Modern Management of Cardiometabolic Continuum: From Overweight/Obesity to Prediabetes/Type 2 Diabetes Mellitus. Recommendations from the Eastern and Southern Europe Diabetes and Obesity Expert Group.

The increasing global incidence of obesity and type 2 diabetes mellitus (T2D) underscores the urgency of addressing these interconnected health challenges. Obesity enhances genetic and environmental influences on T2D, being not only a primary risk factor but also exacerbating its severity. The complex mechanisms linking obesity and T2D involve adiposity-driven changes in ß-cell function, adipose tissue functioning, and multi-organ insulin resistance (IR). Early detection and tailored treatment of T2D and obesity are crucial to mitigate future complications. Moreover, personalized and early intensified therapy considering the presence of comorbidities can delay disease progression and diminish the risk of cardiorenal complications. Employing combination therapies and embracing a disease-modifying strategy are paramount. Clinical trials provide evidence confirming the efficacy and safety of glucagon-like peptide 1 receptor agonists (GLP-1 RAs). Their use is associated with substantial and durable body weight reduction, exceeding 15%, and improved glucose control which further translate into T2D prevention, possible disease remission, and improvement of cardiometabolic risk factors and associated complications. Therefore, on the basis of clinical experience and current evidence, the Eastern and Southern Europe Diabetes and Obesity Expert Group recommends a personalized, polymodal approach (comprising GLP-1 RAs) tailored to individual patient's disease phenotype to optimize diabetes and obesity therapy. We also expect that the increasing availability of dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists will significantly contribute to the modern management of the cardiometabolic continuum.

A lifestyle pattern characterised by high consumption of sweet and salty snacks, sugar sweetened beverages and sedentary time is associated with blood pressure in families at risk for type 2 diabetes mellitus in Europe. The Feel4Diabetes Study.

BACKGROUND: Individuals from families at high-risk for type 2 diabetes mellitus (T2DM) are also at high risk for hypertension (HTN) and cardiovascular disease. Studies identifying lifestyle patterns (LPs) combining dietary, physical activity or sedentary variables and examining their possible role with respect to developing blood pressure (BP) are limited. The present study aimed to examine the association of different LPs with BP levels in families at high risk for T2DM in Europe. METHODS: In total, 1844 adults (31.6% males) at high-risk for T2DM across six European countries were included in this cross-sectional study using data from the baseline assessment of the Feel4Diabetes Study. BP measurements and dietary and physical activity assessments were conducted, and screen times were surveyed. LPs were revealed with principal component analysis of various data regarding diet, physical activity, screen time and smoking. RESULTS: Three LPs were identified. LP3 (high consumption of sweet and salty snacks, sugar sweetened soft drinks and juices, and high amount of screen time) was positively associated with diastolic BP (B, 0.52; 95% confidence interval = 0.05-0.99) and the existence of HTN (odds ratio = 1.12; 95% confidence interval = 1.00-1.25). Participants in the highest tertile of LP3 spent mean 3 h of screen time, consumed 1.5 portions of sweet and/or salty snacks and 1 L of soft drinks on a daily basis, were associated with 12% higher risk of HTN. CONCLUSIONS: Focusing on the combination of eating and lifestyle behaviours may more accurately identify, and therefore guide preventive measures tailored to the specific needs of high-risk populations.

Comparative Evaluation of the Diagnostic Value of Procalcitonin and hsCRP for the Presence of Mild-to-Moderate Diabetic Foot Infections.

