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Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study

Gian Gastone Neri Serneri, Sergio Coccheri, Ettore Marubini, Francesco Violi
DOI: http://dx.doi.org/10.1016/j.ehj.2004.07.013 1845-1852 First published online: 2 October 2004

Abstract

Aims Patients with diabetes are at excessive risk of mortality and cardiovascular morbidity. Previous studies suggest that aspirin may be less effective in diabetic patients. In this multi-centre, randomized, double blind trial picotamide, a dual inhibitor of thromboxane A2 synthase and receptor, was compared with aspirin for the prevention of mortality and major cardiovascular events in diabetics with peripheral arterial disease (PAD).

Methods and results A total of 1209 adults aged 40–75 years with type 2 diabetes and PAD were randomized to receive picotamide (600 mg bid) or aspirin (320 mg od) for 24 months. The cumulative incidence of the 2 years overall mortality was significantly lower amongst patients who received picotamide (3.0%) than in those who received aspirin (5.5%) with a relative risk ratio for picotamide versus aspirin of 0.55 (95% CI: 0.31–0.98%). Events were reported in 43 patients (7.1%) on picotamide and 53 (8.7%) on aspirin. The combined endpoint of mortality and morbidity had a slightly lower incidence in the picotamide group but this difference did not reach statistical significance.

Conclusion Picotamide is significantly more effective than aspirin in reducing overall mortality in type 2 diabetic patients with associated PAD.

See page 1769 for the editorial comment on this article (doi:10.1016/j.ehj.2004.08.008)

Keywords Diabetes; Peripheral arterial disease; Thromboxane synthase inhibitors; Aspirin; Picotamide; Antiplatelet therapy

Introduction

An excessive mortality and morbidity rate, particularly as a result of cardiovascular complications, has been reported in patients with both types of diabetes mellitus. This was originally shown in prospective studies conducted in the 1970s and 1980s,1,2 and has been confirmed more recently.3,4 Numerous studies and two large meta-analyses of randomized trials have shown that aspirin is effective in preventing vascular events, including non-fatal myocardial infarction, non-fatal stroke, and death from vascular causes in patients with a variety of vascular conditions.5,6 However, the efficacy of aspirin and other antiplatelet agents is suggested to be low in diabetic patients. In a recent meta-analysis,6 the odds reduction of major vascular events with antiplatelet drugs in the diabetic subgroups with or without previous vascular events was only 7%, and did not achieve statistical significance. Regarding peripheral arterial disease (PAD), the use of aspirin is recommended by the American College of Chest Physicians;7 however, a Food and Drug Administration expert panel found insufficient evidence to approve labelling of aspirin as indicated for patients with PAD.8 It is clear therefore, that new drugs may be needed for better protection from death and morbidity in diabetic patients, and particularly in those with PAD.

Picotamide, a derivative of methoxy-isophtalic acid, is an antagonist of thromboxane A2/prostaglandin endoperoxide H2 (TXA2/PGH2) receptors, and also inhibits thromboxane A2 (TXA2) synthase at equivalent concentrations.9–12 This results in effective inhibition of TXA2-mediated events. This dual action may have potentially enhanced therapeutic efficacy in the prevention of thrombosis, including inhibition of platelet aggregation and accumulation of antiaggregatory prostaglandins (PGI2 and PGD2).13 Hence, picotamide may be useful in diabetic patients, who have increased platelet activation and TXA2 synthesis.14 In a double blind, placebo-controlled study15 in 2313 patients with PAD, picotamide significantly reduced the relative risk of combined major and minor cardiovascular events by 23% compared to placebo. A post hoc subgroup analysis of 438 PAD patients with diabetes suggested a reduction of 45.2% of the risk of combined major and minor events in those treated with picotamide.16 The encouraging results in this subgroup prompted us to investigate the efficacy of picotamide versus aspirin in a specifically designed, double blind, randomized study in diabetics with PAD.

