Treatment approach to type 2 diabetes: Past, present and future.

Type 2 diabetes mellitus (DM) is a lifelong metabolic disease, characterized by hyperglycaemia which gradually leads to the development and progression of vascular complications. It is recognized as a global burden disease, with substantial consequences on human health (fatality) as well as on health-care system costs. This review focuses on the topic of historical discovery and understanding the complexity of the disease in the field of pathophysiology, as well as development of the pharmacotherapy beyond insulin. The complex interplay of insulin secretion and insulin resistance developed from previously known "ominous triumvirate" to "ominous octet" indicate the implication of multiple organs in glucose metabolism. The pharmacological approach has progressed from biguanides to a wide spectrum of medications that seem to provide a beneficial effect on the cardiovascular system. Despite this, we are still not achieving the target treatment goals. Thus, the future should bring novel antidiabetic drug classes capable of acting on several levels simultaneously. In conclusion, given the raising burden of type 2 DM, the best present strategy that could contribute the most to the reduction of morbidity and mortality should be focused on primary prevention.

[CROATIAN GUIDELINES FOR THE PHARMACOTHERAPY OF TYPE 2 DIABETES]. / HRVATSKE SMJERNICE ZA FARMAKOLOSKO LIJECENJE SECERNE BOLESTI TIPA 2.

INTRODUCTION: The Croatian Association for Diabetes and Metabolic Disorders of the Croatian Medical Association has issued in 2011 the first national guidelines for the nutrition, education, self-control, and pharmacotherapy of diabetes type 2. According to the increased number of available medicines and new evidence related to the effectiveness and safety of medicines already involved in the therapy there was a need for update of the existing guidelines for the pharmacotherapy of type 2 diabetes in the Republic of Croatia. PARTICIPANTS: as co-authors of the Guidelines there are listed all members of the Croatian Association for Diabetes and Metabolic Diseases, as well as other representatives of professional societies within the Croatian Medical Association, who have contributed with comments and suggestions to the development of the Guidelines. EVIDENCE: These guidelines are evidence-based, according to the GRADE system (eng. Grading of Recommendations, Assessment, Development and Evaluation), which describes the level of evidence and strength of recommendations. CONCLUSIONS: An individual patient approach based on physiological principles in blood glucose control is essential for diabetes' patients management. Glycemic targets and selection of the pharmacological agents should be tailored to the patient, taking into account the age, duration of disease, life expectancy, risk of hypoglyce- mia, comorbidities, developed vascular and other complications as well as other factors. Because of all this, is of national interest to have a practical, rational and applicable guidelines for the pharmacotherapy of type 2 diabetes.

NOCTURNAL HYPOGLYCEMIA--THE MAIN INDICATION FOR INSULIN PUMP THERAPY IN ADULTHOOD.

The aim was to determine which adult type 1 diabetic patient receiving multiple daily injection therapy is the most appropriate candidate for insulin pump therapy, while taking into consideration limited insulin pump affordability in Croatia. A total of 145 type 1 diabetic patients (52% diagnosed in adult age) were monitored at the Department of Endocrinology, Clinical Department of Internal Medicine, Zagreb University Hospital Center from 2009 to 2014. Twenty-one patients started insulin pump therapy in adulthood (seven men and 14 women, median age 27). Five patients had chronic complications (retinopathy in two, polyneuropathy in one, and both nephropathy and retinopathy in two patients). The median HbA1c at the initiation of pump therapy was 6.95% versus 6.5% after 1 year of pump therapy. Patients were stratified according to indications for insulin pump therapy (frequent and/or severe hypoglycemia, specific lifestyle, having not reached glycemic goals despite adherence/labile diabetes, and preconception). Patients could meet more than one criterion. Initially, the occurrence of hypoglycemia was analyzed by 6-day continuous glucose monitoring, while re-evaluation was done after collecting history data at 1 year ± 3 months. Initially, all patients had a median of 5 hypoglycemias/6 days (30% nocturnal) versus 1 hypoglycemia/6 days (without nocturnal) after 1 year. The Wilcoxon signed-rank test yielded a statistically significant difference in hypoglycemic events, nocturnal hypoglycemia and HbA1c. Patients commencing insulin pump therapy due to hypoglycemia initially had median HbA1c of 6.7% with 7 hypoglycemia/6 days (50% nocturnal). After one year, median HbA1c was 6% with 1 hypoglycemia/6 days (without nocturnal). In conclusion, the main indication for insulin pump therapy in adults is the frequency of hypoglycemia, especially nocturnal ones.

[Quaternary prevention as a basis for rational approach to the patient in family practice]. / Kvartarna prevencija kao temelj racionalnog pristupa pacijentu u obiteljskoj medicini.