The aim of this study is to compare the efficacy of procalcitonin (PCT) and high-sensitive C-reactive protein (hsCRP) as diagnostic biomarkers in patients with diabetes and mild-to-moderate diabetic foot infections. A total of 119 patients (102 with type 2 diabetes and 17 with type 1 diabetes), of mean age 60.29 ± 10.05 years, divided into 3 groups-diabetic foot ulcer (DFU) with active infection (IDFU group, n = 41), DFU without clinical signs of infection (non-IDFU group, n = 35), and a control group with diabetes without DFU (n = 43). Infection severity was graded according to the International Working Group on the Diabetic Foot guideline-non-IDFU group as Grade 1, IDFU group as Grade 2 (n = 22), and Grade 3 (n = 19). Serum hsCRP was assessed by the immunoturbidimetric method and PCT by the enzyme chemiluminescence immunoassay (ECLIA) method. Levels of white blood cells (WBC) were assessed using the Medonic hematology analyzer and erythrocyte sedimentation rate (ESR) by the Westergren method. Serum hsCRP, WBC count, and ESR were significantly higher in the IDFU group as compared to non-IDFU and control groups, whereas PCT levels did not differ between the groups. hsCRP presented with higher sensitivity (80%), specificity (79%), area under the curve (AUC) 0.856, in comparison to PCT (sensitivity 63%, specificity 62%, AUC 0.617) for the presence of IDFU, as well as in the Grade 3 subgroup (84% sensitivity and specificity, AUC 0.911). The combined model of both markers did not present with better accuracy than using hsCRP alone. In conclusion, hsCRP appears to be a better diagnostic biomarker than PCT in the diagnosis of moderate foot ulcer infection. Both markers fail to distinguish mild infection.

Association of diet quality with glycemia, insulinemia, and insulin resistance in families at high risk for type 2 diabetes mellitus in Europe: Feel4 Diabetes Study.

OBJECTIVE: The aim of the present study was to investigate the association of diet quality with fasting glycemia, insulinemia, and insulin resistance in a cross-sectional sample of adults from families at high risk for type 2 diabetes mellitus (T2DM) from six European countries, taking into account their socioeconomic status (SES). METHODS: Baseline data from non-diabetic adults from the Feel4 Diabetes study were used and diet was assessed by the Healthy Diet Score (HDS). Insulin resistance (IR) was determined by homeostasis model assessment of IR (HOMA-IR). Sociodemographic and lifestyle characteristics were assessed through standardized questionnaires. Multiple linear regressions were adjusted for many confounders, in the total sample and by SES category. RESULTS: In 1980 adults, the third tertile of diet quality was inversely associated with insulin levels (-1.48; 95% confidence interval [CI], -2.34 to 0.62), and HOMA-IR (-0.33; 95% CI, -0.57 to 0.09), yet with no statistically significant results for glucose levels. In the SES subgroup analysis, in the high SES group, both second and third diet score tertiles were inversely associated with insulin levels (-1.81; 95% CI, -2.66 to 0.95) and HOMA-IR values (-0.45; 95% CI -0.69 to 0.21), independent of age, sex, smoking and body mass index. No such associations were observed for glucose levels in the high SES group and for all indices in the low SES group. CONCLUSION: In adults from families at high risk for T2DM, higher diet quality was negatively associated with fasting insulin levels and IR, only in the high SES group and not in the low SES group. Future larger studies may be able to explore further this association, as well as the potential factors that mitigate its strength in the low SES groups.

Sociodemographic, anthropometric, and lifestyle correlates of prediabetes and type 2 diabetes in europe: The Feel4Diabetes study.

BACKGROUND AND AIMS: The current work aimed to identify the predominant correlates of prediabetes and T2DM among a variety of socio-demographic, anthropometric and lifestyle indices, in a large sample of adults from families at high risk for T2DM. METHODS AND RESULTS: In this cross-sectional study, 2816 adults were recruited from low-socioeconomic areas in high-income countries (HICs) (Belgium-Finland), HICs under austerity measures (Greece-Spain), and low/middle-income countries (LMICs) (Bulgaria-Hungary). A positive association between the male sex (OR, 95% C.I.2.77 (1.69-4.54)) and prediabetes was revealed compared to females, while there was a negative association between younger age (<45 years) (OR, 95% C.I. 0.58 (0.37-0.92)), and low/medium levels of waist circumference (OR, 95% C.I. 0.44 (0.22-0.89)) with prediabetes compared to older age and high levels of waist circumference, respectively. Concerning T2DM, 0-0.5 cups/day of fruits and berries (OR, 95% C.I.2. 13 (1.16-3.91)) and 150-300 g fish/week (OR, 95% C.I. 2.55 (1.01-6.41)) have a positive association compared to higher consumptions, respectively. Conversely, <1 cup/week legumes (OR, 95% C.I. 0.55 (0.31-0.99) as well as 0-0.5 servings (OR, 95% C.I. 0.34 (0.12-0.95) and 0.5-1 servings (OR, 95% C.I. 0.37 (0.19-0.71) of full-fat dairy/day have a negative association compared to higher consumptions, respectively. CONCLUSION: These findings indicate the need for diabetes prevention measures targeting young adults and especially men, above 45 years of age, with central obesity and poor dietary habits and prioritize vulnerable groups and populations living in LMICs. NATIONAL CLINICAL TRIAL NUMBER: NCT02393872.

