Clinical impact of high platelet reactivity in patients with atrial fibrillation and concomitant percutaneous coronary intervention on dual or triple antithrombotic therapy.

High platelet reactivity (HPR) on clopidogrel is an established thrombotic risk factor after percutaneous coronary intervention (PCI). The introduction of more potent antiplatelet drugs has partially surpassed this issue. However, in the setting of concomitant atrial fibrillation (AF) and PCI clopidogrel is still the most adopted P2Y12 inhibitor. In the present study all consecutive patients with history of AF discharged from our cardiology ward with dual (DAT) or triple (TAT) antithrombotic therapy after a PCI from April 2018 to March 2021 were enrolled in an observational registry. For all subjects, blood serum samples were collected and tested for platelet reactivity by arachidonic acid and ADP (VerifyNow system) and genotyping of the CYP2C19*2 loss-of-function polymorphism. We recorded at 3 and 12-months follow-up: (1) major adverse cardiac and cerebrovascular events (MACCE), (2) major hemorrhagic or clinically relevant non-major bleeding and (3) all-cause mortality. A total of 147 patients were included (91, 62% on TAT). In 93.4% of patients, clopidogrel was chosen as P2Y12 inhibitor. P2Y12 dependent HPR resulted an independent predictor of MACCE both at 3 and 12 months (HR 2.93, 95% C.I. 1.03 to 7.56, p = 0.027 and HR 1.67, 95% C.I. 1.20 to 2.34, p = 0.003, respectively). At 3-months follow-up the presence of CYP2C19*2 polymorphism was independently associated with MACCE (HR 5.21, 95% C.I. 1.03 to 26.28, p = 0.045). In conclusion, in a real-world unselected population on TAT or DAT, the entity of platelet inhibition on P2Y12 inhibitor is a potent predictor of thrombotic risk, suggesting the clinical utility of this laboratory evaluation for a tailored antithrombotic therapy in this high-risk clinical scenario. The present analysis was performed in patients with AF undergoing PCI on dual or triple antithrombotic therapy. At 1 year follow-up MACCE incidence was consistent, and it was not different in different antithrombotic pattern groups. P2Y12 dependent HPR was a potent independent predictor of MACCE both at 3- and 12-months follow-up. In the first 3 months after stenting the carriage of CYP2C19*2 allele was similarly associated with MACCE. Abbreviation: DAT, dual antithrombotic therapy; HPR, high platelet reactivity; MACCE, major adverse cardiac and cerebrovascular events; PRU, P2Y12 reactive unit; TAT, triple antithrombotic therapy. Created with BioRender.com.

Relationship between hyponatremia at hospital admission and cardiopulmonary profile at follow-up in patients with SARS-CoV-2 (COVID-19) infection.

PURPOSE: Hyponatremia occurs in about 30% of patients with pneumonia, including those with SARS-CoV-2 (COVID-19) infection. Hyponatremia predicts a worse outcome in several pathologic conditions and in COVID-19 has been associated with a higher risk of non-invasive ventilation, ICU transfer and death. The main objective of this study was to determine whether early hyponatremia is also a predictor of long-term sequelae at follow-up. METHODS: In this observational study, we collected 6-month follow-up data from 189 laboratory-confirmed COVID-19 patients previously admitted to a University Hospital. About 25% of the patients (n = 47) had hyponatremia at the time of hospital admission. RESULTS: Serum [Na+] was significantly increased in the whole group of 189 patients at 6 months, compared to the value at hospital admission (141.4 ± 2.2 vs 137 ± 3.5 mEq/L, p < 0.001). In addition, IL-6 levels decreased and the PaO2/FiO2 increased. Accordingly, pulmonary involvement, evaluated at the chest X-ray by the RALE score, decreased. However, in patients with hyponatremia at hospital admission, higher levels of LDH, fibrinogen, troponin T and NT-ProBNP were detected at follow-up, compared to patients with normonatremia at admission. In addition, hyponatremia at admission was associated with worse echocardiography parameters related to right ventricular function, together with a higher RALE score. CONCLUSION: These results suggest that early hyponatremia in COVID-19 patients is associated with the presence of laboratory and imaging parameters indicating a greater pulmonary and right-sided heart involvement at follow-up.