Methods

Study design and organization

The drug evaluation in atherosclerotic vascular disease in diabetics (DAVID) study was a multi-centre, randomized, double blind, parallel group trial. Prior to participation in the study, all patients provided written informed consent. The study was performed in accordance with the Declaration of Helsinki and its Amendments, and the protocol was approved by the Institutional Review Board (IRB) at each centre before initiation. The study involved 86 clinical centres from various regions of Italy and followed US Investigational New Drug regulation and European Good Clinical Practice Guidelines as well as local requirements. The Steering Committee formed by five University-based scientists, had overall responsibility for the design, execution and reporting of the study. An independent external Safety and endpoint Validation Committee was responsible for validation of all clinical events occurring during enrolment and follow-up. At the end of the trial and before the statistical analysis, all the clinical events were reviewed and validated by the Steering and Safety Committees in joint meetings. The statistical analysis was performed by an independent statistical University centre in Milan. The study protocol was designed by the Steering Committee, which also surveyed all phases of the trial. Site monitoring and data collection were performed by a designated contract research organization.

Patients eligibility

Patients of both sexes, between 40 and 75 years of age and with a history of type 2 diabetes for 5 years or more and PAD were eligible for inclusion in the study. PAD was defined as the presence of two or more of the following: (1) history of intermittent claudication lasting more than 2 months (WHO, leg pain on walking, disappearing in less than 10 min on standing); (2) loss of posterior tibial pulse in the foot; (3) ankle/arm pressure ratio <0.90 or >1.30 in the posterior or anterior tibial artery of the foot (measured by Doppler probe); (4) amputation or reconstructive surgery in patients with previous history of intermittent claudication; (5) angioplasty with no persisting complication from intervention.

The exclusion criteria were: (1) myocardial infarction, stroke or unstangina in the 6 months prior to enrolment; (2) severe neurological or mental deficits likely to make the patient non-compliant; (3) severe co-morbidity likely to limit patient's life expectancy to less than 2 years; (4) serum creatinine >2.0 mg/dl; (5) high risk of endo-ocular bleeding; (6) alanine aminotransferase (ALT) or aspartate aminotransferase (AST) over three times the upper limit of normal (ULN); (7) platelets <100,000 per mm3; (8) active peptic ulcer or gastro-enteric bleeding in the 6 months prior to enrolment; (9) pregnancy; (10) severe, uncontrolled hypertension; (11) total cholesterol level ⩾300 mg/dl; (12) picotamide or aspirin sensitivity. Patients scheduled for major surgery or requiring long-term anticoagulant treatment were also excluded.

Endpoints and definitions

The study was designed with two endpoints. The primary endpoint was the overall mortality and the secondary one was the combined incidence of death and non-fatal vascular events including myocardial infarction, ischaemic stroke and major amputation.

Myocardial infarction was defined as the presence of at least two of the following conditions: history of prolonged (>20 min) chest pain; elevation of CK, CK-MB, LDH or AST to 2× upper limit of laboratory normal; typical ECG changes (development of new >40 ms Q waves in at least two adjacent leads or new dominant R wave in V1 or evolutionary ST-T changes). Ischaemic stroke was taken to be an acute neurological vascular event with focal signs for ⩾24 h and a CT scan recognition of a proper ischaemic lesion, without evidence of intracranial haemorrhage. Amputation was defined as major if performed above the ankle and not because of trauma or cancer.

Procedures

After the screening phase, eligible patients were randomly allocated to one of two treatment groups to receive either one picotamide 600 mg tablet twice daily or one aspirin 320 mg tablet once daily in the morning plus one placebo tablet once daily in the evening and followed for 24 months. Blinding was maintained by the use of indistinguishable active drugs and placebo tablets in separate bottles labelled for morning and evening intake. The randomization list was performed stratified by centre with treatment in balanced blocks of four patients within each centre; a 1:1 treatment allocation was used. Study visits were scheduled at 4 month intervals (baseline, 4, 8, 12, 16, 20 and 24 months) after enrolment. Routine clinical and safety check-ups were performed at each visit and blood samples for haematological and biochemical assessments were taken for analysis at baseline and 12 and 24 months thereafter. Electrocardiograms (ECG) were performed according to normal practice at each centre. At each study visit, compliance was assessed by counting the tablets returned by the patient. Concomitant medications were monitored by questioning patients at each visit. No concomitant medications that affected platelet function or blood coagulation were permitted during the 24 month study period. Adverse events were monitored throughout the trial.

