Association of Renal Function and Statin Therapy with Lipoprotein(a) in Patients with Type 2 Diabetes.

AIM: A high level of serum lipoprotein(a) [Lp(a)] is associated with kidney disease development in patients with type 2 diabetes (T2DM). Recent studies have suggested that statins may affect serum levels of Lp(a). However, the statin effect is not well-defined in patients with T2DM with kidney dysfunction. This retrospective study aimed to investigate the relevance of kidney dysfunction and statin therapy to Lp(a) in patients with T2DM. METHODS: Japanese patients with T2DM (n=149, 96 men and 53 women) were divided into two groups: statin users (n=79) and non-statin users (n=70). Multiple logistic regression analyses were performed with Lp(a) as the objective variable and estimated glomerular filtration rate (eGFR), hemoglobin A1c, age, gender, and body mass index as the explanatory variables. RESULTS: Lp(a) serum levels were higher in statin users than in non-statin users (P=0.022). Multivariate regression analysis results showed an inverse correlation of eGFR to log Lp(a) in all patients (P=0.009) and in non-statin users (P=0.025), but not in statin users. In a multiple logistic regression analysis for median Lp(a), there was an inverse association between eGFR and Lp(a) level (odds ratio, 0.965; 95% confidence interval, 0.935-0.997; P=0.030) in non-statin users as well as in all participants, but not in statin users. CONCLUSIONS: The present study suggests that a high Lp(a) level in patients with T2DM, except in statin users, is significantly associated with decreased eGFR, indicating that the increased Lp(a) levels under statin therapy might diminish the relationship between Lp(a) and eGFR.

Associations of Homocysteine with B Vitamins and Zinc in Serum Levels of Patients with Type 2 Diabetes Mellitus: A Cross-Sectional Study.

The association of homocysteine metabolism-related nutrients along with renal function to homocysteine levels is not well known in patients with type 2 diabetes mellitus (T2DM). We investigated the relevance of kidney function, albuminuria, and nutritional factors to serum homocysteine in T2DM patients. This cross-sectional study enrolled 149 T2DM patients (96 men and 53 postmenopausal women), and patient characteristics and laboratory data including kidney-related data [glomerular filtration rate (eGFR), urinary albumin excretion (UACR), uric acid] and metabolism parameters (hemoglobin A1c and lipids) were collected from the medical record and serum levels of vitamin B12, folic acid, zinc, homocysteine and UACR were also acquired. In total subjects, serum levels of homocysteine, vitamin B12, and folic acid were within reference intervals, but zinc levels were close to lower limits of its reference interval. A multivariate-adjusted analysis showed that gender (ß=-0.259, p<0.001), uric acid (ß=0.267, p<0.001), eGFR (ß=-0.188, p=0.001), log UACR (ß=0.190, p=0.002), log folic acid (ß=-0.259, p<0.001), log vitamin B12 (ß=-0.224, p<0.001) and zinc (ß=-0.169, p=0.006) were correlated to log homocysteine. In multiple regression analysis by gender, these correlations were found similarly in men, but neither log folic acid nor zinc showed correlations with log homocysteine in women. The present study suggests that renal function parameters and the certain nutritional factors have a possible influence on serum homocysteine, in T2DM patients including diabetes kidney disease.

Biphasic insulin aspart-30 reduces glycemic variability to a greater degree than insulin detemir: A randomized controlled trial of once-daily insulin regimens using continuous glucose monitoring.

INTRODUCTION: We compared the efficacy of insulin detemir and biphasic insulin aspart-30 given in the morning as an add-on to oral hypoglycemic agents in type 2 diabetes patients. MATERIALS AND METHODS: The present study enrolled 30 patients with poorly controlled type 2 diabetes (8% ≤ glycated hemoglobin < 11%) being treated with oral hypoglycemic agent mono- or combination therapy with biguanides, sulfonylureas or thiazolidinediones. The patients were randomly assigned to insulin detemir (group D) or insulin aspart-30 (group A) given in the morning as add-on to oral hypoglycemic agents. After adjusting their insulin doses, the patients that underwent continuous glucose monitoring during a 3-day hospitalization and with day 2 continuous glucose monitoring data were subjected to analysis. RESULTS: There was no significant difference in patient background, baseline glycated hemoglobin levels and insulin doses during continuous glucose monitoring between the two groups. The percent coefficient of variation of 24-h glucose levels was significantly lower in group A (20.4 ± 7.6) than in group D (27.1 ± 6.5; P = 0.015). Similarly, mean amplitude of glycemic excursions was significantly smaller in group A (80 ± 32) than in group D (102 ± 14; P = 0.021). Postprandial glucose excursions were significantly smaller after breakfast in group A (65 ± 31 mg/dL) than in group D (106 ± 32 mg/dL; P = 0.002). CONCLUSIONS: As once-daily insulin injection therapy given before breakfast in type 2 diabetes patients, the biphasic insulin analog might represent a better insulin option in significantly lowering the percent coefficient of variation and mean amplitude of glycemic excursions than the long-acting insulin preparation.