Tenosynovial complications identify TTR cardiac amyloidosis among patients with hypertrophic cardiomyopathy phenotype.

Recent evidence suggests that carpal tunnel syndrome (CTS) and brachial biceps tendon rupture (BBTR) represent red flags for ATTR cardiac amyloidosis (ATTR-CA). The prevalence of upper limb tenosynovial complications in conditions entering differential diagnosis with CA, such as HCM or Anderson-Fabry disease (AFD), and hence their predictive accuracy in this setting, still remains unresolved. OBJECTIVE: To investigate the prevalence of CTS and BBTR in a consecutive cohort of ATTR-CA patients, compared with patients with HCM or AFD and with individuals without cardiac disease history. PARTICIPANTS: Consecutive patients with a diagnosis of ATTR-CA, HCM and AFD were evaluated. A control group of consecutive patients was recruited among subjects hospitalized for noncardiac reasons and no cardiac disease history. The presence of BBTR, CTS or prior surgery related to these conditions was ascertained. RESULTS: 342 patients were prospectively enrolled, including 168 ATTR-CA (141 ATTRwt, 27 ATTRm), 81 with HCM/AFD (N = 72 and 9, respectively) and 93 controls. CTS was present in 75% ATTR-CA patients, compared with 13% and 10% of HCM/AFD and controls (P = 0.0001 for both comparisons). Bilateral CTS was present in 60% of ATTR-CA patients, while it was rare (2%) in the other groups. BBTR was present in 44% of ATTR-CA patients, 8% of controls and 1% in HCM/AFD. CONCLUSIONS: CTS and BBTR are fivefold more prevalent in ATTR-CA patients compared with cardiac patients with other hypertrophic phenotypes. Positive predictive accuracy for ATTR-CA is highest when involvement is bilateral. Upper limb assessment of patients with HCM phenotypes is a simple and effective way to raise suspicion of ATTR-CA.

Clinical aspects and diagnostic relevance of neuroautonomic evaluation in patients with unexplained falls.

OBJECTIVE: To evaluate the diagnostic relevance of neuroautonomic evaluation in patients with unexplained falls compared to those with a syncope etiologically unexplained after initial evaluation. METHODS: It is an observational study, comparing 298 patients with unexplained fall with 989 patients with unexplained syncope. Each patient underwent supine and upright blood pressure measurement, tilt testing (TT) and carotid sinus massage (CSM). RESULTS: Patients with unexplained falls were older (75.3 ± 11.1 vs. 63.2 ± 19.2 years, p < 0.001), were more frequently hypertensive (66.1 vs. 47.2 %, p < 0.001) and more frequently prescribed antihypertensive drugs (62.4 vs. 48.7 %, p < 0.001) or benzodiazepines (15.7 vs. 10.6 %, p = 0.01), and in a greater proportion they experienced major traumatic injuries (77.5 vs. 29.6 %, p < 0.001) as a consequence of falls. The TT was less frequently positive in patients with unexplained falls (36 vs. 51.3 %, p < 0.001), whereas a Carotid Sinus Syndrome as suggested by CSM had a similar prevalence in the two groups (14.3 vs. 10.5 %, p = 0.074). Overall, either TT or CSM were positive in 61 % of patients with unexplained falls, and in 64 % of those with syncope (p = 0.346). After matching by age 298 patients with falls (75.3 ± 11.1 years) and 298 patients with unexplained syncope (75.4 ± 11.1 years), we found that the positivity prevalence of TT and CSM were similar in the two groups. CONCLUSIONS: The positivity prevalence of TT and CSM in patients with unexplained falls compared to patients with unexplained syncope is similar. Given its high diagnostic relevance, the neuroautonomic evaluation should be routinely performed in older patients with unexplained falls.

