Search

OBJECTIVE Nonalbuminuric diabetic kidney disease (DKD) has become the prevailing phenotype in patients with type 2 diabetes. However, it remains unclear whether its prognosis is poorer than that of other DKD phenotypes. RESEARCH DESIGN AND METHODS A total of 2,953 Japanese patients with type 2 diabetes and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, enrolled in an observational cohort study in 2004, were followed until 2015. On the basis of albuminuria (>30 mg/g creatinine) and reduced eGFR ( RESULTS During the mean follow-up of 9.7 years, 113 patients died and 263 developed CVD. In nonalbuminuric DKD, the risks of death or CVD were not higher than those in no-DKD (adjusted hazard ratio 1.02 [95% CI 0.66, 1.60]) and the annual decline in eGFR was slower than in other DKD phenotypes. The risks of death or CVD in nonalbuminuric DKD without prior CVD were similar to those in no-DKD without prior CVD, whereas the risks in nonalbuminuric DKD with prior CVD as well as other DKD phenotypes were higher. CONCLUSIONS Nonalbuminuric DKD did not have a higher risk of mortality, CVD events, or renal function decline than the other DKD phenotypes. In nonalbuminuric DKD, the presence of macrovascular complications may be a main determinant of prognosis rather than the renal phenotype.

OBJECTIVE The effect of additional treatment with oral hypoglycemic agents on the progression of atherosclerosis remains unknown in insulin-treated patients with type 2 diabetes mellitus (T2DM). We assessed the effects of sitagliptin, a dipeptidyl peptidase 4 inhibitor, on carotid intima-media thickness (IMT) in T2DM. RESEARCH DESIGN AND METHODS This prospective, randomized, open-label, blinded end point, multicenter, parallel-group, comparative study included 282 insulin-treated patients with T2DM free of a history of apparent cardiovascular diseases who were recruited at 12 clinical units and randomly allocated to either the sitagliptin group (n = 142) or the control group (n = 140). The primary outcomes were changes in mean and maximum IMT of the common carotid artery measured by echography at the end of a 104-week treatment period. RESULTS Sitagliptin had a more potent glucose-lowering effect compared with the conventional treatment (−0.5 ± 1.0% vs. −0.2 ± 0.9%; P = 0.004), without increasing hypoglycemic episodes or body weight. Changes in the mean and left maximum IMT, but not right maximum IMT, of the common carotid arteries were significantly greater after sitagliptin treatment compared with conventional treatment (−0.029 [SE 0.013] vs. 0.024 [0.013] mm [P = 0.005]; −0.065 [0.027] vs. 0.022 [0.026] mm [P = 0.021]; −0.007 [0.031] vs. 0.027 [0.031] mm [P = 0.45], respectively). Over 104 weeks, sitagliptin, but not conventional treatment, significantly reduced the mean IMT and left maximum IMT of common carotid arteries relative to the baseline. CONCLUSIONS Sitagliptin attenuated the progression of carotid IMT in insulin-treated patients with T2DM free of apparent cardiovascular disease compared with conventional treatment.

OBJECTIVE Recent experimental studies have shown that dipeptidyl peptidase 4 (DPP-4) inhibitors have antiatherosclerotic benefits in glucagon-like peptide 1–dependent and –independent manners. The current study investigated the effects of alogliptin, a DPP-4 inhibitor, on the progression of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS This prospective, randomized, open-label, blinded-end point, multicenter, parallel-group, comparative study included 341 patients with T2DM free of a history of apparent cardiovascular diseases recruited at 11 clinical units and randomly allocated to treatment with alogliptin (n = 172) or conventional treatment (n = 169). Primary outcomes were changes in mean common and maximum intima-media thickness (IMT) of the carotid artery measured by carotid arterial echography during a 24-month treatment period. RESULTS Alogliptin treatment had a more potent glucose-lowering effect than the conventional treatment (−0.3 ± 0.7% vs. −0.1 ± 0.8%, P = 0.004) without an increase of hypoglycemia. Changes in the mean common and the right and left maximum IMT of the carotid arteries were significantly greater after alogliptin treatment than after conventional treatment (−0.026 mm [SE 0.009] vs. 0.005 mm [SE 0.009], P = 0.022; −0.045 mm [SE 0.018] vs. 0.011 mm [SE 0.017], P = 0.025, and −0.079 mm [SE 0.018] vs. −0.015 mm [SE 0.018], P = 0.013, respectively). CONCLUSIONS Alogliptin treatment attenuated the progression of carotid IMT in patients with T2DM free of apparent cardiovascular disease compared with the conventional treatment.

