moderately to vigorously active. Outcome measures were Hemoglobin A1c (HbA1c), BMI, and hypoglycemic episodes. Results: LTPA effect on the HbA1c reduction was present in diabetes type 1 patients. Patients who were involved in the moderate to vigorous-intensity physical activity had a greater decrease in the HbA1c (p = 0.048) than patients with low physical activity (p = 0.085). Level of LTPA was neither associated with increased number of hypoglycemic episodes, nor BMI. After an average of 4 years of diabetes, the number of patients requiring more than one antidiabetic agent increased, although the observed difference did not correlate with LTPA level. Conclusions: LTPA has an influence on the regulation of diabetes type 1, and intensification of medical treatment is compensating for the lack of lifestyle change—especially in type 2 diabetics.

Gastrin - A Potential Predictor of Response to Incretin Therapy in Diabetes Type 2 Patients.

BACKGROUND AND OBJECTIVES Personalized management of diabetes has become an imperative since majority of monotherapy fails within 3 years of its use. Identifying responders from nonresponders for a certain type of therapy would reduce a period of unsuccessful treatment and minimize health care costs. Incretin therapies, mainly glucagon-like peptide (GLP)-1 receptor agonists (GLP- 1RA) are relatively new glucose-lowering agents which increase insulin and lower glucagon response as well as slow down glucose absorption by acting on gastric emptying. However, problem with incretin- based therapy is distinguishing responders from non-responders and currently lack of specific predictors of treatment response. DISCUSSION Experimental data demonstrated that activation of GLP-1 and gastrin signaling induces beta cell neogenesis, leading to glucose-dependent insulin secretion. Several studies demonstrated better glycemic control in patients with type 2 diabetes (DMT2) co-treated with proton pump inhibitors (PPI) and incretin based therapy agents. CONCLUSION Higher gastrin levels in patients with diabetes prior to initiation of treatment with incretin mimetics could suggest a better potential for reversible human β-cell reprogramming with concomitant incretin therapy. Therefore, baseline levels of endogenous gastrin could be used as a predictor of response to GLP-1 therapy. In addition, treatment with PPI could also raise gastrin levels and in patients treated with GLP-1RA, lead to better glycemic control by initiating β-cell neogenesis and proliferation of pancreatic β-cells.

Serum Osteoprotegerin in Patients with Calcified Aortic Valve Stenosis in Relation to Heart Failure

The aim of the study was to assess the role of serum osteoprotegerin (OPG) as a biomarker in patients with aortic valve stenosis (AS) in relation to heart failure and symptomatic status. This was a case control study, which included 51 patients with AS and 39 control subjects. At the time of study enrolment, detailed medical history was obtained and all subjects underwent physical examination, chest x-ray and echocardiography. OPG levels were measured in all subjects, and serum N-terminal of the pro b-type natriuretic peptide (NT pro BNP) levels were determined in patients with AS. Serum OPG levels were elevated in patients with AS compared to control subjects (p=0.001). Patients with heart failure due to AS had elevated serum OPG levels in comparison to patients without heart failure (p=0.001). A significant correlation between OPG and symptomatic status was observed in all patients with AS (p<0.001), however, it was not the case in patients without heart failure (p=0.425). There was a positive correlation between OPG and NT pro BNP concentrations with objective signs of heart failure on chest x-ray (p<0.001). Negative correlation of OPG concentrations with aortic valve area was present (p<0.040), as well as with left ventricular ejection fraction (p<0.001). Serum OPG could be a valuable biomarker in the evaluation of severity of calcified AS and serve as an additional indicator besides clinical presentation and echocardiography in the assessment of surgical treatment or aortic valve replacement.

Assessment of Environmental and Hereditary Influence on Development of Pituitary Tumors Using Dermatoglyphic Traits and Their Potential as Screening Markers

The aim of this study was to assess environmental and hereditary influence on development of pituitary tumors using dermatoglyphic traits. The study was performed on 126 patients of both genders with pituitary tumors (60 non-functional and 66 functional pituitary tumor patients) in comparison to the control group of 400 phenotypically healthy individuals. Statistical analysis of quantitative and qualitative traits of digito-palmar dermatoglyphics was performed, and hormonal status was determined according to the standard protocols. Although we did not find markers that could specifically distinguish functional from non-functional tumors, we have found markers predisposing to the development of tumors in general (a small number of ridges between triradius of both hands, a smaller number of ridges between the triradius of c–d rc R), those for endocrine dysfunction (increased number of arches and reduced number of whorls, difference of pattern distribution in the I3 and I4 interdigital space), and some that could potentially be attributed to patients suffering from pituitary tumors (small number of ridges for variables FRR 5, smaller number of ridges in the FRL 4 of both hands and difference of pattern distribution at thenar of I1 and I2 interdigital space). The usage of dermatoglyphic traits as markers of predisposition of pituitary tumor development could facilitate the earlier detection of patients in addition to standard methods, and possibly earlier treatment and higher survival rate. Finally, our results are consistent with the hypothesis about multifactorial nature of pituitary tumor etiology comprised of both gene instability and environmental factors.