Poor diagnostic performance of tilt testing in hypertensive patients with unexplained syncope.

Syncope is a common condition. Tilt testing with sublingual nitroglycerin (TT-TNT) provides a test with good specificity and positivity rate in young and old patients. Its use in hypertensive patients with unexplained syncope has not been validated. The aims of this study were to evaluate the positivity rate, specificity and tolerability of TT-TNT in hypertensive patients with unexplained syncope. Five hundred and ten subjects (mean age 55 years) were enrolled, 388 patients with unexplained syncope (73 hypertensive and 315 normotensive) and 122 controls (59 hypertensive and 63 normotensive). All subjects underwent TT-TNT. The responses were classified as positive, negative or exaggerated (aspecific). In hypertensive patients, the usual hypotensive therapy was taken on the day of the test. In hypertensive controls, the positive responses were higher than in normotensives (19% vs 6%, P<0.001). The overall specificity was 81% in hypertensives and 94% in normotensives. The positivity rate was significantly lower in hypertensives (55% vs 72%, P<0.03). There was no significant difference between young patients and patients >65 years. TT was well tolerated, and no serious side effects occurred. TT potentiated with TNT has a lower positivity rate and specificity in hypertensive than in normotensive patients with syncope.

HbA1c levels and all-cause mortality in type 2 diabetic patients: epidemiological evidence of the need for personalised therapeutic targets.

BACKGROUND AND AIM: The aim of the present case-control study is to explore the effect of case mix on the relationship between glycated haemoglobin (HbA1c) and mortality in type 2 diabetic patients. METHODS AND RESULTS: A nested case-control study data set was generated from the cohort-study data set (n = 4140 type 2 diabetic outpatients) by sampling controls from the risk sets. Cases (n = 427) were compared with an equal number of controls chosen from those members of the cohort who were at risk for the same follow-up time of the case, matched for age (±3 years), sex, body mass index (BMI) (±2 kg m(-2)), duration of diabetes (±5 years), and Charlson's Comorbidity Score (CCS) (±1). The main predefined analysis was the comparison of cases and controls for proportion of patients with each HbA1c class (<6.5%, 6.5-7.4%, 7.5-8.4% and ≥8.5%). During a mean follow-up of 5.7 ± 3.5 years, 427 deaths were recorded. The lowest risk of death was observed in the HbA1c 6.5-7.4% category; a lower HbA1c was associated with a non-significant trend towards a higher risk. The risk associated with a low (<6.5%) HbA1c was significantly greater in patients who were insulin-treated than in the rest of the sample. CONCLUSIONS: The present study suggests that glycaemic targets should be individualised on the basis of the characteristics of each patient, considering age, co-morbidity and duration of diabetes. Caution should be used in prescribing insulin to reach near-normoglycaemia, particularly in older, frail patients.

Subthreshold depression in older subjects: an unmet therapeutic need.

Major depression, defined according to DSM IV TR criteria, is less common in older subjects, while other types of depression are two to three times more prevalent. This heterogeneous group of disturbances has received different names: depression not otherwise specified, minor depression, subthreshold or subsyndromal depression. Moreover, each condition has been defined using heterogeneous criteria by different authors. The term of subthreshold depression will be adopted in this position statement. Subthreshold depression has been associated with the same negative consequences of major depression, including reduced well being and quality of life, worsening health status, greater disability, increased morbidity and mortality. Nevertheless, there is a dearth of clinical trials in this area, and therefore older patients with subthreshold depression are either not treated or they are treated with the same non pharmacological and pharmacological therapies used for major depression, despite the lack of supporting scientific evidence. There is an urgent need to reach a consensus concerning the diagnostic criteria for subthreshold depression as well as to perform clinical trials to identify effective and safe therapies in this too long neglected patient group.

