Efficacy and safety analyses across 4 subgroups combining low and high age and body mass index groups in Japanese phase 3 studies of dulaglutide 0.75 mg after 26 weeks of treatment.

In 855 Japanese patients with type 2 diabetes receiving once weekly dulaglutide 0.75 mg in 3 phase 3 studies, the effects on efficacy and safety at week 26 (last observation carried forward) were investigated in a post hoc descriptive analysis of subgroups of age (<65 years [young], ≥65 years [elderly]) and body mass index (BMI [<25 kg/m2, ≥25 kg/m2]). The 4 subgroups were as follows: 1) the young/low-BMI subgroup (Y/L) (n = 255); 2) the young/high-BMI subgroup (Y/H) (n = 386), 3) the elderly/low-BMI subgroup (E/L) (n = 137), and 4) the elderly/high-BMI subgroup (E/H) (n = 77). The mean changes from baseline in glycated hemoglobin (HbA1c) and body weight, respectively, were -1.69% and -0.29 kg in the Y/L subgroup; -1.48% and -0.09 kg in the Y/H subgroup; -1.68% and -0.20 kg in the E/L subgroup; and -1.72% and -0.26 kg in the E/H subgroup. The incidences of nausea and hypoglycemia, respectively, were 6.7% and 11.0% in the Y/L subgroup; 7.0% and 8.0% in the Y/H subgroup; 10.2% and 18.2% in the E/L subgroup; and 3.9% and 22.1% in the E/H subgroup. Dulaglutide improved HbA1c regardless of age or BMI; a higher incidence of hypoglycemia was observed in elderly patients compared to younger patients.

A randomized controlled trial of liraglutide versus insulin detemir plus sitagliptin: Effective switch from intensive insulin therapy to the once-daily injection in patients with well-controlled type 2 diabetes.

This study aimed to compare the efficacy and safety of liraglutide versus insulin detemir plus sitagliptin in Japanese patients with type 2 diabetes treated with a basal-bolus insulin regimen. In this multicenter, open-label trial, 90 patients whose diabetes had been controlled well or moderately (glycated hemoglobin [HbA1c ] ≤ 7.3%) with basal-bolus insulin regimen were randomly assigned to a liraglutide group or a detemir group and were followed up for 24 weeks. The primary end point was HbA1c change from baseline to 24 weeks. Of the 90 enrolled patients, 82 completed this trial. At 24 weeks, the mean changes in HbA1c from baseline were 0.1% ± 0.9% versus 0.3% ± 0.8% in the liraglutide versus detemir groups, respectively (P = .46). The "overall" satisfaction score for the Diabetes Treatment Satisfaction Questionnaire changed from 25.2 ± 7.4 to 29.9 ± 5.3 (P < .001) and from 26.4 ± 6.1 to 28.3 ± 6.4 (P = .12) in the liraglutide and detemir groups, respectively. Although the mean change difference in HbA1c between both groups was not significant, switching from a basal-bolus insulin regimen to liraglutide once daily improved patient satisfaction levels without loss of glycemic control.

N-terminal fragment of probrain natriuretic peptide is associated with diabetes microvascular complications in type 2 diabetes.

AIM/INTRODUCTION: Circulating levels of N-terminal fragment of probrain natriuretic peptide (NT-proBNP) are established as a risk factor for cardiovascular disease and mortality in patients with diabetes, as well as in the general population. We sought to examine the possibility of NT-proBNP as a biomarker of microvascular complications in patients with type 2 diabetes. MATERIALS AND METHODS: In total, 277 outpatients with type 2 diabetes were consecutively enrolled as a hospital cohort. Two hundred and seventeen of these patients (132 males; mean age, 63.4 years) were designated as cases with any of the diabetic complications (retinopathy, neuropathy, nephropathy, ischemic heart disease, strokes, peripheral artery disease), and 60 (42 males; mean age, 54.1 years) were set as controls without clinical evidence of diabetic complications. Diabetic complications were evaluated by medical record and routine laboratory examinations. NT-proBNP was measured and investigated with regard to the associations with diabetic complications. RESULTS: Mean NT-proBNP levels were significantly higher in patients with any of the diabetic complications (59 versus 33 pg/mL; P<0.0001). In logistic regression analysis, NT-proBNP levels >79 pg/mL, which was the highest tertile, were independently associated with a 5.04 fold increased risk of all complications (P<0.0051) compared to the lowest tertile (NT-proBNP levels <31 pg/mL). Odd ratios of cardiovascular disease and nephropathy, neuropathy, and retinopathy were 9.33, 6.23, 6.6 and 13.78 respectively, in patients with NT-proBNP values in the highest tertile (>79 pg/mL), independently of age, sex, duration of diabetes or other risk factors, such as body mass index or hemoglobin A1c. In addition, NT-proBNP levels were associated with surrogate markers of atherosclerosis, such as brachial-ankle pulse wave velocity (r=0.449, P<0.0001) and left ventricular hypertrophy (r=0.212, P<0.001). CONCLUSION: In this hospital-based cohort of type 2 diabetes, the NT-proBNP levels were associated with systemic atherosclerosis and comorbid diabetic microvascular as well as macrovascular complications. It is useful to stratify high-risk diabetic patients by measuring NT-proBNP and to start comprehensive care for preventing the progression of diabetic complications. It is necessary to elucidate the underlying mechanism for the progression of diabetic complications represented by an elevation of NT-proBNP and to demonstrate the ability of NT-proBNP as a predictive global biomarker for diabetic complications in Japanese type 2 diabetic patients.

