Ioannis Ioannidis

Epidemiological Survey for the Prevalence of Overweight and Abdominal Obesity in Greek Adolescents

This study was designed to provide estimates of overweight (OW), obesity (OB), and abdominal OB (AO) in a representative sample of adolescents throughout the whole of Greece. A total of 14,456 adolescents aged 13–19 years (6,677 boys and 7,779 girls) had direct measurements (height, weight, waist circumference (WC)) taken at school during 2003. The overall prevalence of OW including OB in the population studied was 29.4% in boys and 16.7% in girls. OB prevalence was also higher in boys than in girls (6.1% vs. 2.7%), whereas prevalence of AO was higher in girls than in boys (21.7% vs. 13.5%). Rates of OW, OB, and AO were significantly more prevalent in the Greek than in the foreign male population (immigrants). OW% in adolescent girls was independently associated with smoking and alcohol consumption. The prevalence of OW and OB in Greek adolescents is high, particularly in boys, comparable with that reported for most Mediterranean European countries. AO, mainly in adolescent girls, also appears high. Preventive and treatment strategies are urgently needed to combat this OB epidemic in Greece.

The J‐shape effect of alcohol intake on the risk of developing acute coronary syndromes in diabetic subjects: the CARDIO2000 II Study

Aims  To identify the threshold of alcohol consumption above which the balance of risk and benefit becomes adverse in diabetic subjects.

Expert consensus on the rational clinical use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors

Two proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab and alirocumab, have recently been approved by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of hypercholesterolemia. These fully human monoclonal antibodies selectively block PCSK9, thus permitting the low-density lipoprotein (LDL) receptor to effectively recycle to the surface of liver cells. The administration of these antibodies leads to robust LDL cholesterol (LDL-C) lowering by 50-60% on top of maximum hypolipidemic treatment. At least 4 randomized, placebo-controlled studies are under way and will address the question of whether the administration of these PCSK9 inhibitors is associated with a significant reduction of cardiovascular events. Because of the high cost associated with the use of these medications it is very important to consider which patients may gain the most benefit, at least until the results of outcome studies are available. In this Consensus paper, 34 clinicians/scientists define 3 groups of patients that should be currently considered as candidates for the use of these novel drugs. These include: 1a. Adults with established cardiovascular disease and LDL-C≥100 mg/dL while on lifestyle modifications and maximally tolerated hypolipidemic treatment, i.e. high-intensity statin + ezetimibe, 1b. Adults with diabetes and established cardiovascular disease or chronic kidney disease or target organ damage and LDL-C ≥100 mg/dL while on lifestyle modifications and maximally tolerated hypolipidemic treatment, i.e. high-intensity statin + ezetimibe, 2. Adults with familial hypercholesterolemia (FH) without established cardiovascular disease and LDL-C ≥130 mg/dL while on lifestyle modifications and maximally tolerated hypolipidemic treatment, i.e. high-intensity statin + ezetimibe (evolocumab is also indicated in children above 12 years with homozygous FH), and 3. Adults at high or very high cardiovascular risk who are statin intolerant and have an LDL-C ≥100 and ≥130 mg/dL, respectively, while on any tolerated hypolipidemic treatment.

Correlation between mesenteric fat thickness and serum apolipoproteins in patients with peripheral arterial occlusive disease

BackgroundVisceral fat possesses the most detrimental potential for cardiovascular morbidity through the release of adipokines, as well as metabolic and proinflammatory mediators, which adversely affect metabolic and vascular homeostasis. Among the different types of visceral adipose tissue, mesenteric fat is considered particularly detrimental, due to its close proximity to the portal circulation, affecting directly the liver, which is the main regulator of body metabolic homeostasis. Mesenteric fat can be reliably estimated using abdominal ultrasonography, the only available imaging method able to depict individual mesenteric leaves. Aim of the present study was to investigate the correlation of mesenteric fat thickness (MFT) with serum apolipoprotein levels in patients undergoing digital subtraction angiography in a single center.Methods35 male patients with peripheral arterial disease were examined. After careful examination of the periumbilical area, the mesenteric leaves were identified. The maximal distance between each pair of sequential leaves was measured, and the mean value of the three thickest leaves was determined as the mesenteric fat thickness. Six apolipoprotein fasting serum concentrations were measured using a Luminex proteomics platform (xMAP Multiplex immunoassay): apolipoprotein A-I (apoAI), apolipoprotein A-II (apoAII), apolipoprotein B (apoB), apolipoprotein C-II (apoCII), apolipoprotein C-III (apoCIII) and apolipoprotein E (apoE).ResultsMFT correlated with apoAII and apoB serum concentrations. The correlations with apoAII and apoB remained significant following correction for BMI. No correlations were noted between MFT and serum apoAI, apoCII, apoCIII or apoE levels before or after adjustment for BMI.ConclusionsOur study indicates that MFT is significantly correlated with the concentration of atherogenic low density lipoproteins particles, as well as with apoAII, a determinant of free fatty acids levels. No correlation was observed between mesenteric fat thickness and very low density lipoprotein or chylomicron particles concentration.