Prediction of nocturnal hypoglycemia unawareness by fasting glucose levels or post-breakfast glucose fluctuations in patients with type 1 diabetes receiving insulin degludec: A pilot study.

OBJECTIVE: To evaluate whether nocturnal asymptomatic hypoglycemia (NAH) can be predicted by fasting glucose levels or post-breakfast glucose fluctuations in patients with type 1 diabetes (T1D) receiving insulin degludec. METHODS: Patients with T1D receiving insulin degludec underwent at-home CGM assessments. Indices for glycemic variability before and after breakfast included fasting glucose levels and the range of post-breakfast glucose elevation. For comparison, the patients were classified into those with NAH and those without. The optimal cut-off values for the relevant parameters were determined to predict NAH using ROC analysis. RESULTS: The study included a total of 31 patients (mean HbA1c values, 7.8 ± 0.7%), and 16 patients (52%) had NAH. Those with NAH had significantly lower fasting glucose levels than did those without (82 ± 48 mg/dL vs. 144 ± 69 mg/dL; P = 0.009). The change from pre- to post-breakfast glucose levels was significantly greater among those with NAH (postprandial 1-h, P = 0.028; postprandial 2-h, P = 0.028). The cut-off values for prediction of NAH were as follows: fasting glucose level <84 mg/dL (sensitivity 0.80/specificity 0.75/AUC 0.80; P = 0.004), 1-h postprandial elevation >69 mg/dL (0.75/0.67/0.73; P = 0.033), and 2-h postprandial elevation >99 mg/dL (0.69/0.67/0.71; P = 0.044). CONCLUSIONS: The results suggest that fasting glucose level of < 84 mg/dL had approximately 80% probability of predicting the occurrence of NAH in T1D receiving insulin degludec. It was also shown that the occurrence of hypoglycemia led to greater post-breakfast glucose fluctuations and steeper post-breakfast glucose gradients.

Comparison of glycemic variability in Japanese patients with type 1 diabetes receiving insulin degludec versus insulin detemir using continuous glucose monitoring: a randomized, cross-over, pilot study.

OBJECTIVE: To use continuous glucose monitoring (CGM) to compare glycemic variability in patients with type 1 diabetes (T1D) treated with insulin degludec (IDeg) versus insulin detemir (IDet). METHODS: Ten patients with T1D were randomly assigned to receive once-daily IDeg, followed by twice-daily IDet, or vice versa. Glucose variability was evaluated by CGM after >4 weeks of the first insulin and again after crossover to the second insulin. RESULTS: The total daily insulin dose (U/kg/day) and the total daily basal insulin dose (U/kg/day) were significantly lower during treatment with IDeg than with IDet [median (interquartile range): 0.55 (0.54-0.73) vs. 0.64 (0.54-0.83); P = 0.028, 0.24 (0.19-0.36) vs. 0.30 (0.19-0.39); P = 0.027]. The 24-hour mean glucose levels were not significantly different. However, their standard deviation (SD) was significantly smaller during treatments with IDeg than those with IDet [59.5 (39.5-71.0) vs. 72.8 (61.8-92.8); P = 0.008]. Their mean fasting glucose levels and the mean postprandial peak levels after breakfast and after dinner were significantly lower with IDeg. CONCLUSIONS: A CGM-based comparison demonstrated that once-daily IDeg showed fewer glycemic fluctuations than twice-daily IDet. IDeg appears to stabilize blood glucose levels better during both daytime and nighttime (particularly, before and after breakfast) with a lower insulin dosage.

Population-based cross-sectional study on insulin resistance and insulin-secretory capacity in Japanese school children.