Effects of antihypertensive treatments on incidence of diabetes: a case-control study.

AIMS: Aim of this case-control study is the assessment of the relationship between antihypertensive treatment and incidence of diabetes in an unselected cohort of subjects participating in a screening program for diabetes. METHODS: A case-control study nested within a cohort of nondiabetic subjects with a mean follow-up of 27.7 ± 11.3 months was performed, comparing 40 cases of incident diabetes and 160 controls matched for age, sex, body mass index, fasting plasma glucose, 2-h post-load glycemia, smoking and alcohol abuse. RESULTS: When considering antihypertensive treatment at enrolment, a lower proportion of cases was exposed to ACE-inhibitors/angiotensin receptor blockers (ACE-i/ARB) in comparison with controls. A non-significant trend toward a higher exposure to diuretics, which were mainly represented by thiazide diuretics, was observed in cases. In a multivariate analysis, including both ACE-i/ARB and diuretics, a protective effect of ACEi/ARB, and an increased risk with diuretics were observed. Similar results were obtained in alternative models, after adjusting for systolic and diastolic blood pressure at enrolment, diagnosis of hypertension, concurrent treatment with ß-blockers or calcium-channel blockers, and number of antihypertensive medications. CONCLUSIONS: Diuretics seem to be associated with a higher incidence of diabetes, whereas treatment with ACEi/ARB could have a protective effect.

Prognostic significance of serum uric acid in outpatients with chronic heart failure is complex and related to body mass index: data from the IN-CHF Registry.

BACKGROUND AND AIMS: In the field of cardiovascular diseases, elevated levels of serum uric acid (UA) reflect a marked activation of the xanthine oxidase pathway with increase in free radicals production; it is often associated with an inflammatory state, oxygen consumption and endothelial dysfunction. All these associations have been also confirmed in heart failure (HF) but the pathophysiological role of UA in this setting is not well understood. The aim of this study was to evaluate the prognostic role of UA in outpatients enrolled in the Italian Registry of Congestive Heart Failure (IN-CHF). METHODS AND RESULTS: All patients met the European Society of Cardiology (ESC) criteria for diagnosis of HF. We considered patients with complete clinical data and UA level available at the baseline and at 1-year follow-up. The study population was composed of 877 patients aged 63 ± 12 years. One-year mortality was 10.8% and dead patients had a higher level of UA than survivors (7.1 mg dl⁻¹ vs 6.6 mg dl⁻¹, p < 0.0207). In multivariable full model of analysis, UA did not result in an independent predictor of death in overall population, but only in patients with low body mass index (BMI) (≤22 kg m⁻²) (hazard ratio (HR): 2.38, 95% confidence interval (CI) 1.36-4.18). In this subgroup, a statistically significant gradual relationship between UA and survival was detected starting from values higher than 8 mg dl⁻¹. CONCLUSION: Elevated level of UA is not an independent predictor of mortality in chronic HF, but it markedly worsens outcome if associated with low level of BMI. This association is likely an indicator of chronic inflammatory and catabolic state.

Adiponectin in outpatients with coronary artery disease: independent predictors and relationship with heart failure.