Management Strategies for Hyperglycemia Associated with the α-Selective PI3K Inhibitor Alpelisib for the Treatment of Breast Cancer.

Alpelisib is an α-selective phosphatidylinositol 3-kinase inhibitor used for treating hormone receptor-positive (HR+), human epidermal growth receptor 2-negative (HER2-), PIK3CA-mutated locally advanced or metastatic breast cancer following disease progression on or after endocrine therapy. Hyperglycemia is an on-target effect of alpelisib affecting approximately 60% of treated patients, and sometimes necessitating dose reductions, treatment interruptions, or discontinuation of alpelisib. Early detection of hyperglycemia and timely intervention have a key role in achieving optimal glycemic control and maintaining alpelisib dose intensity to optimize the benefit of this drug. A glycemic support program implemented by an endocrinology-oncology collaborative team may be very useful in this regard. Lifestyle modifications, mainly comprising a reduced-carbohydrate diet, and a designated stepwise, personalized antihyperglycemic regimen, based on metformin, sodium-glucose co-transporter 2 inhibitors, and pioglitazone, are the main tools required to address the insulin-resistant hyperglycemia induced by alpelisib. In this report, based on the consensus of 14 oncologists and seven endocrinologists, we provide guidance for hyperglycemia management strategies before, during, and after alpelisib therapy for HR+, HER2-, PIK3CA-mutated breast cancer, with a focus on a proactive, multidisciplinary approach.

Efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial.

BACKGROUND: Semaglutide is an effective treatment for type 2 diabetes; however, 20-30% of patients given semaglutide 1·0 mg do not reach glycaemic treatment goals. We aimed to investigate the efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in adults with inadequately controlled type 2 diabetes on a stable dose of metformin with or without a sulfonylurea. METHODS: We did a 40-week, randomised, active-controlled, parallel-group, double-blind, phase 3B trial (SUSTAIN FORTE) at 125 outpatient clinics in ten countries. Participants (≥18 years) with inadequately controlled type 2 diabetes (HbA1c 8·0-10·0%) with metformin and with or without sulfonylurea were randomly assigned (1:1) by an interactive web-response system to 2·0 mg or 1·0 mg once-weekly semaglutide. Participants, site personnel, the clinical study group, and investigators were masked to the randomised treatment. Outcomes included change from baseline at week 40 in HbA1c (primary outcome) and bodyweight (secondary confirmatory outcome), evaluated through trial product estimand (no treatment discontinuation or without rescue medication) and treatment policy estimand (regardless of treatment discontinuation or rescue medication) strategies. This study is registered with ClinicalTrials.gov, NCT03989232; EudraCT, 2018-004529-96; and WHO, U1111-1224-5162. FINDINGS: Between June 19 and Nov 28, 2019, of 1515 adults assessed for eligibility, 961 participants (mean age 58·0 years [SD 10·0]; 398 [41%] women) were included. Participants were randomly assigned to once-weekly semaglutide 2·0 mg (n=480 [50%]) or 1·0 mg (n=481 [50%]); 462 (96%) patients in the semaglutide 2·0 mg group and 471 (98%) in the semaglutide 1·0 mg group completed the trial. Mean baseline HbA1c was 8·9% (SD 0·6; 73·3 mmol/mol [SD 6·9]) and BMI was 34·6 kg/m2 (SD 7·0). Mean change in HbA1c from baseline at week 40 was -2·2 percentage points with semaglutide 2·0 mg and -1·9 percentage points with semaglutide 1·0 mg (estimated treatment difference [ETD] -0·23 percentage points [95% CI -0·36 to -0·11]; p=0·0003; trial product estimand) and -2·1 percentage points with semaglutide 2·0 mg and -1·9 percentage points with semaglutide 1·0 mg (ETD -0·18 percentage points [-0·31 to -0·04]; p=0·0098; treatment policy estimand). Mean change in bodyweight from baseline at week 40 was -6·9 kg with semaglutide 2·0 mg and -6·0 kg with semaglutide 1·0 mg (ETD -0·93 kg [95% CI -1·68 to -0·18]; p=0·015; trial product estimand) and -6·4 kg with semaglutide 2·0 mg and -5·6 kg with semaglutide 1·0 mg (ETD -0·77 kg [-1·55 to 0·01]; p=0·054; treatment policy estimand). Gastrointestinal disorders were the most commonly reported adverse events (163 [34%] in the 2·0 mg group and 148 [31%] in the 1·0 mg group). Serious adverse events were similar between treatment groups, reported for 21 (4%) participants given semaglutide 2·0 mg and 25 (5%) participants given semaglutide 1·0 mg. Three deaths were reported during the trial (one in the semaglutide 1·0 mg group and two in the semaglutide 2·0 mg group). INTERPRETATION: Semaglutide 2·0 mg was superior to 1·0 mg in reducing HbA1c, with additional bodyweight loss and a similar safety profile. This higher dose provides a treatment intensification option for patients with type 2 diabetes treated with semaglutide in need of additional glycaemic control. FUNDING: Novo Nordisk.