OBJECTIVE Studies on the rate of remission of macroalbuminuria in patients with type 2 diabetes mellitus (T2DM) and the effects of reduction in albuminuria on renal prognosis in a primary care setting are absolutely lacking. RESEARCH DESIGN AND METHODS A total of 211 T2DM patients with albuminuria ≥300 mg/g were enrolled in a prospective observational study (mean of 4.5 years). The incidence of patients with remission of macroalbuminuria at every 1-year study time point after starting intensified diabetes treatment and the factors associated with remission were evaluated. The association of reduction in albuminuria with renal events (doubling of serum creatinine and end-stage renal disease) was also investigated. RESULTS During the 5-year study period, remission to microalbuminuria occurred in 116 patients and the 5-year cumulative incidence was 58.3%. Notably, most cases (82.8%) obtained remission at the 1-year study time point. The remission rate increased with achieving therapeutic targets for blood pressure and blood glucose. Remission and reduction in albuminuria of ≥50% were associated with preservation of renal function. In particular, patients who obtained both remission and 50% reduction at the 1-year study time point exhibited a significantly reduced risk for renal events as compared with those with no remission and no reduction (adjusted hazard ratio 0.30 [95% CI 0.12–0.76]). CONCLUSIONS Remission of macroalbuminuria occurs frequently and is associated with the preservation of renal function in T2DM patients. The initial adequate diabetes treatment aimed at reducing albuminuria may lead to improved renal prognosis in the primary care setting.

Previous studies have reported a marked variation in the prevalence of microalbuminuria in type 2 diabetic patients ranging from 7 to 47% (1–13). The variation could arise from ethnic/genetic differences in susceptibility (3–11) and from methodological issues for investigating the prevalence, such as small-sized populations (3,12,13); single clinic–based studies (8,12); use of the dipstick method instead of quantitative determinations (4,5); or only a single measurement of urinary albumin excretion (UAE) (3–13), whereas multiple measurements have been recommended for years (14). In terms of investigating the prevalence of microalbuminuria in type 2 diabetic patients, we performed this study with the aim of investigating patients with a specific ethnicity (i.e., Japanese). The study had a large-sized population, a nationwide multicenter-based design, and a high proportion of data availability for clinical variables and for multiple measurements of UAE. A cross-sectional study was conducted that included 29 medical clinics (i.e., general practitioners) or general/university-affiliated hospitals from different areas in Japan, using the same software to incorporate patient records, as a working study group. Known as the Japan Diabetes Clinical Data Management Study Group (15), this group consists of medical doctors who volunteered to dedicate daily standard clinical work to scientific analysis. The study was performed …

The effect of additional treatment with oral hypoglycemic agents on the progression of atherosclerosis remains unknown in insulin-treated patients with type 2 diabetes mellitus (T2DM). We assessed the effects of sitagliptin, a dipeptidyl peptidase 4 inhibitor, on carotid intima-media thickness (IMT) in T2DM.This prospective, randomized, open-label, blinded end point, multicenter, parallel-group, comparative study included 282 insulin-treated patients with T2DM free of a history of apparent cardiovascular diseases who were recruited at 12 clinical units and randomly allocated to either the sitagliptin group (n = 142) or the control group (n = 140). The primary outcomes were changes in mean and maximum IMT of the common carotid artery measured by echography at the end of a 104-week treatment period.Sitagliptin had a more potent glucose-lowering effect compared with the conventional treatment (-0.5 ± 1.0% vs. -0.2 ± 0.9%; P = 0.004), without increasing hypoglycemic episodes or body weight. Changes in the mean and left maximum IMT, but not right maximum IMT, of the common carotid arteries were significantly greater after sitagliptin treatment compared with conventional treatment (-0.029 [SE 0.013] vs. 0.024 [0.013] mm [P = 0.005]; -0.065 [0.027] vs. 0.022 [0.026] mm [P = 0.021]; -0.007 [0.031] vs. 0.027 [0.031] mm [P = 0.45], respectively). Over 104 weeks, sitagliptin, but not conventional treatment, significantly reduced the mean IMT and left maximum IMT of common carotid arteries relative to the baseline.Sitagliptin attenuated the progression of carotid IMT in insulin-treated patients with T2DM free of apparent cardiovascular disease compared with conventional treatment.