Statistical analysis

The sample size of the trial was calculated to show a difference between treatments in 2 year overall mortality based on published mortality and risk reduction data. It has been reported that 2-year mortality in patients with type 2 diabetes mellitus is 8.4%.17 Considering a 23–25% risk reduction due to treatment with aspirin, as reported by the Antiplatelet Trialist's (APT) Collaboration5 and more recently by the Antithrombotic Trialist's (ATT) Collaboration,6 a 2-year overall mortality rate of 6.3–6.5% could be predicted for the aspirin group. Assuming a 2-year mortality rate of 6.5% in the aspirin group of our study, we surmised that an absolute reduction of mortality under picotamide of 3.5% in 2 years, equivalent to little more than 1.5% per year, could offer acceptable clinical relevance and allow for a reasonable number of the study population. In fact, we calculated that 584 patients per group were required to detect this difference, with a power of 80% and a significance level set at 0.05 (two-sided). We therefore aimed at recruiting a target sample size of 1200 patients (600 patients per group).

As regards overall 2-year mortality, time from randomization to the date of death for any cause was considered the response; for survivors the length of observation was censored at the date of the last follow-up visit.

Comparison of mortality between the two arms was carried out by the log-rank test. The Kaplan–Meier method was used to estimate survival probabilities; their complement to one is the cumulative incidence of mortality and was used to draw the pertinent curves of mortality for the length of time to death.

As regards the combined endpoint, time from randomization to the date of the first event, regardless of its nature, was considered the response; for patients withdrawn alive without events, time of observation was censored at the date of the last follow-up visit (after some 24 months). As the censoring of patients lost to follow-up could be informative, loss to follow-up was considered to be a competing risk cause for the combined endpoint. Therefore the comparison between treatment groups was accomplished using Gray's test;18 coherently the crude cumulative incidence19 curves were drawn to depict the pattern for the length of time to first event, whichever its nature, in the combined endpoint.

To describe the occurrence of each event, the cumulative incidence was computed.

The comparison of frequency of gastrointestinal discomfort between treatments was analysed with the χ2 test.

The statistical analyses were performed on all randomized patients following the intention-to-treat approach and all the tests were two-sided.

Results

Study population

A total of 1209 patients at 86 centres were enrolled in the study between February 1996 and October 1998. Of these, 603 patients were randomly allocated to receive picotamide and 606 to receive aspirin (Fig. 1). The median duration of the follow-up was 2 years (interquartile range 1.9–2.1). During the study, 32 patients (5.3%) in the picotamide group and 26 (4.3%) in the aspirin group were lost to follow-up and therefore had no endpoint data.

In total, 319 patients (26.4%) prematurely discontinued study drugs. Of these, 159 (26.4%) patients were in the picotamide group and 160 (26.4%) in the aspirin group. The reasons for premature withdrawal from the study were similar in the two groups. Adverse events were the most common reason for discontinuation (11.9% and 14.4% in the picotamide and aspirin groups, respectively) followed by withdrawal of consent (10.1% and 8.6%), taking contraindicated medications (1.5% and 1.3%), non-compliance (1.2% and 0.8%) and other reasons (1.7% and 1.3%).

Demographics and baseline characteristics

The treatment groups were well-matched with respect to sex, age, BMI, mean values of blood pressure (systolic and diastolic), heart rate, cardiovascular risk factors (smoking, hypertension, hyperlipidaemia) and previous stroke or coronary heart disease. Diabetes treatment and other cardiovascular therapies were also distributed similarly between the two groups (Table 1).