The association between physical activity and the development of acute coronary syndromes in diabetic subjects (the CARDIO2000 II study).

Background The prevalence of type-2 diabetes is increasing dramatically, primarily being driven by environmental factors, like dietary and exercise habits. In this study we investigated the association of physical activity and acute coronary events in diabetic patients, an issue that has not been adequately studied so far. Design Cross-sectional, case-control study. Methods We studied demographic, lifestyle, dietary and clinical information in 216 hospitalized diabetic patients (171 men, 45 women) with a first event of an acute coronary syndrome and 196 frequency matched (by age and sex) diabetic controls (154 men, 42 women) without any evidence of coronary heart disease. Physical activity was evaluated according to the kcal/min expended and the weekly frequency of exercise. Physically active were considered those who reported nonoccupational physical activity > once/week (at least 30min/time). Results Seventy-eight (36%) of 216 patients and 110 (56%) of 196 controls were classified as physically active (P< 0.001). Multivariate conditional logistic regression analysis revealed that the odds ratio for developing an acute coronary event in diabetic subjects who reported moderate levels of physical activity was 0.22 [95% confidence interval (CI): 0.12–0.47], while in those who reported vigorous physical activity it was 0.33 (95% CI: 0.21–0.59), after adjusting for age, sex, and the conventional cardiovascular risk factors. Conclusions Physical activity (moderate and vigorous) seems to be associated with a lower prevalence of acute coronary events in the investigated group of diabetic subjects. Light physical activity does not seem to have any significant association with the development of acute coronary events.

Possible mechanisms of direct cardiovascular impact of GLP-1 agonists and DPP4 inhibitors

Diabetes mellitus is a leading cause of cardiovascular morbidity and mortality worldwide. Traditional antidiabetic therapies targeting hyperglycemia reduce diabetic microvascular complications but have minor effects on macrovascular complications, including cardiovascular disease. Instead, cardiovascular complications are improved by antidiabetic medications (metformin) and other therapies (statins, antihypertensive medications) ameliorating insulin resistance and other associated metabolic abnormalities. Novel classes of antidiabetic drugs have proven efficacious in improving glycemia, while at the same time exert beneficial effects on pathophysiologic mechanisms of diabetes-related cardiovascular disease. In the present review, we will present current evidence of the cardiovascular effects of two new classes of antidiabetic medications, glucagon-like peptide 1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP4) inhibitors, focusing from mechanistic preclinical and clinical investigation to late-phase clinical testing.

Cost-Effectiveness of Empagliflozin for the Treatment of Patients with Type 2 Diabetes Mellitus at Increased Cardiovascular Risk in Greece

Background and objectiveType 2 diabetes mellitus (T2DM) is frequently associated with co-morbidities that exacerbate cardiovascular (CV) risk. CV disease is the leading cause of death in people with diabetes across the world and accounts for approximately half the deaths in the T2DM population. Hence, the objective of present study was to evaluate the cost-effectiveness of empagliflozin, in addition to standard of care (SoC), for the treatment of adult patients with T2DM and high CV risk in Greece.MethodsA health economic model was used to project clinical and economic outcomes of patients receiving empagliflozin plus SoC compared with those receiving SoC alone over a lifetime horizon. CV and renal event rates were derived from patient level data from the EMPA-REG-OUTCOME® trial by fitting time-dependent parametric survival functions. 5000 individual patient profiles randomly sampled from the trial were simulated using a time-to-event approach. Model extrapolated outcomes included life years (LYs), quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratio (ICER). Following a Greek third-party payer perspective, only direct medical costs related to drug acquisition as well as fatal and non-fatal diabetes-related complications were considered (€2016). Cost units and utility data were extracted from the literature and publicly available official sources. Sensitivity analyses explored the impact of changes in input data.ResultsOver a patient’s lifetime, empagliflozin was predicted to result in longer mean survival (14.01 LY vs. 11.87 LY with SoC) and reduced rate of clinical events accumulating 7.75 QALYs versus 6.83 QALYs on SoC alone at additional costs of €4235. The generated ICER of empagliflozin was €4633 per QALY gained. One-way sensitivity analysis confirmed empagliflozin’s cost-effective profile. At the defined willingness-to-pay threshold of €34,000 per QALY gained, probabilistic sensitivity analysis showed that empagliflozin was estimated to have a 100% probability of being cost-effective relative to SoC.ConclusionsEmpagliflozin added to SoC was estimated to be a highly cost-effective treatment option for the treatment of T2DM in adults with increased CV disease risk in Greece.

Screening for diabetes in obese women: comparison between the New American Diabetes Association and WHO criteria.