Recent experimental studies have shown that dipeptidyl peptidase 4 (DPP-4) inhibitors have antiatherosclerotic benefits in glucagon-like peptide 1-dependent and -independent manners. The current study investigated the effects of alogliptin, a DPP-4 inhibitor, on the progression of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM).This prospective, randomized, open-label, blinded-end point, multicenter, parallel-group, comparative study included 341 patients with T2DM free of a history of apparent cardiovascular diseases recruited at 11 clinical units and randomly allocated to treatment with alogliptin (n = 172) or conventional treatment (n = 169). Primary outcomes were changes in mean common and maximum intima-media thickness (IMT) of the carotid artery measured by carotid arterial echography during a 24-month treatment period.Alogliptin treatment had a more potent glucose-lowering effect than the conventional treatment (-0.3 ± 0.7% vs. -0.1 ± 0.8%, P = 0.004) without an increase of hypoglycemia. Changes in the mean common and the right and left maximum IMT of the carotid arteries were significantly greater after alogliptin treatment than after conventional treatment (-0.026 mm [SE 0.009] vs. 0.005 mm [SE 0.009], P = 0.022; -0.045 mm [SE 0.018] vs. 0.011 mm [SE 0.017], P = 0.025, and -0.079 mm [SE 0.018] vs. -0.015 mm [SE 0.018], P = 0.013, respectively).Alogliptin treatment attenuated the progression of carotid IMT in patients with T2DM free of apparent cardiovascular disease compared with the conventional treatment.

OBJECTIVE Elevated concentrations of serum sialic acid, a potent cardiovascular risk factor in the general population, have been found in patients with IDDM and microalbuminuria. We investigated whether a coincidence exists between the increase of sialic acid concentrations and albuminuria in the transition from normoalbuminuria to microalbuminuria. Furthermore, the predictability of increased sialic acid as well as von Willebrand factor (vWF) and total and HDL cholesterol concentrations in development of persistent microalbuminuria in IDDM was investigated. RESEARCH DESIGN AND METHODS This 10-year prospective study was carried out in a cohort of 209 IDDM patients with normoalbuminuria at baseline. RESULTS Of the cohort, 198 patients completed the follow-up period and 27 developed persistent microalbuminuria (urinary albumin excretion rate [UAER] ≥ 30 mg/24 h). A coincident increase of UAER and serum sialic acid concentration was seen before persistent microalbuminuria was diagnosed. Elevation of serum sialic acid concentrations in those who later developed microalbuminuria occurred 3 years before the diagnosis of persistent microalbuminuria. Baseline serum sialic acid concentrations were significantly higher in the group of patients who later developed microalbuminuria than in the group who remained normoalbuminuric (2.02 ± 0.41 vs. 1.85 ± 0.31 mmol/l [means ± SD], P < 0.05). Baseline serum sialic acid concentration correlated significantly with HbA1c, UAER, blood pressure, total cholesterol, HDL cholesterol, and vWF and was significantly predictive for development of microalbuminuria (hazards ratio [95% CI], 3.1 [1.2–8.1]; P = 0.02) after adjustments for sex, duration of diabetes, smoking, blood pressure, vWF, total cholesterol, and HDL cholesterol. Adjustment for the effects of HbA1c and UAER, however, canceled out the predictive effect of serum sialic acid. CONCLUSIONS UAER and serum sialic acid concentration increase coincidentally before the onset of persistent microalbuminuria. An increased serum sialic acid concentration is predictive for the onset of microalbuminuria independent of age, sex, diabetes duration, smoking, blood pressure, vWF, and total HDL cholesterol.