European Childhood Obesity Risk Evaluation (CORE) index based on perinatal factors and maternal sociodemographic characteristics: the Feel4Diabetes-study.

The aim of this study was to develop and examine the predictive accuracy of an index that estimates obesity risk in childhood based on perinatal factors and maternal sociodemographic characteristics. Analysis was conducted by using cross-sectional and retrospective data collected from a European cohort of 2775 schoolchildren and their families participating in the Feel4Diabetes-study. The cohort was randomly divided by using two-thirds of the sample for the development of the index and the remaining one third for assessing its predictive accuracy. Logistic regression analyses determined a prediction model for childhood obesity. The area under the receiver operating characteristic curve (AUC-ROC), sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated. Cut-off analysis was applied to identify the optimal value of the index score that predicts obesity with the highest possible sensitivity and specificity. Eight factors were found to be significantly associated with obesity and were included as components in the European "Childhood Obesity Risk Evaluation" (CORE) index: region of residence, maternal education, maternal pre-pregnancy weight status, gestational weight gain, maternal smoking during pregnancy, birth weight for gestational age, infant growth velocity, and exclusive breastfeeding during the first 6 months. Risk score ranged from 0 to 22 corresponding to a risk from 0.9 to 54.6%. The AUC-ROC was 0.725 with optimal cut-off ≥9 (sensitivity = 74.1%, specificity = 61.0%, PPV = 11.3%, NPV = 97.2%).Conclusion: The European CORE index can be used as a screening tool for the identification of infants at high-risk for becoming obese at 6-9 years. This tool could assist healthcare professionals in initiating preventive measures from the early life.Trial registration: The Feel4Diabetes-intervention is registered at https://clinicaltrials.gov/ ; number, CT02393872; date, March 20, 2015. What is Known: • As prevention of obesity should start early in life, there is a compelling rationale for the early identification of high-risk children to facilitate targeted intervention. What is New: • This study developed and assessed the predictive accuracy of an index for the Childhood Obesity Risk Evaluation (CORE), combining certain perinatal factors and maternal sociodemographic characteristics in a large European cohort. • The European CORE index can be used as a screening tool for identifying infants at high-risk for becoming obese at 6-9 years and assist health professionals in initiating early prevention strategies.

Lifestyle Changes Observed among Adults Participating in a Family- and Community-Based Intervention for Diabetes Prevention in Europe: The 1st Year Results of the Feel4Diabetes-Study.