View this table:

Table 1. Baseline characteristics

CharacteristicPicotamide (n=603)Aspirin (n=606)
Males (n, %)443 (73.5)435 (71.8)
Females (n, %)160 (26.5)171 (28.2)


Age (years; m±SD)63.8±7.264.6±7.3
BMI (m±SD)28.4 5.428.4±5.5


BP (mmHg; m±SD)
Systolic146.1±16.3147.3±15.7
Diastolic82.8 8.283.2±8.1


HR (beat/min; m±SD)75.4±9.075.5±9.4


Smoking (n, %)
Smokers184 (30.5)172 (28.4)
Ex-smokers95 (15.8)89 (14.7)
Non-smokers324 (53.7)345 (56.9)


Hypertension (n, %)351 (58.2)337 (55.6)
Hyperlipidaemia (n, %)229 (38.0)233 (38.4)
Previous stroke (n, %)63 (10.4)62 (10.2)
Coronary artery disease (n, %)117 (19.4)115 (19.0)
Diet (n, %)531 (88.0)548 (90.4)
Previous antiplatelets (n, %)185 (30.7)210 (34.7)


Concomitant therapies (n, %)
Oral antidiabetics421 (69.8)433 (71.5)
Insulin198 (32.8)182 (30.0)
Peripheral vasodilators129 (21.4)123 (20.3)
Nitrates87 (14.4)79 (13.0)
Digoxin44 (7.3)57 (9.4)
Diuretics60 (10.0)91 (15.0)
ACE-inhibitors192 (31.8)194 (32.0)
Antihypertensives301 (49.9)289 (47.7)
Antiarrhythmics16 (2.7)16 (2.6)
Antidislipidaemics89 (14.8)87 (14.4)

Endpoints and related observations

Overall mortality

Mortality data were available for 571 (94.7%) and 580 (95.7%) patients in the picotamide and aspirin group, respectively.

Causes of death according to treatment group are given in Table 2. The cumulative incidence of the two years overall mortality in the two groups is given in Fig. 2 and the results of the pertinent log-rank test is χ2=3.9299 (p=0.0474).

Fig. 2

Kaplan–Meier analysis of the time-to-death according to treatment assignment.

View this table:

Table 2. Mortality according to treatment groups

Picotamide (n=603)Aspirin (n=606)
nCumulative incidence (%)nCumulative incidence (%)
Deaths (all causes)173.0315.5


Vascular deaths122.1224.1
Ischaemic stroke04
Myocardial infarction57
Haemorrhagic stroke01
Other vascular deaths710


Non-vascular deaths50.991.4
Cancer47
Other12

Overall mortality, the predefined primary endpoint, was significantly lower amongst patients who received picotamide (3.0%) than in those who received aspirin (5.5%). The relative risk of death in the picotamide group compared to the aspirin group was 0.55 (95% CI: 0.31–0.98%).

Mortality and morbidity

Morbidity data were available for 491 (80.4%) and 504 (83.2%) patients in the picotamide and aspirin group, respectively. Events were reported in 43 patients (7.1%) receiving picotamide and in 53 (8.7%) receiving aspirin (Table 3). Analysis of the predefined secondary endpoint of combined mortality and morbidity showed a slightly lower incidence in the picotamide group over the course of the study (Fig. 3). However, this difference did not reach statistical significance (Gray's test z=1.072, p=0.300).

Fig. 3

Crude cumulative incidence curves of first event for combined endpoint, considering lost to follow-up a competing risk.

View this table:

Table 3. Mortality and morbidity events by treatment groups

Type of eventPicotamide (n=603)Aspirin (n=606)
nCumulative incidence (%)nCumulative incidence (%)
Myocardial infarction (fatal and non-fatal)152.9193.6
Stroke (fatal and non-fatal)142.7122.2
Amputation40.840.8
Other deaths122.2193.8


At least one event4353

Vascular and non-vascular mortality

Vascular mortality alone was not a predefined endpoint, and involved a considerably lesser number of events than overall mortality (34 vascular out of 48 deaths) (Table 2). A reduction in vascular mortality consistent with that of total mortality was seen in the picotamide group, although it did not reach statistical significance (data not reported). The proportion of non-vascular over total deaths was similar in the two groups.

Safety

Analysis of adverse events revealed no unusual findings in either treatment group. Bleeding events were reported in eight patients (1.3%) in the picotamide group and in 12 patients (2.0%) in the aspirin group. The frequency of bleeding events leading to hospitalisation was 0.2% in the picotamide group (one hospitalisation) and 1.2% in the aspirin group (seven hospitalisations). One patient in the aspirin group died due to a haemorrhagic event, namely a cerebral haemorrhage. The frequency of gastrointestinal discomfort was significantly lower in the picotamide than in the aspirin group (10.9% versus 18.3%, respectively; p<0.0001) (Table 4). The proportion of patients prematurely discontinuing study drug due to adverse events was comparable in both treatment groups [11.9% (72 patients) in the picotamide group versus 14.4% (87 patients) in the aspirin group].