BACKGROUND AND AIMS: Chronic heart failure (HF) is characterised by a neurohormonal dysfunction associated with chronic inflammation. A role of metabolic derangement in the pathophysiology of HF has been recently reported. Adiponectin, an adipose-tissue-derived cytokine, seems to play an important role in cardiac dysfunction. We investigated the variation of circulating adiponectin in patients with coronary artery disease (CAD), with or without HF, in order to identify its independent predictors. METHODS AND RESULTS: A total of 107 outpatients with CAD were enrolled in the study and divided into three groups: CAD without left ventricular systolic dysfunction (group 1); CAD with left ventricular dysfunction without HF symptoms (group 2) and CAD with overt HF (group 3). Plasma adiponectin was determined by enzyme-linked immunosorbent assay. Adiponectin concentrations increased progressively from group 1 (7.6 ± 3.6 ng ml⁻¹) to group 2 (9.1 ± 6.7 ng ml⁻¹) and group 3 (13.7 ± 7.6 ng ml⁻¹), with the difference reaching statistical significance in group 3 versus 1 and 2 (p < 0.001). A multivariable model of analysis demonstrated that the best predictors of plasma adiponectin were body mass index, N-terminal pro-brain natriuretic peptide and high-density lipoprotein cholesterol. However, even after adjusting for all three independent predictors, the increase of adiponectin in group 3 still remained statistically significant (p = 0.015). CONCLUSION: Our data confirm the rise of adiponectin in overt HF. The levels of circulating adipokine seem to be mainly predicted by the metabolic profile of patients and by biohumoral indicators, rather than by clinical and echocardiographic indexes of HF severity.

Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials.

AIM: Some studies suggested that metformin could reduce cardiovascular risk to a greater extent than that determined by glucose reduction. Aim of the present meta-analysis is to assess the effects of metformin on the incidence of cardiovascular events and mortality. METHODS: An extensive search of Medline, EMBASE and the Cochrane Library (any date up to 31 October 2009) was performed for all trials containing the word 'metformin'. Randomized trials with a duration ≥52 weeks were included. A meta-regression analysis was also performed to identify factors associated with cardiovascular morbidity and mortality in metformin-treated patients. RESULTS: A total of 35 clinical trials were selected including 7171 and 11 301 participants treated with metformin and comparator, respectively, who had 451 and 775 cardiovascular (CV) events, respectively. Overall, metformin was not associated with significant harm or benefit on cardiovascular events (MH-OR 0.94[0.82-1.07], p = 0.34). A significant benefit was observed in trials versus placebo/no therapy (MH-OR 0.79[0.64-0.98], p = 0.031), but not in active-comparator trials (MH-OR 1.03[0.72-1.77], p = 0.89). Meta-regression showed a significant correlation of the effect of metformin on cardiovascular events with trial duration and with minimum and maximum age for inclusion, meaning that the drug appeared to be more beneficial in longer trials enrolling younger patients. It is likely that metformin monotherapy is associated with improved survival (MH-OR: 0.801[0.625-1.024], p = 0.076). However, concomitant use with sulphonylureas was associated with reduced survival (MH-OR: 1.432[1.068-1.918], p = 0.016). CONCLUSION: Available evidence seems to exclude any overall harmful effect of metformin on cardiovascular risk, suggesting a possible benefit versus placebo/no treatment. The observed detrimental effect of the combination with sulphonylureas deserves further investigation.

Is suboptimal prescribing a risk factor for poor health outcomes in community-dwelling elders? The ICARe Dicomano study.

PURPOSE: Mostly because of comorbidity and drugs consumption, older persons are often exposed to an increased risk of sub-optimal prescribing (SP). At present, few studies investigated the association between SP and long-term health outcomes. We examined the relation between SP and the risk of mortality and hospitalization in Italian older community-dwellers. METHODS: Older (65+ years) community-dwelling residents of a small town in Tuscany were enrolled in a longitudinal study. SP was defined as polypharmacy (use of 5+ drugs), prescription of inappropriate drugs (ID) according to Beers' criteria, and of potentially interacting drugs (PID), evaluated in 1995 and 1999. These three forms of SP were entered as time-dependent exposures into multivariable Cox regression analysis models, whose outcomes were mortality and hospitalizations through 2003. RESULTS: Of 1022 participants (mean age 73.0 +/- 6.8, 57% women), 220 were evaluated in 1995, 234 in 1999 and 568 in both waves. In univariate analysis, mortality was two-fold higher in participants with polypharmacy (73.4/1000 person/years, 95% CI 58.2-92.4 vs. 34.1, 95% CI 29.7-39.2; p < 0.001) or PID (72.7/1000 person/years, 95% CI 46.3-113.9 vs. 38.0, 95% CI 33.5-43.1; p < 0.001), whereas it was unrelated to the presence of ID. Hospitalization rates were independent of any form of SP. In multivariable models, polypharmacy, ID, and PID were no longer associated with an increased risk of death, and ID predicted a slightly increased risk of hospitalizations (HR 1.03, 95% CI 1.0-1.06, p = 0.048). CONCLUSIONS: In this cohort, SP was not associated with an excess risk of poor health outcomes.