The Feel4Diabetes intervention was a school and community-based intervention aiming to promote healthy lifestyle and tackle obesity and obesity-related metabolic risk factors for the prevention of type 2 diabetes (T2D) among families at risk of developing this disease. The current study aims to present the results on lifestyle behaviors obtained from parents during the first year of the Feel4Diabetes intervention. This multicomponent intervention had a cluster randomized design and was implemented in Belgium, Bulgaria, Finland, Greece, Hungary and Spain over two years (2016-2018). Standardized protocols and procedures were used by the participating centers in all countries to collect data on parents' lifestyle behaviors (diet, physical activity, sedentary behavior). The Feel4Diabetes intervention was registered at clinicaltrials.gov (registration number: NCT02393872). In total, 2110 high-risk parents participated in the baseline and 12-month follow-up examination measurements. Participants allocated to the intervention group reduced their daily consumption of sugary drinks (p = 0.037) and sweets (p = 0.031) and their daily screen time (p = 0.032), compared with the control group. In addition, participants in the intervention group in Greece and Spain increased their consumption of breakfast (p = 0.034) and fruits (p = 0.029), while in Belgium and Finland they increased their water intake (p = 0.024). These findings indicate that the first year of the Feel4Diabetes intervention resulted in the improvement of certain lifestyle behaviors in parents from high-risk families.

Two-stage, school and community-based population screening successfully identifies individuals and families at high-risk for type 2 diabetes: the Feel4Diabetes-study.

BACKGROUND: The implementation of population screening and early prevention strategies targeting individuals at high-risk for type 2 diabetes (T2D) seems to be a public health priority. The current work aimed to describe the screening procedure applied in the Feel4Diabetes-study and examine its effectiveness in identifying individuals and families at high risk, primarily for T2D and secondarily for hypertension, among vulnerable populations in low to middle-income countries (LMICs) and high-income countries (HICs) across Europe. METHODS: A two-stage screening procedure, using primary schools as the entry-point to the community, was applied in low socioeconomic status (SES) regions in LMICs (Bulgaria-Hungary), HICs (Belgium-Finland) and HICs under austerity measures (Greece-Spain). During the first-stage screening via the school-setting, a total of 20,501 parents (mothers and/or fathers) of schoolchildren from 11,396 families completed the Finnish Diabetes Risk Score (FINDRISC) questionnaire, while their children underwent anthropometric measurements in the school setting. Parents from the identified "high-risk families" (n = 4484) were invited to participate in the second-stage screening, including the measurement of fasting plasma glucose (FPG) and blood pressure (BP). In total, 3153 parents participated in the second-stage screening (mean age 41.1 ± 5.6 years, 65.8% females). RESULTS: Among parents who attended the second-stage screening, the prevalence of prediabetes (as defined by impaired fasting glucose; FPG 100-125 mg/dl) and T2D (FPG > 126 mg/dl) was 23.2 and 3.0% respectively, and it was found to be higher in the higher FINDRISC categories. The percentage of undiagnosed T2D among the participants identified with T2D was 53.5%. The prevalence of high normal BP (systolic BP 130-139 mmHg and/ or diastolic BP 85-89 mmHg) and hypertension (systolic BP ≥ 140 mmHg and/ or diastolic BP ≥ 90 mmHg) was 14 and 18.6% respectively, which was also higher in the higher FINDRISC categories. The percentage of cases not receiving antihypertensive treatment among the participants identified with hypertension was 80.3%. CONCLUSION: The findings of the current study indicate that the two-stage school and community-based screening procedure followed, effectively identified high-risk individuals and families in vulnerable populations across Europe. This approach could be potentially scalable and sustainable and support initiatives for the early prevention of T2D and hypertension. TRIAL REGISTRATION: The Feel4Diabetes-intervention is registered at https://clinicaltrials.gov/ (NCT02393872; date of trial registration: March 20, 2015).

The relationship between glucose variability and insulin sensitivity and oxidative stress in subjects with prediabetes.