View this table:

Table 4. Adverse events

Picotamide (n=603)Aspirin (n=606)
n%n%
Gastrointestinal6610.911118.3
Genitourinary162.7233.8
Respiratory172.8203.3
Nervous193.2193.1
Ocular162.7152.5
Skin142.3162.6
Locomotor122.081.3

Discussion

In this double blind study picotamide, an inhibitor of thromboxane synthase and of platelet thromboxane and endoperoxide receptors, was compared with aspirin in patients with type 2 diabetes mellitus and PAD. The predefined primary endpoint of the study was overall mortality. Treatment with picotamide was associated with an almost halved 2-year mortality rate, with a relative risk of 0.55 versus aspirin, and was statistically significant.

The secondary study endpoint, mortality plus non-fatal vascular events, was only slightly reduced under picotamide. The evaluation of this combined endpoint may have been partially flawed by the proportion of patients (around 20% in each group) lost to follow-up for non-fatal events. Being "lost to follow-up" was considered as a competing risk and the calculations were performed only on the "intention to treat" population. Thus, the number of non-fatal events recorded is likely to be underestimated, possibly affecting the outcome of this endpoint.

The efficacy of antiplatelet drugs (in particular, aspirin) in patients with type 2 diabetes, who are at high risk of vascular mortality and morbidity, is still a matter of debate.20 Although aspirin is generally considered effective in diabetic subjects, many of the results on which this belief is based originate from subgroup data of trials or meta-analyses including both diabetic and (mainly) non-diabetic patients, rather than from trials carried out in diabetics alone.

More recently, in an analysis of the diabetic subgroup of a large study of primary prevention of cardiovascular events, aspirin was found non-effective on the composite endpoints of cardiovascular death, stroke and myocardial infarction.21 Although results from subgroup analyses should be considered with reservations, similar data had also been obtained in a large specific trial of patients with diabetes, the Early Treatment of Diabetic Retinopathy (ETDR) study, in which aspirin did not reduce the incidence of major cardiovascular events.22

While only few of the diabetic patients enrolled in the EDTR study had previously suffered major vascular events, those included in the present trial had type 2 diabetes plus associated PAD. In this regard it should be recalled that PAD, also independently of associated diabetes, carries an increased risk of major vascular events.23 In fact, in patients with PAD there is clear evidence of a systemic atherothrombotic state24 and the burden of cardiovascular risk is greatly increased.25 Patients with both PAD and diabetes appear to be even at a higher risk, regarding both limb deterioration and vascular morbidity and mortality.26

With regard to antiplatelet prophylaxis in overall PAD patients, in the 1994 APT meta-analysis5 the observed relative risk reduction (17.8%) was not statistically significant. If the results are recalculated by including only the trials using aspirin,21 the resulting relative risk reduction amounts to only 6.7%. It is true that in the more recent ATT meta-analysis,6 the specific subgroup with intermittent claudication showed a risk reduction of 19%, reaching statistical significance; however much of the additional evidence in respect to the previous meta-analysis came from the ADEP trial15 in which the study drug was precisely picotamide.

On the other hand specific studies of antithrombotic prophylaxis in patients with both diabetes and PAD are scanty. The only prospective study to our knowledge27 investigated the efficacy of aspirin and dipyridamole in preventing disease progression and major vascular events in diabetic patients with critical limb ischaemia or recent amputation. Antiplatelet treatment had no effect on vascular death and subsequent amputation, and a slight, non-significant effect on the combined endpoint of stroke and TIA.