OBJECTIVE Tissue factor pathway inhibitor (TFPI) is bound to vascular endothelium (presumably to heparan sulfate) and circulates in complex with plasma lipoproteins. It directly binds and inhibits factor Xa. The purpose of the study is to investigate whether plasma TFPI activity is altered in IDDM and nephropathy and to evaluate the possible determinants of the alteration. RESEARCH DESIGN AND METHODS We assessed plasma concentration of TFPI (total, truncated, and domain 3 TFPI) and plasma activity of factor Xa inhibition in nondiabetic control subjects (n = 22) and in IDDM patients with normoalbuminuria (urinary albumin excretion rate [UAE] < 30 mg/24h, n = 17), incipient nephropathy (UAE 30-300 mg/24 h, n = 17), clinical nephropathy (UAE > 300 mg/24h, n = 25). RESULTS Total, truncated, and domain 3 TFPI concentrations were increased in IDDm patients compared with those in control subjects and were more pronounced in IDDM patients with nephropathy. Plasma activity of factor Xa inhibition measured by HEPTEST (Haemachem, St. Louis, MO) assay was increased in IDDM patients, especially in those with nephropathy. TFPI-dependent factor Xa inhibition, obtained as the difference in clotting time with and without adding activity-neutralizing anti-TFPI antibody to samples, was increased in IDDm patients with nephropathy. This was, however, not sufficient to inhibit the biological activity of factor Xa as demonstrated by increased levels of prothrombin fragment 1 + 2. LDL cholesterol and HbA1c were independently correlated to plasma TFPI. CONCLUSIONS Inhibition of factor Xa activity is increased in IDDM patients with nephropathy, mainly because of increased plasma TFPI activity. The increased plasma TFPI activity in these patients may be associated with and regulated by LDL in plasma and metabolic control. The anticoagulant activity of TFPI may attenuate the hypercoagulable state in diabetes but does not seem to be able to normalize hemostasis.

OBJECTIVE Raised serum sialic acid concentration is a strong predictor of cardiovascular mortality in the general white population. A progressive increase in cardiovascular morbidity and mortality takes place in relation to increasing albuminuria in NIDDM patients. Therefore, we investigated the potential association between serum sialic acid and micro- and macroangiopathy in NIDDM patients. RESEARCH DESIGN AND METHODS We studied a prevalence cohort of all white NIDDM patients < 76 years of age attending a diabetic clinic during 1 year. Of the patients, 319 had normoalbuminuria, 148 had microalbuminuria, and 75 had macroalbuminuria (diabetic nephropathy was in 47 of 75 patients); 66 nondiabetic age- and sex-matched subjects acted as a control group. Blood samples were taken for measurements of sialic acid, lipids, creatinine, and HbA1c. Retinopathy was assessed by funduscopy. The prevalence of cardiovascular disease was based on Minnesota-coded electrocardiograms and the World Health Organization cardiovascular questionnaire. RESULTS A progressive raise in serum sialic acid was demonstrated with an increasing urinary albumin excretion rate: [median (range)] 2.02 (1.55–2.63); 2.42 (1.47–6.48); 2.67 (1.57–5.86), and 2.95 (1.52–7.86) mmol/l in nondiabetic subjects, NIDDM patients with normoalbuminuria, microalbuminuria, and diabetic nephropathy, respectively (P < 0.05 or less for differences between groups). Multiple linear regression analysis showed that serum cholesterol concentration, serum HDL cholesterol concentration, BMI, albuminuria, smoking, and cardiovascular disease correlate independently with logarithmic (10) serum sialic acid concentration. CONCLUSIONS Our study revealed a progressive raise in serum sialic acid with increasing urinary albumin excretion rate in NIDDM patients. Furthermore, several modifiable cardiovascular risk factors were associated with serum sialic acid.