AIM: The present study assessed the relationship between glucose variability (GV) and insulin levels, insulin resistance and oxidative stress at early stages of glucose intolerance. MATERIAL AND METHODS: A total of 50 subjects - 12 males and 38 females, mean age 55.6 ±â€¯9.7 years, mean BMI 28.4 ±â€¯6.4 kg/m2, divided into 2 groups according to glucose tolerance: 32 with prediabetes and 18 with normal glucose tolerance were included. Glucose tolerance was assessed by OGTT according to WHO 2006 criteria. Plasma glucose and serum insulin were measured at fasting, 120-minute and 180-minute during the test; and oxLDL and 3-Nitrotyrosine - at fasting and 120-minute. HOMA-IR and OGIS indexes were calculated. HbA1c and lipid levels was assessed. Continuous glucose monitoring was performed with a blind sensor (FreeStyle Libre Pro) for a mean period of 13.6 ±â€¯2.3 days. RESULTS: Our results demonstrate significantly increased insulin resistance in subjects with prediabetes, whereas there is no difference in oxidative stress markers between the two groups. OxLDL and 3-NT correlate positively with insulin levels and HOMA-IR and negatively with OGIS in both groups. There is a positive association between oxidative stress markers and 120-minute glucose in the prediabetes group. Insulin levels and HOMA-IR are positively related to plasma glucose and reciprocally to CV and M-Value in prediabetes, since the latter association is with borderline significance after adjustment for hypertension and smoking. CONCLUSIONS: Our results demonstrate a significant correlation between oxidative stress and insulin resistance at early stages of glucose intolerance. Both chronic hyperglycemia and GV seem to be related to insulin levels and insulin resistance, and just postload glycaemia to oxidative stress in prediabetes.

A school- and community-based intervention to promote healthy lifestyle and prevent type 2 diabetes in vulnerable families across Europe: design and implementation of the Feel4Diabetes-study.

OBJECTIVE: To describe the design of the Feel4Diabetes-intervention and the baseline characteristics of the study sample. DESIGN: School- and community-based intervention with cluster-randomized design, aiming to promote healthy lifestyle and tackle obesity and obesity-related metabolic risk factors for the prevention of type 2 diabetes among families from vulnerable population groups. The intervention was implemented in 2016-2018 and included: (i) the 'all-families' component, provided to all children and their families via a school- and community-based intervention; and (ii) an additional component, the 'high-risk families' component, provided to high-risk families for diabetes as identified with a discrete manner by the FINDRISC questionnaire, which comprised seven counselling sessions (2016-2017) and a text-messaging intervention (2017-2018) delivered by trained health professionals in out-of-school settings. Although the intervention was adjusted to local needs and contextual circumstances, standardized protocols and procedures were used across all countries for the process, impact, outcome and cost-effectiveness evaluation of the intervention. SETTING: Primary schools and municipalities in six European countries. SUBJECTS: Families (primary-school children, their parents and grandparents) were recruited from the overall population in low/middle-income countries (Bulgaria, Hungary), from low socio-economic areas in high-income countries (Belgium, Finland) and from countries under austerity measures (Greece, Spain). RESULTS: The Feel4Diabetes-intervention reached 30 309 families from 236 primary schools. In total, 20 442 families were screened and 12 193 'all families' and 2230 'high-risk families' were measured at baseline. CONCLUSIONS: The Feel4Diabetes-intervention is expected to provide evidence-based results and key learnings that could guide the design and scaling-up of affordable and potentially cost-effective population-based interventions for the prevention of type 2 diabetes.

Safety of sitagliptin in patients with type 2 diabetes and chronic kidney disease: outcomes from TECOS.

AIMS: To characterize the incidence of diabetes-associated complications and assess the safety of sitagliptin in participants with chronic kidney disease (CKD) in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). MATERIALS AND METHODS: For participants with baseline eGFR measurements (n = 14 528), baseline characteristics and safety outcomes were compared for the CKD cohort (eGFR < 60 mL/min per 1.73 m2 ) vs those without CKD. Within the CKD cohort, the same analyses were performed, comparing sitagliptin- and placebo-assigned participants. Baseline characteristics were summarized for all participants, and serious adverse events were analysed in those who received at least 1 dose of study medication. Adverse events of interest and diabetes complications were summarized for the intention-to-treat population. RESULTS: CKD was present in 3324 (23%) participants at entry into TECOS. The mean (SD) age for this CKD cohort was 68.8 (7.9) years, mean diabetes duration was 13.7 (9.0) years, and 62% were men. Incidences of serious adverse events, malignancy, bone fracture, severe hypoglycaemia and most categories of diabetes complications were higher in the CKD cohort compared with those without CKD. Over ~2.8 median years of follow-up, CKD participants assigned to sitagliptin had rates of diabetic eye disease, diabetic neuropathy, renal failure, malignancy, bone fracture, pancreatitis and severe hypoglycaemia similar to those of placebo-assigned participants. CONCLUSIONS: Participants in TECOS with CKD had higher incidences of serious adverse events and diabetes complications than those without CKD. Treatment with sitagliptin was generally well tolerated, with no meaningful differences in safety outcomes observed between those with CKD assigned to sitagliptin or placebo.