Sirs: Protease inhibitors (PI) are currently used to treat HIV infection. They inhibit HIV protease which is necessary for the processing of viral proteins in the last stage of the viral cycle, and can achieve an undetectable viral load when used in combination with nucleoside analogues in triple therapy. However, PI are not free of adverse effects (Flexner, 1998). Hyperlipidaemia and abnormal fat distribution were soon related to the use of these drugs (Massip et al., 1997). The latter occurred between two and 12 months after beginning treatment and was not preceded by weight loss (Viraben & Aquilina, 1998). The lipoatrophy was noted mainly in the legs, arms and face, sparing the central portion of the body (Carr et al., 1998a). Hyperglycaemia was also noted with the use of PI (FDA, 1997) and new onset diabetes mellitus, easily controlled with the use of hypoglycaemic agents or insulin (Eastone & Decker, 1997), or even severe diabetes (Visnegarwala et al., 1997) have been reported. However, treatment with PI could not to be discontinued in the majority of patients (Ault, 1997). In 1998, an association between the syndrome of lipodystrophy, hyperlipidaemia and insulin resistance, with the appearance of overt diabetes mellitus in less than 2% of the cases was demonstrated (Carret al., 1998a). A recent publication indicated a prevalence of 83% for lipodystrophy which can be severe in 11% of cases, and abnormalities in glucose homeostasis in 23% of patients, with less than 1% of cases with diabetes mellitus and less than 3% with glucose intolerance, after 21 months of treatment with PI (Carret al., 1999). There is no information on the long-term natural history or complications of the diabetes associated to the use of PI nor about its reversibility after cessation of therapy. We report a patient with complete resolution of PI induced diabetes mellitus. In all of these communications, nothing was said about the natural history of the diabetes associated to the use of protease inhibitors. Nevertheless, it was proposed that cessation of therapy might be considered for patients with difficult control of severe diabetes mellitus. A 47-year-old man presented with polyuria, polydipsia, polyphagia, blurred vision and weight loss of four kilograms for one month. He had HIV infection in A2 stage and had received treatment with indinavir and two nucleoside analogues (stavudine and lamivudine) for 10 months. He had no personal nor familial history of diabetes mellitus or hyperglycaemia. He had not suffered acute nor chronic pancreatitis and never received treatment with anabolic steroids, pentamidine or other hyperglycaemia associated drugs apart from protease inhibitors. Physical examination revealed fat wasting of face, legs and arms, sparing the abdomen and central part of the body. Height was 1·79 m, weight 79 kg and BMI 24·6. No acanthosis nigricans was noted. He had a CD4 level of 515 per mm and a viral load of less than 1·7 logs (less than 50 virions per mm), showing a good response to treatment. He presented with a fasting glucose level of 43·6 mmol/l, venous pH 7·37, ketonuria almost undetectable, triglycerides 6·54 mmol/l, cholesterol 7·68 mmol/l, HDL 0·80 mmol/l, LDL 5·22 mmol/l, HbA1c 12·9%. Levels of CH-50 and C3 were 0·89 mmol/l and 1·19 mmol/l, respectively. Islet cell autoantibody were absent. Treatment with the PI was stopped and insulin was started (Fig. 1). C-peptide rose after injection of glucagon was from 0·72 nmol/l (0) to 1·39 nmol/l (6) with glucose levels of 8·27 mmol/l and 9·27 mmol/l, respectively. Basal insulin was 153 pmol/l for a fasting glucose level of 8·27 mmol/l. Insulin resistance calculated by HOMA was 7·86. The patient was discharged with insulin therapy, lipid lowering treatment with atorvastatin and treatment for HIV infection with nevirapine (a non-nucleoside antiretroviral), lamivudine and stavudine (both nucleoside analogues). One month later, insulin was withdrawn, and basal and postprandial glucose levels were normal (Fig. 1). The patient was admitted into our Metabolic Unit in order to perform a glucagon test and basal measurements of insulin. C-peptide levels were of 1·25 nmol/l (0 ) to 2·44 nmol/l (6), and glucose levels of 4·7 mmol/l and 5·38 mmol/l, respectively. Basal insulin determination was of 406 pmol/l for a glucose level of 4·7 mmol/l. Insulin resistance was 11·83 determined by HOMA model. Triglycerides were 2·23 mmol/l and cholesterol 6·1 mmol/l on atorvastatin treatment, and lipodystrophy was still clinically evident. The present case shows that PI induced diabetes mellitus can be a rapidly reversible phenomenon after cessation of the drug. The inhibition of proteins involved in regulation of blood lipid levels and in adipocyte proliferation, has been proposed as a cause of lipodystrophy and insulin resistance (Carr et al., 1998b). However, decreased insulin secretion may also play a role in the pathogenesis of associated diabetes mellitus (Visnegarwala et al., 1997). In our patient, both insulin resistance and defective insulin secretion were shown. HOMA model is accurate for the estimation of the degree of insulin resistance (Matthews et al., 1985) and the response of C-peptide to glucagon was used as an estimation of b-cell function. Since insulin resistance was present even after the complete resolution of clinical and biochemical diabetes mellitus in our patient, and the response of C-peptide to a glucagon stimulus improved after resolution