The present trial was aimed at the evaluation of an antiplatelet drug, picotamide, which has a mechanism of action potentially advantageous versus that of aspirin, particularly in diabetic patients. A major feature of our study was to have chosen overall mortality as the primary endpoint. This was certainly a difficult challenge for the study drug, but ultimately proved rewarding, as it yielded unequivocal evidence of efficacy in favour of picotamide. It can be added that, considering the size of the benefit (13–15 %) of antiplatelet drugs on total mortality shown in the APT meta-analyses, and in the light of the recent debate on the efficacy of aspirin in preventing fatal events,28 it seems especially relevant that picotamide almost halved all-cause mortality in PAD patients with type 2 diabetes in comparison with aspirin. Moreover this result was achieved with a tolerability profile somewhat advantageous over that of aspirin, especially because of fewer bleeding events requiring hospitalisation and fewer cases of gastric discomfort.

This study was clearly not designed to investigate the mechanisms by which picotamide is especially effective in preventing fatal events in diabetic patients with PAD. According to some studies,29,30 particularly high amounts of thromboxane and endoperoxides are produced in diabetics through the increased platelet turnover mechanisms alternative to the cyclo-oxygenase pathway,31,32 and an exceedingly high thromboxane production could be relevant in the pathogenesis of the more severe, and hence the fatal complications of diabetes. During the time elapsed from submission of this paper, it has been reported that platelets from type 2 diabetic patients frequently show reduced ex vivo response to aspirin33 and the clinical relevance of this finding has been commented upon in an editorial by one of us.34

The combined properties of picotamide to antagonize TxA2 receptors and inhibit TxA2 synthase9,11 may result in a more effective inhibition of TxA2-mediated effects. Moreover, picotamide is provided with other properties, which appear to confer additional advantages over aspirin. Aspirin remains in plasma in its active, acetylated form for only a few minutes and is unable to reach the extravascular spaces.35 Conversely, picotamide remains active in plasma for 8–10 h36 and easily diffuses from the plasma to the arterial wall.37 At this location, it binds to TXA2/PGH2 receptors on smooth muscle cells and may inhibit TXA2 locally formed by TXA2 synthase.38

In conclusion, the main message of this study is that picotamide, a dual inhibitor of thromboxane A2 synthase and thromboxane-endoperoxide receptor, is significantly more effective than aspirin in reducing overall mortality in type 2 diabetic patients with associated peripheral arterial disease. However, this was a survival study and a possible advantage of picotamide versus aspirin on vascular events could not be firmly established. Thus, further confirmatory studies with this agent seem worthwhile in the future.

Committees and investigators

Steering Committee: G G Neri Serneri, S Coccheri, G Agrifoglio, P Rizzon, B Trimarco

Safety and Validation Committee: M Cortellaro, F Violi, E Marubini (statistician)