Red or white wine assumption and serum antioxidant capacity.

The biochemistry of reactive oxygen species is an important field with wide implications. Both preventive and chain breaking antioxidants have a role in the limitation of oxidative stress that accompanies aging and diseases. The potent antioxidant activity of phenolic substances of red wine, in particular, have been proposed as an explanation for the "French Paradox" (the apparent incompatibility of a high fat diet with a low incidence of coronary heart diseases). A lot of researchers emphasize beneficial effects of red wine and insist on lower or no antioxidant effect of white wine. We have been studying the effect of both white and red wine on blood antioxidant capacity in humans. The white wine we have been testing was produced by an ancient Tuscany procedure (the same used for red winemaking) which includes fermentation with grapes juice together with peelings and seeds. A statistically significant increase in total antioxidant capacity (TAC) levels was observed after 2h from red or white wine ingestion. White wine effect appears to be faster than that of the red one, since a significant difference can also be reported after 1h. We can conclude that the big difference in the results of serum TAC due to white wine reported by us, in comparison to those reported by others relatively to white wine produced using the French method, can be explained by the difference in the winemaking procedure we adopted.

Glucagon-like peptide-1 response to meals and post-prandial hyperglycemia in Type 2 diabetic patients.

BACKGROUND: The impaired response of glucagonlike peptide-1 (GLP-1) to meals in diabetic patients can contribute to the pathogenesis of impaired insulin secretion and post-prandial hyperglycemia. This study is aimed at the assessment of the relationship between meal-induced GLP-1 and post-prandial hyperglycemia in Type 2 diabetic patients. METHODS: Twenty-one drug-naïve Type 2 diabetic patients were studied. Blood glucose and active GLP-1 levels were measured 0, 30, 60, 90, and 120 min after a standard test meal. A continuous glucose monitoring (CGM) system was applied for the following 3 days. Nutrient intake at each meal was calculated on the basis of patients' food records. For each patient, post-prandial 120-min glucose incremental area under the curve (iAUC) was included in linear regression model exploring its relationship with total energy and carbohydrate intake, and the angular coefficient for total energy (EAC) and carbohydrate (CAC) was calculated. RESULTS: GLP-1 levels peaked 30 min after the test meal. Logarithmically transformed 60-min GLP-1 iAUC showed a significant inverse correlation with glycated hemoglobin (HbA1c) (p<0.01). A significant inverse correlation of 60-min GLP-1 iAUC was also observed with EAC and CAC (both p<0.01), meaning that patients with a lower GLP-1 response to the test meal had a higher increment of post-prandial glucose for each additional unit of total energy or carbohydrate intake. CONCLUSIONS: In Type 2 diabetic patients, a lower GLP-1 response to meals is associated with a higher HbA1c, and with a greater degree of meal-induced hyperglycemia, both in a meal test and during CGM in "real-life" conditions.

Dipeptydil peptidase-4 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials.