Quaternary prevention is an action taken to identify a patient at risk of overmedicalisation, to protect him from new medical invasion, and to suggest to him interventions which are ethically acceptable. It belongs mostly to family medicine because of the family physician's position who is the first contact to the patient and "leader" of patient through health care system. Family physician must have a skill to locate the patient's symptom to the proper organ system and also to find the appropriate procedure for the patient. This is very complex in a situation when the patient has symptoms and complaints and the physician doesn't find the disease. In these situations individual approach to the patient, good communication, balance between finding appropriate procedures and defining neccessary procedures together with evidence based medicine make quaternary prevention, which becomes a neccessity in the process of leading the patient through modern health care system.

Genetic evaluation of the TNF-α -238G>A and -308G>A promoter polymorphisms in Croatian patients with type I diabetes.

A case-control study was performed to establish a potential association of two TNF-α gene promoter SNPs (-238G>A and -308G>A) with occurrence of type 1 Diabetes mellitus (T1DM) in Croatian population (174 patients and 193 healthy controls). Genotypes (obtained by polymerase chain reaction-restriction fragment length polymorphism), and the clinical parameters of T1DM patients were statistically evaluated by SPSS 13 and Arlequin software, G*Power 3.0.10 program, and calculator for Hardy-Weinberg equilibrium. The frequency of the risk (A) allele, as well as the distribution of high-expression (GA, AA) genotypes were significantly higher (p < 0.0001) in T1DM patients only at locus -308. The distribution of the -238G/-308A haplotype was also significantly higher in patients compared with controls (27.6% vs 9.6%, p < 0.0001). Gender-dependent analysis revealed that female T1DM -308GA genotype carriers exhibit considerably stronger association with T1DM (odds ratio = 6.37, 95% confidence interval = 3.16-12.85) than male -308GA patients (odds ratio = 2.71, 95% confidence interval = 1.31-5.59). Clinical parameter analysis of T1DM patients revealed significantly decreased level of hemoglobin A(1)c (HbA(1)c) in -238A allele carriers compared with -238G allele carriers (6.55% vs 7.17%, p = 0.022), as well as the tendency of the risk allele carriers at -238 or -308 locus to develop T1DM earlier in life compared with non-risk allele carriers. In conclusion, susceptibility to T1DM in the Croatian population is strongly associated with the TNF-α -308G>A polymorphism, especially in women. In addition, significantly lower HbA(1c) levels found in T1DM -238A allele carriers might indicate better glycemic control in these patients.

A prospective observational study of the relationship of critical illness associated hyperglycaemia in medical ICU patients and subsequent development of type 2 diabetes.

INTRODUCTION: Critical illness is commonly complicated by hyperglycaemia caused by mediators of stress and inflammation. Severity of disease is the main risk factor for development of hyperglycaemia, but not all severely ill develop hyperglycemia and some do even in mild disease. We hypothesised that acute disease only exposes a latent disturbance of glucose metabolism which puts those patients at higher risk for developing diabetes. METHODS: Medical patients with no history of impaired glucose metabolism or other endocrine disorder admitted to an intensive care unit between July 1998 and June 2004 were considered for inclusion. Glucose was measured at least two times a day, and patients were divided into the hyperglycaemia group (glucose ≥7.8 mmol/l) and normoglycaemia group. An oral glucose tolerance test was performed within six weeks after discharge to disclose patients with unknown diabetes or pre-diabetes who were excluded. Patients treated with corticosteroids and those terminally ill were also excluded from the follow-up which lasted for a minimum of five years with annual oral glucose tolerance tests. RESULTS: A five-year follow-up was completed for 398 patients in the normoglycaemia group, of which 14 (3.5%) developed type 2 diabetes. In the hyperglycaemia group 193 patients finished follow-up and 33 (17.1%) developed type 2 diabetes. The relative risk for type 2 diabetes during five years after the acute illness was 5.6 (95% confidence interval (CI) 3.1 to 10.2). CONCLUSIONS: Patients with hyperglycaemia during acute illness who are not diagnosed with diabetes before or during the hospitalization should be considered a population at increased risk for developing diabetes. They should, therefore, be followed-up, in order to be timely diagnosed and treated.

Association of PTPN22 C1858T and CTLA-4 A49G polymorphisms with Type 1 Diabetes in Croatians.

In this case-control study the association between the PTPN22 1858T and CTLA-4 49G gene variants and T1D in Croatian population was examined. We found that distribution of PTPN22 C1858T and CTLA-4 A49G genotypes between T1D patient (n=102) and control (n=193) groups differ significantly (p<0.0001 and p=0.012, respectively). Moreover, although the risk alleles of both SNPs are distributed more frequently in patients, the significant difference is observed only for PTPN22 1858T allele (p<0.0001). This is therefore the first evidence that analyzed gene variants contribute to T1D pathogenesis in Croatian population.

Chronic patients--persons with diabetes frequent attenders in Croatian family practice.

