Intensive glucose control and recurrent cardiovascular events: 14-year follow-up investigation of the ACCORDION study.

Aims While cardiovascular disease in patients with type 2 diabetes commonly progresses with the occurrence of repeated events, most trials consider the effect of glucose-lowering strategies only on the first event. We examined the Action to Control Cardiovascular Risk in Diabetes trial and its observational follow-up study (ACCORDION) to investigate the effect of intensive glucose control on multiple events and further identify any subgroup effects. Materials and Methods A recurrent events analysis, using a negative binomial regression model, was applied to estimate the treatment effect on different consecutive cardiovascular disease events, including non-fatal myocardial infarction, non-fatal stroke, hospitalisation from heart failure, and cardiovascular death. Interaction terms were used to identify potential effect modifiers. The robustness of the results was confirmed in sensitivity analyses using alternative models. Results The median duration of follow-up was 7.7 years. Of the 5128 participants in the intensive and 5123 in the standard glucose control arm, respectively, 822 (16.0%) and 840 (16.4%) participants experienced a single event; 189 (3.7%) and 214 (4.2%) participants experienced two events; 52 (1.0%) and 40 (0.8%) experienced three events; and 1 (0.02%) and 1 (0.02%) experienced four events. There was no evidence of a treatment effect, with a rate difference of 0.0 (−0.3, 0.3) per 100 person-years comparing intensive versus standard intervention, although with non-significantly lower event rates in younger patients with HbA1c Discussion Intensive glucose control may not affect cardiovascular disease progression except in select subgroups. Since time-to-first event analysis may miss beneficial or harmful effects of glucose control on the risk of cardiovascular disease, recurrent events analysis should be routinely analysed in cardiovascular outcome trials, particularly when investigating long-term treatment effects.</p

Haemostatic and oxidative biomarker parameters^§ of T2-DM patients with and without any form of angiopathies.

§<p>The values of mean±SD are listed in the table.</p

Cleavage by ADAMTS-13 of VWF multimers in a pool obtained from two T2DM patients and two healthy subjects (Ctrl).

<p>Purified VWF multimers were digested by 5 nM ADAMTS-13 for 60 min in the presence of 1.2 mg/ml ristocetin under the experimental conditions detailed in the text. The same protein amounts were loaded on the gels. The samples from diabetic patients had the highest VWF carbonyl content (380 pmol/mg), whereas the controls had a lower carbonyl content (40 pmol/mg).</p

Multivariable-adjusted^* logistic regression for thrombotic angiopathies with haemostatic and oxidation variables in T1– and T2DM patients (n = 83).

*<p>Adjusted for age and sex.</p

Haemostatic and oxidative biomarker levels in T1- and T2-DM patients and respective controls.

*<p>Comparison with respective controls;</p>**<p>Comparison between type 1 and type 2 patients.</p>§<p>The values of mean±SD are listed in the table.</p

Correlation between total carbonyl content of plasma proteins and that of VWF purified from plasma samples of type 2 diabetes patients.

<p>The continuous line was drawn according to this phenomenological equation VWFcarb = (VWFcarb)max x (Pcarb)h/(P50h+Pcarbh), where (VWFcarb)max is the asymptotic value of VWF carbonyls (best fit value: 587±146 pmol/mg), Pcarb is the carbonyl content of plasma proteins, h is an exponential parameter (best fit = 3.6±0.6) and P50 is the concentration of plasma proteins carbonyls equal to (VWFcarb)max/2 (best fit: 706±107 pmol/mg). The vertical bars are the standard errors. In the inset, the SDS-PAGE gel (4–12%) of the purified and reduced VWF preparation is shown. On the left the molecular weight standards are also shown.</p

Biochemical characteristics and therapy of T1- and T2-DM patients and respective controls.

<p>Legend: ^§The values of mean±SD are listed;</p>*<p>Comparison with respective controls;</p>**<p>Comparison between type 1 and type 2 patients;</p>***<p>v.n. <25 mg/L The parameters with significantly different (p<0.05) values are listed in bold.</p

Statistical comparison between calculated VWF-bound-carbonyl levels in type 2 diabetic patients with and without microangiopathic complications (renal and retinal).

<p>According to Mann-Whitney test, VWF-bound carbonyls had higher values in microangiopathic subjects than in non macroangiopathic diabetics (mean values ± SD: 92±22 vs 35±8 pmol/mg, respectively, p = 0.022).</p

Comparison of total carbonyl content of plasma proteins, VWF-bound carbonyls and VWF:act between type 2 diabetic patients with and without macroangiopathies (AMI, stroke and PAD).

<p>According to Mann-Whitney test, all these parameters showed higher values in macroangiopathics than in non macroangiopathic diabetics (mean values ± SD: A) total carbonyl content of plasma proteins, 380±37 pmol/mg vs 270±25 pmol/mg, p = 0.0234; B) VWF-bound carbonyls, 82±20 vs 33±9 pmol/mg, p = 0.028; C) and 177±16% vs 132±12%, p = 0.032, respectively.</p

Comparison of SDS-agarose gel electrophoresis and western blot of VWF multimers between type 2 diabetic patients with low VWF-bound carbonyls without microangiopathy and those with high levels of VWF-bound carbonyls and several forms of microangiopathies.

<p>A) SDS-agarose gel electrophoresis and western blot of VWF multimers from a pool (n = 10) of type 2 diabetic patients without microangiopathy and low VWF-bound carbonyls (<50 pmol/mg) (1) and with high levels of VWF-bound carbonyls (>100 pmol/mg) and several forms of microangiopathies (2: nefropathy; 3: nefropathy+grade 3 retinopathy; 4: nefropathy+retinopathy+autonomic neuropathy; 5: nefropathy+grade 3 retinopathy; autonomic neuropathy+coronary microangiopathy). The agarose gel was discontinuous (0.4% agarose in stacking gel and 1.2% agarose in running gel. The amount of loaded VWF was similar in all samples (about 2 µg). B) SDS-agarose gel electrophoresis and western blot of VWF multimers from type 2 diabetic patients without macroangiopathy (1) and with several forms of macroangiopathies (2–4: coronaropathy; 5: coronaropathy+PAD). The presence of UL-VWF in samples is indicated between the dashed lines.</p