BACKGROUND AND AIM: The role of Dipeptidyl Peptidase-4 (DPP-4) inhibitors in the treatment of type 2 diabetes is debated; many recent trials, which were not included in previous meta-analyses, could add relevant information. METHODS AND RESULTS: All available randomized controlled trials (RCTs), either published or unpublished, performed in type 2 diabetic patients with DPP-4 inhibitors, with a duration >12 weeks were meta-analyzed for HbA1c, BMI, hypoglycemia, and other adverse events. A total of 41 RCTs (9 of which are unpublished) was retrieved and included in the analysis. Gliptins determine a significant improvement of HbA1c in comparison with a placebo (-0.7 [-0.8:-0.6]), with a low risk of hypoglycemia. DPP-4 inhibitors show a similar efficacy in monotherapy and in combination with other agents. The risk of cardiovascular events and all-cause death with DPP-4 inhibitors is 0.76 [0.46-1.28] and 0.78 [0.40-1.51], respectively. CONCLUSIONS: DPP-4 inhibitors reduce HbA1c, although to a lesser extent than sulphonylureas, with no weight gain and no hypoglycemic risk; further data are needed to assess their long-term safety.

The management of syncope in older adults.

Syncope is a frequent symptom in older patients. The diagnostic and therapeutic management may be complex, particularly in older adults with syncope and comorbidities or cognitive impairment. Morbidity related to syncope is more common in older persons and ranges from loss of confidence, depressive illness and fear of falling, to fractures and consequent institutionalization. Moreover, advan-ced age is associated with short and long-term morbidity and mortality after syncope. A standardized approach may obtain a definite diagnosis in more than 90% of the older patients with syncope and may reduce diagnostic tools and hospitalizations. The initial evaluation, including anamnesis, medical examination, orthostatic hypotension test and electrocardiogram (ECG), may be more difficult in the elderly, specially for the limited value of medical history, particularly for the certain diagnosis of neuro-mediated syncope. For this reason neuroautonomic assessment is an essential step to confirm a suspect of neuromediated syncope. Orthostatic blood pressure measurement, head up tilt test, carotid sinus massage and insertable cardiac monitor are safe and useful investigations, particularly in older patients. The most common causes of syncope in the older adults are orthostatic hypotension, carotid sinus hypersensitivity, neuromediated syncope and cardiac arrhythmias. The diagnostic evaluation and the treatment of cardiac syncope are similar in older and young patients and for this reason will not be discussed. In older patients unexplained falls could be related to syncope, particularly in patients with retrograde amnesia. There are no consistent differences in the treatment of syncope between older and younger population, but a specific approach is necessary for orthostatic hypotension, drug therapy and pacemaker implantation.

Prevention of cardiovascular disease through glycemic control in type 2 diabetes: a meta-analysis of randomized clinical trials.

BACKGROUND AND AIMS: Randomized clinical trials (RCTs) aimed at the assessment of the efficacy of lowering blood glucose in the prevention of diabetic complications have always failed to detect a significant effect on cardiovascular events. Aim of this meta-analysis is the assessment of the effects of improvement of glycemic control on the incidence of cardiovascular diseases in patients with type 2 diabetes. METHODS: The RCTs were included in this meta-analysis if: a) the between-group difference in mean HbA1c during the trial was at least 0.5%, b) they had a planned duration of treatment of at least 3 years, c) if they had a cardiovascular endpoint. Data for analysis were extracted independently by two observers and potential contrasts were resolved by a senior investigator. RESULTS: Five studies (17,267 and 15,362 patients in the intensive and conventional therapy groups, respectively) were included. Intensive treatment, which reduced mean HbA1c by 0.9% on average, was associated with a significant reduction of incident cardiovascular events and myocardial infarction (OR 0.89 [0.83-0.95] and 0.86 [0.78-0.93], respectively), but not of stroke or cardiovascular mortality (OR 0.93 [0.81-1.07] and 0.98 [0.77-1.23], respectively). In meta-regression analysis, a higher BMI duration of diabetes, and incidence of severe hypoglycaemia were associated with greater risk for cardiovascular death in intensive treatment groups. CONCLUSION: Intensified hypoglycaemic treatment in type 2 diabetic patients leads to a significant reduction of the incidence of myocardial infarction, while it does not affect the incidence of stroke and cardiovascular mortality. Hypoglycemia induced by intensified treatment could be associated with increased cardiovascular mortality.