The lack of long-range negative correlations in glucose dynamics is associated with worse glucose control in patients with diabetes mellitus.

Glucose dynamics measured in ambulatory settings are fluid in nature and exhibit substantial complexity. We recently showed that a long-range negative correlation of glucose dynamics, which is considered to reflect blood glucose controllability over a substantial period, is absent in patients with diabetes mellitus. This was demonstrated using detrended fluctuation analysis (DFA), a modified random-walk analysis method for the detection of long-range correlations. In the present study, we further assessed the relationships between the established clinical indices of glycemic or insulinogenic control of hemoglobin A(1c) (HbA(1c)), glycated albumin (GA), 1,5-anhydroglucitol, and urine C-peptide immunoreactivity and the recently proposed DFA-based indices obtained from continuous glucose monitoring in 104 Japanese diabetic patients. Significant correlations between the following parameters were observed: (1) HbA(1c) and the long-range scaling exponent α(2) (r = 0.236, P < .05), (2) GA and α(2) (r = 0.254, P < .05), (3) GA and the short-range scaling exponent α(1) (r = 0.233, P < .05), and (4) urine C-peptide immunoreactivity and the mean glucose fluctuations (r = -0.294, P < .01). Therefore, we concluded that increases in the long-range DFA scaling exponent, which are indicative of the lack of a long-range negative correlation in glucose dynamics, reflected abnormalities in average glycemic control as clinically determined using HbA(1c) and GA parameters.

N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) for predicting silent myocardial ischaemia in type 2 diabetes mellitus independent of microalbuminuria.

BACKGROUND: In the early identification of cardiovascular risk, it is essential to establish a biological marker for cardiac complications that is comparable to albuminuria for nephropathy. We tested the hypothesis that N-terminal pro-brain natriuretic peptide (NT-proBNP) might be a marker for silent myocardial ischaemia in diabetes. METHODS: In forty consecutively recruited subjects without evident coronary artery disease, serum NT-proBNP was measured together with multi-slice computed tomography. With patients suspected of having significant coronary artery stenosis by multi-slice computed tomography, coronary angiography was performed. Silent myocardial ischaemia was defined as the presence of significant coronary artery stenosis with more than 50% luminal narrowing by angiography. RESULTS: Thirteen patients (32.5%) had silent myocardial ischaemia. NT-proBNP levels were significantly higher in these patients (181.1 ± 43.8 versus 55.2 ± 9.7 pg/mL, p < 0.005) but HbA(1c), lipid profiles, and creatinine were similar in the two groups. Moreover, log NT-proBNP was identified as an independent predictor of silent myocardial ischaemia (R(2) = 0.502, p < 0.05) after adjustment for HbA(1c), creatinine, albuminuria, hypertension, hyperlipidaemia, or smoking. After stratifying patients by NT-proBNP, the upper tertile compared to the lowest tertile was significantly associated with silent myocardial ischaemia (odds ratio: 26.7, p < 0.05). Receiver operation characteristics analysis with a cut-off value of 52 pg/mL showed 92% sensitivity and 75% specificity for predicting silent myocardial ischaemia (positive predictive value 64.7%, negative predictive value 94.3%). CONCLUSIONS: The outstandingly high negative predictive value of NT-proBNP enables us to focus on diabetic patients with occult coronary disease, independently of microalbuminuria.

Associations of renal vascular resistance with albuminuria and other macroangiopathy in type 2 diabetic patients.