Pancreatic Safety of Sitagliptin in the TECOS Study.

OBJECTIVE: We evaluated the incidence of acute pancreatitis and pancreatic cancer in patients with type 2 diabetes and cardiovascular disease who were treated with sitagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i). RESEARCH DESIGN AND METHODS: In the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study, a cardiovascular safety study of sitagliptin, all suspected cases of acute pancreatitis and pancreatic cancer were collected prospectively for 14,671 participants during a median follow-up time of 3 years, and were adjudicated blindly. RESULTS: Baseline differences were minimal between participants confirmed to have no pancreatic events, acute pancreatitis, or pancreatic cancer. Among those participants randomized to receive sitagliptin, 23 (0.3%) (vs. 12 randomized to receive placebo [0.2%]) had pancreatitis (hazard ratio 1.93 [95% CI 0.96-3.88], P = 0.065; 0.107 vs. 0.056/100 patient-years), with 25 versus 17 events, respectively. Severe pancreatitis (two fatal) occurred in four individuals allocated to receive sitagliptin. Cases of pancreatic cancer were numerically fewer with sitagliptin (9 [0.1%]) versus placebo (14 [0.2%]) (hazard ratio 0.66 [95% CI 0.28-1.51], P = 0.32; 0.042 vs. 0.066 events/100 patient-years). Meta-analysis with two other DPP-4i cardiovascular outcome studies showed an increased risk for acute pancreatitis (risk ratio 1.78 [95% CI 1.13-2.81], P = 0.01) and no significant effect for pancreatic cancer (risk ratio 0.54 [95% CI 0.28-1.04], P = 0.07). CONCLUSIONS: Pancreatitis and pancreatic cancer were uncommon events with rates that were not statistically significantly different between the sitagliptin and placebo groups, although numerically more sitagliptin participants developed pancreatitis and fewer developed pancreatic cancer. Meta-analysis suggests a small absolute increased risk for pancreatitis with DPP-4i therapy.

Current indications for metformin therapy.

Metformin (dimethyl-biguanide) is an oral antidiabetic drug, which decreases hepatic glucose production (gluconeogenesis) and increases peripheral glucose uptake by muscles. Metformin is a first-line drug in the treatment of overweight and obese type 2 diabetic patients, offering a selective pathophysiological approach by its effect on insulin resistance. It has been shown in a number of studies to improve clinical outcomes in type 2 diabetic patients. It has been demonstrated in a number of studies that metformin has multiple biological effects - it has been shown to have platelet antiaggregating effects, to reduce the rate of formation of advanced glycation end products (AGEs) and to decrease the cellular oxidative reactions, thus demonstrating the antioxidant effects of the drug, which may largely explain its vascular protective effect. A number of studies have established the favorable effect of metformin on body weight, insulin resistance, hyperinsulinaemia, lipid parameters (total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides), arterial hypertension, fibrinolysis, endothelial dysfunction. Thus metformin appears to have a broad set of pharmacological properties, making the drug potentially applicable even in nondiabetic situations such as obesity, extreme insulin resistance with acanthosis nigricans, polycystic ovary syndrome, etc. Metformin has been demonstrated in the Diabetes Prevention Program to be a drug with great potential in preventing the conversion of IGT to type 2 diabetes. Thus, metformin appears to be a drug with multiple therapeutic effects far beyond its effect on lowering blood glucose in diabetes mellitus.