Writing Committee: G G Neri Serneri, S Coccheri, E Marubini, F Violi

Investigators: A Pezzarossa, A Guberti (Cattedra di Endocrinologia, Dipartimento di Medicina Interna e Scienze Metaboliche, Università di Parma), M Messina, S Gamba (U O A Endocrinologia-Diabetologia, Ospedale Maria Vittoria, Torino), G Allochis, C Cusaro (U O A Malattie Metaboliche e Diabetologia, Ospedale Maggiore della Carità, Novara), E Ansaldi, M Battezzati (U O A Malattie Metaboliche e Diabetologia, Ospedale SS Antonio e Biagio e C Arrigo, Alessandria), G Bargero, G Ghezzo (U O A Diabetologia, Ospedale Santo Spirito, Casale Monferrato), S Fontana, L Dimitri (U O Medicina B, Ospedale di Biella), L Cataldi, C Bordone (Servizio di Diabetologia, A O San Martino, Genova), D Bessarione, G Grillo (U O Medicina Interna Generale, A O S Martino, Genova), M Domanin, A Gotti (Istituto di Chirurgia Vascolare e Angiologia, Università di Milano), G Pizzi, O Disoteo (Centro di Diabetologia e Malattie Metaboliche, Ospedale Niguarda Cà Granda, Milano), G Testori (U O Diabetologia, A O Fatebenefratelli, Milano), M Puttini, P R Barbano (S C Chirurgia Vascolare, Ospedale Niguarda Cà Granda, Milano), G Emanuelli, P Viganò (Modulo di Chirurgia Vascolare, A O San Gerardo, Monza), C Mazzi, G Morandi (Divisione di Endocrinologia e Medicina Costituzionale, Ospedale S Antonio Abate, Gallarate), U G Cereda, V Vinci (U O Medicina 2, Ospedale di Saronno), E Costantini Brancadoro, A M Socrate (Chirurgia Vascolare, Ospedale di Busto Arsizio), P Bossolo, A Vailati (Medicina Interna e Oncologia Medica, Policlinico San Matteo, Pavia), A Giustina, A Burattin (Sezione di Endocrinologia, Dipartimento di Scienze Mediche e Chirurgiche, Università di Brescia), W Colosio (Divisione Medicina, A O Mellino Mellini, Chiari), G Pascal, F Saggiani (Struttura Complessa di Medicina Generale, Ospedale Carlo Poma, Mantova), E Bobbio Pallavicini, C Cazzalini (Divisione di Medicina, Ospedale Maggiore, Crema), A Ballini, G Maccagni (Divisione di Medicina Interna 2, Ospedali Riuniti, Treviglio), M Marchesi, C Tomasi (Divisione di Medicina Interna 1, Ospedale di Bolzano), R Mingardi, G Erle (U O Malattie Metaboliche, Ospedale di Vicenza), A Tiengo, S Vigili de Kreutzenberg (Cattedra Malattie del Metabolismo, Università di Padova), D Fedele, G Bax (Servizio di Diabetologia, Dietetica e Nutrizione Clinica, Università di Padova), N Simioni, S Donazzan (Servizio di Diabetologia, Presidio Ospedaliero di Cittadella), E Arosio, S De Marchi (Divisione di Riabilitazione Cardiovascolare, Università di Verona), G Monesi, F Mollo (U O Malattie Metaboliche e Diabetologia, Ospedale di Rovigo), A Ceriello, A Russo (Cattedra di Medicina Interna, Università di Udine), M Moretti (Centro Antidiabetico, Presidio Ospedaliero di Portogruaro), A M Cernigoi (Servizio di Diabetologia, Presidio Ospedaliero di Monfalcone), S Bottazzo, P Zanchi (Centro Prevenzione Aterosclerosi, Ospedale Umberto I, Mestre), A Bonanome, A Pagnan (Cattedra di Medicina Interna, Università di Padova, sede di Castelfranco Veneto), A Megha (Day-Hospital Medico-Chirurgico, Colorno), D G Pierfranceschi (U O Diabetologia, Presidio Ospedaliero di Piacenza), T Curti, A Tedesco (Cattedra di Chirurgia Vascolare, Università di Bologna), A De Fabritiis, L Martini (Cattedra e Divisione di Angiologia, Policlinico S Orsola-Malpighi, Bologna), G Scondotto (U O C Angiologia, Azienda USL Città di Bologna, Bologna), G Coppi, R Marra (U O Chirurgia Vascolare, Modena), I Portioli, E Manicardi (Centro Diabete e Malattie Metaboliche, Medicina 2, A O Santa Maria Nuova, Reggio Emilia), L Poggesi, P A Modesti (Istituto di Clinica Medica e Cardiologia, Università di Firenze), A Lagi, G Bandinelli (U O Medicina Interna, P O Santa Maria Nuova, Firenze), C Pratesi, R Pulli (Cattedra e Scuola di Specializzazione di Chirurgia Vascolare, Università di Firenze), G Sabbatini (Sezione di Diabetologia e Malattie Metaboliche, Azienda USL 9, Grosseto), F Galeone, A V Magiar (Servizio Autonomo di Diabetologia e Malattie