Chronic diseases cause high frequency visits and generate the long-term frequent attenders (FAs). The connection between frequent attendance and specific morbidities in the health care systems in transitional Europe has been underestimated. We investigated whether frequent visits of chronic patients in primary care are related to characteristic of chronic disease (diabetes mellitus) and whether this is influenced by the family practice in the transitional health care. We analyzed the number of visits a day time work for 490 persons with diabetes in the period 1997 to 2000. As the cut-off points between frequent attenders and non frequent attenders (NFAs) we used the value of the third quartile (Q3) of visits determined for the sex and age groups in the parallel study in the whole population. The analysis was performed for 23 variables: demographic characteristics of patients, disease characteristic and variables of physician. Logistic regressions were employed to identify the predictors of FAs/NFAs. 56.9% (in 1997) to 62.4% (in 2000) persons with diabetes were FAs, compared to 22.4% to 24.3% FAs patients in the whole population. Logistic regression analysis significantly differentiated the two group of visits with 68% accuracy. 4 variables are significant predictors for FAs/NFAs: diabetes as the main disease (p = 0.0005), diet-only-treatment (p = 0.0062), treatment by secondary care (p = 0.0116), and if glycated hemoglobin test (HbA1c) is determined (p = 0.0272). Understanding the similarities and differences of FAs/NFAs persons with diabetes may be important in improving the care and management of chronic diseases in family medicine in transitional health care systems.

[CroDiab GP--follow up of diabetics protection in general medicine]. / CroDiab GP--pracenje zastite dijabetickih bolesnika u obiteljskoj medicini.

INTRODUCTION: There is an increasing number of diabetics in the population. Care of diabetes mellitus type 2 has been transferred from specialist care to the level of general practice. Collecting data and making database of diabetic care are set as quality indicators of diabetic care. AIM: The aim is to present the electronic CroDiab GP program as a tool for collecting data on diabetics in family practice in Croatia. Another aim is to track diabetic quality care and include patients in the national registry of diabetics. METHODS: The program was demonstrated on a sample of 10 family practice units with approximately 18,000 patients from four districts in north Croatia. These units are involved in the project of tracking diabetic care quality in family medicine. The core population for data collection is set by the basic diagnostic unit according to ICD-10: E10-E14. The program mainframe is the CroDiab NET computer system. The central module of CroDiab NET is BIS (Basic Information Sheet). It is set as optimal data collection that allows tracking diabetic care quality. Sixteen diabetic variables were analyzed. These variables refer to the type of disease, duration, treatment, and procedure for early detection of complications. RESULTS: In the population of 18,0000 patients there were 822 (4.6%) diabetics. There were 6.3% of patients with type 1 diabetes and 87.4% with type 2 diabetes; 6.3% were unknown. There were 16.0% diabetics on diet therapy, 60.7% on oral medication (1 to 3 medications), and 13.4% on insulin therapy, 8.4 diabetics were on both insulin and oral medication. CONCLUSION: Family medicine should present parameters of the quality of diabetic care. It is possible to collect data in electronic media, make statistical analysis and present data. The next step is entering patient data in the national registry of diabetics.

Structure of visits persons with diabetes in Croatian family practice--analysis of reasons for encounter and treatment procedures using the ICPC-2.

The reasons for encounter and the procedures conducted during the visit persons with diabetes to family practice have been investigated. Five family practitioners located in two Croatian counties took part in this study. In this study patients with diagnoses E10-E14 according to International Classification Disease-10 (ICD-10), were involved. There were 543 persons with diabetes (women 324) in the total population of 10,150 patients Data were registered according to the International Classification Primary Care-2 (ICPC-2) (components 1-7 for reasons of encounter, and components 2-6 for procedures during the visit), in period october till december 2005. 871 visits of persons with diabetes (average age 65.7 +/- 12.5 were registered. Patients presented in total 1921 reasons for encounter or 2.1 +/-1.1 per visit. Family practitioner made in total 2,341 procedures or 2.6 +/- 1.5 procedures per visit. 85.0% of patients had 1 to 3 reasons for encounter, 78.4% of patients had 1 to 3 procedures per visit. 64.4% of patients with diabetes presented at least one reason for encounter connected to diabetes. The most common reasons for encounter were prescriptions of medication 46.4 per 100 reasons for encounter, the second was dignostic procedure 19.9, request for analysis of findings 11.1, symptoms complaints 11, request for referrals to diagnostic procedures or specialist consultation 8.9 and administrative reuqests 1.6 per 100 reasons for encounter. Family practitioner performed procedure prescriptions of medication 47 per 100 procedures. The second was dignostic procedure 32.8 per 100 procedures, referrals to diagnostic procedures or specialist consultation 14.7 and administrative procedures 1.7 per 100 procedures. From the total number of 100 referrals to specialist, 23 were to diabetologist, 15 to ophtalmologist, 13 to cardiologist. The largest proportion of procedure belong to diabetics 33.8%, followed by the circulatory system 25.4%, musculosceletal 6.9%, symptoms 5.1%, respiratory 4.5%. The reasons for encounter and the procedures conducted during the visit have direct influence to the quality of care for persons with diabetes. It is necessery collecting the data and research in the field of reasons for encounter and procedures during the visit of person with diabetes. The results then can be compared to the results already found in literature.