OBJECTIVE: Albuminuria can be caused by endothelial dysfunction as a result of ischemic nephropathy rather than classic diabetic nephropathy. We studied whether renal vascular resistance (resistive index [RI]) of the main renal arteries could be associated with albuminuria and further assessed the relationship between RI and aorta stiffness measured by brachial-ankle pulse-wave velocity (baPWV). RESEARCH DESIGN AND METHODS: We consecutively studied 150 patients with type 2 diabetes and the absence of clinically overt renal artery stenosis. Renal function expressed as the estimated glomerular filtration rate (eGFR) was calculated using the modified formula of modification of diet in renal disease (MDRD). The RI [(peak systolic velocity -end-diastolic velocity)/peak systolic velocity] was measured with duplex Doppler ultrasonography. RESULTS: When the presence of albuminuria (uAlb) was defined as urinary albumin-to-creatinine ratio (microg/mg x creatinine) >30, mean RI [(left RI + right RI)/2] was significantly higher in uAlb, compared with that in patients without uAlb. RI had significant associations with age (r = 0.398, P < 0.0001), diastolic blood pressure (r = -0.398, P < 0.0001), eGFR (r = -0.373, P < 0.0001), and baPWV (r = 0.223, P < 0.05), respectively. Multivariate logistic regression analysis showed that increased RI when defined as RI >0.72 (median) was significantly associated with age (P < 0.01, 95%CI 1.02-1.19), diastolic blood pressure (P < 0.01, 0.86-0.97), and uAlb (P < 0.01, 1.53-15.46), respectively. Moreover, RI was an independent risk factor for uAlb after adjustment of both diastolic blood pressure and eGFR. CONCLUSIONS: Renal vascular resistance was associated with albuminuria and aorta stiffness. Increased RI may imply the presence of any type of underlying renal damage, including ischemic nephropathy.

Increased risk for atherosclerosis estimated by pulse wave velocity in hypothyroidism and its reversal with appropriate thyroxine treatment.

Pulse wave velocity (PWV) is known to represent arterial stiffness and is established as a marker for cardiovascular risk and a prognostic factor for mortality in the case of chronic renal failure or hypertension. The application of an automated apparatus for measuring brachial-ankle pulse wave velocity (baPWV) has made PWV measurement non-invasive, easier to screen for cardiovascular risk and as a result, baPWV measurements have become widely applied in clinical practice in recent years. We assessed the baPWV in 7 flank hypothyroidism patients and 28 subclinical hypothyroidism patients. In comparison with age matched healthy controls, 3 hypothyroid patients had advanced values and by replacement therapy, all 7 subjects showed improvement in their baPWV values (1531.2 +/- 242.7 to 1330.2 +/- 208.6 cm/s, p<0.05). In 28 subclinical hypothyroid subjects, 71% also had accelerated baPWV values for their age. Ten subjects (36% of all) had neither hypertension, hyperlipidemia, diabetes nor were taking any medication, and yet 8 patients out of 10 showed advanced baPWV values compared to age matched mean values. The baPWV was not correlated to TSH or total cholesterol levels, and was associated with only age and blood pressure (p = 0.01, <0.001, respectively), which are widely demonstrated as the characteristics for baPWV. In two subclinical hypothyroid subjects, who were normotensive and had no dyslipidemia, thyroxine treatment was performed and the baPWV decreased with unchanged blood pressure and total cholesterol levels. We concluded that the arterial wall stiffness tends to be increased in both overt and subclinical hypothyroid patients, and an appropriate treatment could reverse the abnormalities. It is possible that the initiation of adequate treatment in subclinical hypothyroidism may reduce the cardiovascular risk.

Blood sugar control reverses the increase in urinary excretion of prostaglandin D synthase in diabetic patients.

BACKGROUND/AIMS: We investigated basal levels of serum and urinary lipocalin-type prostaglandin D synthase/beta-trace (L-PGDS) in type-2 diabetic patients and explored whether glycemic control affects L-PGDS status in another 55 diabetic inpatients with normoalbuminuria. METHODS: Fifty-five type-2 diabetic outpatients (HbA1c, 9.14 +/- 0.20%; creatinine (Cr), 85.1 +/- 2.4 micromol/l), and 55 age-matched healthy control subjects were recruited. Serum and urinary levels of L-PGDS were determined with respect to the stage of diabetic nephropathy. The L-PGDS was localized by immunohistochemistry. RESULTS: The urinary L-PGDS index increased in diabetic patients, compared with the controls (234.8 +/- 27.4 vs. 73.8 +/- 7.8 microg/mmol Cr, p < 0.001). Even in normoalbuminuric patients as well as in microalbuminuric patients, urinary L-PGDS indexes were higher than the controls (166.0 +/- 21.1, p < 0.0001 and 338.6 +/- 62.5 microg/mmol Cr, p < 0.0001, respectively), although the serum L-PGDS level was equal to that in the control subjects. Multiple regression analysis revealed that the urinary L-PGDS index was predicted solely by glucose levels and type-IV collagen index, whereas the serum L-PGDS was determined mainly by age and serum Cr. Glycemic control reduced the urinary L-PGDS index towards the normal range in diabetic patients with normoalbuminuria (172.3 +/- 6.6 vs. 118.1 +/- 2.6 (SE) microg/mmol Cr, p < 0.0001). Immunohistochemistry showed that L-PGDS was uniquely present in the renal tubules in diabetes while in nondiabetics, L-PGDS occurred solely in the peritubular interstitium, not in the tubular cells. CONCLUSION: Inadequate glycemic control is responsible for urinary L-PGDS excretion in the diabetic patients. Urinary L-PGDS is useful to predict subclinical renal injury associated with type-2 diabetes.