Metaboliche, Azienda USL 3, Pescia), D Vanni, L Ricci (U O Medicina Interna I, Ospedale S Donato, Arezzo), F Santeusanio, S Bistoni (Dipartimento di Medicina Interna e Scienze Endocrine e Metaboliche, Università di Perugia), U Senin, G Aisa (Sezione di Gerontologia e Geriatria, Dipartimento di Medicina Clinica e Sperimentale, Università di Perugia), M Massi Benedetti, M Orsini Federici (Dipartimento di Medicina Interna, Scienze Endocrine e Metaboliche, Università di Perugia), M Lunetta, A Chiavetta (Servizio di Diabetologia, A O Cannizzaro, Catania), M Belvedere, V Scafidi (Dipartimento di Medicina Clinica e delle Patologie Emergenti, Università di Palermo), G Testa, A Mancini (Servizio di Diabetologia e Malattie Metaboliche, Ospedale S Camillo, Roma), G Pollari, V Tonelli (U O C Angiologia, Ospedale Sandro Pertini, Roma), V Coto, U Oliviero (III Divisione di Medicina Interna, Dipartimento di Medicina Clinica e Scienze Cardiovascolari, Università Federico II, Napoli), R Izzo, L Guerrera (Centro per la Diagnosi e la Cura dell'Ipertensione Arteriosa, Università Federico II, Napoli), G Bracale, M Porcellini (Cattedra di Chirurgia Vascolare, Università Federico II, Napoli), R Carleo, A Gatti (U O C Malattie Metaboliche, Presidio Ospedaliero San Gennaro, Napoli), A Salucci, U Amelia (Servizio di Diabetologia ed Endocrinologia, Ospedale di Nocera Inferiore), V Prisco, R Greco (Centro di Angiologia Medica, Presidio Ospedaliero di Mercato San Severino), A M Terracciano, F Carlino, Centro Antidiabetico A I D, Caserta, N Alberti, A Longo (U O Chirurgia Vascolare, A O Bianchi-Melacrino-Morelli, Reggio Calabria), A Venezia, R Morea (U O Diabetologia e Malattie Metaboliche, Ospedale Madonna delle Grazie, Matera), B Cretella, L Senatore (Servizio Diabetologia e Malattie Metaboliche, Crotone); M Ciccone, P Caputo (Istituto di Malattie dell'Apparato Cardiovascolare, Università di Bari), A Bellomo Damato, S Perrini (Istituto di Clinica Medica, Endocrinologia e Malattie Metaboliche, Università di Bari), C Pellegrino, L Ferrozzi (U O Chirurgia Generale, Ospedali Riuniti di Foggia), G Sabella, M Grilli (Medicina Generale, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo), G Ignone, A D'Adamo (U O Cardiologia, A O Di Summa, Brindisi), M Nuzzo, G Formoso (U O Endocrinologia, A O Vito Fazzi, Lecce), S Novo, R Caruso (Cattedra Malattie dell'Apparato Cardiovascolare, Università di Palermo), G Licata, S Paterna (Istituto di Clinica Medica, Università di Palermo), G Bompiani, S Verga (Istituto di Clinica Medica, Università di Palermo), S S Signorelli, L Di Pino (Dipartimento di Medicina Interna e Medicina Specialistica, Università di Catania), R Giannarelli, A Coppelli (Dipartimento di Endocrinologia e Metabolismo, Università di Pisa), A Saitta, M Bonaiuto (Dipartimento di Medicina Interna, Cattedra di Terapia Medica, Università di Messina), G M Baule, A Manca (III Divisione Medicina e Servizio di Diabetologia e Malattie del Metabolismo, Presidio Ospedaliero di Sassari), R Seguro (Servizio di Diabetologia, A O Brotzu, Cagliari), L Vincis, P Melis (Centrio Diabetologico, Presidio Ospedaliero Sirai, Carbonia), G Bonfardeci, C Cimminiello (Patologia Vascolare e Trombotica, III Divisione Medica, Ospedale San Carlo Borromeo, Milano), A Di Carlo (Servizio di Diabetologia e Malattie Metaboliche, Presidio Ospedaliero di Lucca), G Chesi, M G Dieci (U O Medicina Interna, Castel San Giovanni); A Cardinale, L Tantalo (U O Cardiologia, Ospedale di Matera), C Allegra, I Schachter (Day Hospital Angiologia, A O San Giovanni-Addolorata, Roma) M Trignano, I Pisano (Istituto di Patologia Chirurgica, Università di Sassari), S Pientini, R Carloni (U O Geriatria e Riattivazione, Università di Firenze).

Acknowledgments

N.B. Financial support to the study was provided by Novartis S.p.a., Milan, Italy, as payment of fees to an independent CRO in charge of monitoring. The authors declare they have no conflicts of interest.

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View Abstract