AIMS/INTRODUCTION: Little information is available regarding the status of insulin resistance (IR) and insulin deficiency (ID), as well as their relationship with obesity in children using the homeostasis model assessment (HOMA) in a population-based setting. MATERIALS AND METHODS: The study included a total of 445 ninth-grade children participating in health check-up programs implemented in Tsunan Town, Niigata, Japan (boys/girls, 252/193 [participation rates: 98.1/95.5%]). HOMA of insulin resistance ≥2.5 was defined as IR, and HOMA of ß-cell function <40 defined as ID. RESULTS: The medians (25-75th percentiles) of HOMA of insulin resistance, HOMA of ß-cell function, Disposition Index and body mass index in boys were 1.2 (0.8-1.7), 64 (44-93), 52 (43-64) and 19.2 (18.0-20.7) kg/m2 , respectively, vs 1.5 (1.0-2.0), 86 (63-120), 60 (50-74) and 20.4 (18.9-22.0) kg/m2 , respectively, in girls. The HOMA of insulin resistance, HOMA of ß-cell function and Disposition Index values were significantly higher in the girls (P = 0.002, P < 0.001 and P < 0.001, respectively). Those with IR accounted for a significantly higher proportion of girls than boys (15.5/8.7%; P = 0.027); those with obesity accounted for 9.9/10.7% (boys/girls); and those with IR and obesity accounted for 2.4/4.7%. Those with ID accounted for a significantly higher proportion of boys than girls (20.6/8.8%; P = 0.001), whereas those with ID and obesity accounted for a very small proportion of either group (0.4/0.5%). CONCLUSIONS: The presence of IR was higher among the girls. In contrast, ID was more frequent among the boys. The infrequent presence of ID among children might support the presence of non-obese type 2 diabetes adults in Japan.

Comparison of glycemic variability in Japanese patients with type 1 diabetes receiving insulin degludec versus insulin glargine using continuous glucose monitoring: A randomized, cross-over, pilot study.

AIMS: To compare glucose variability in patients with type 1 diabetes (T1D) treated with insulin glargine (IGla) versus insulin degludec (IDeg) using continuous glucose monitoring (CGM). METHODS: Thirteen patients with T1D were randomly assigned to receive IDeg once-daily followed by IGla twice-daily or vice versa. They were evaluated for glucose variability by CGM after >4weeks of treatment with either insulin, and then were crossed over to the other, and evaluated by CGM after >4weeks. RESULTS: The total daily insulin dose (TDD) (U/kg/day) and the total daily basal insulin dose (U/kg/day) in the patients were significantly lower while taking IDeg than while taking IGla (mean [95% confidence interval] 0.72 [0.61-0.83] vs. 0.76 [0.64-0.88]; P=0.001, 0.29 [0.22-0.36] vs. 0.33 [0.26-0.40]; P=0.001), although no significant difference was noted in the patients while on IDeg versus while on IGla in 24-h mean glucose and SDs of 24-h glucose. Again, the range of postprandial glucose increase was not significantly different between the meals in the patients while taking IDeg (P=0.288) but significantly different in the patients while taking IGla (P=0.033). CONCLUSIONS: The use of once-daily IDeg leads not only to similar glycemic control to that seen with twice-daily IGla even in those who received IGla prior to the study, but also to significant decreases in TDD and long-acting basal insulin dose.

The relationship between HbA1c values and the occurrence of hypoglycemia as assessed by continuous glucose monitoring in patients with type 1 diabetes.

BACKGROUND: We aimed to examine the relationship between the occurrence of hypo-/hyperglycemia and HbA1c values, as assessed by continuous glucose monitoring (CGM) in patients with type 1 diabetes. METHODS: The study subjects comprised 101 type 1 diabetic patients on basal-bolus insulin therapy, who were put on masked CGM immediately after admission. The subjects were divided into four groups equally by HbA1c values and the 24-h CGM data were compared among the groups. RESULTS: Groups A to D comprised 24 patients with HbA1c ≤7.2 %, 26 patients with 7.2 % 9.2 %, respectively. The higher the HbA1c values, the significantly higher the 24-h mean glucose levels [median (25-75 percentiles)], with the HbA1c in groups A to D being 133 (114-155), 158 (132-188), 182 (152-206), and 186 (143-215) mg/dL, respectively (P < 0.001). Conversely, the higher the HbA1c values, the significantly shorter the time in hypoglycemia (<70 mg/dL), with the time in groups A to D being 170 (58-341), 78 (0-210), 45 (0-105), and 20 (0-105) min, respectively (P = 0.014); and the higher the HbA1c values, the significantly shorter the time in nocturnal hypoglycemia, with the time in groups A to D being 120 (5-269), 25 (0-120), 0 (0-60), and 0 (0-89) min, respectively (P = 0.019). No significant difference was seen between groups A to D in the standard deviations (SDs) of 24-h glucose values at 53 (40-65), 54 (45-70), 64 (55-76), and 58 (48-80), respectively. CONCLUSION: In type 1 diabetic patients, lower HbA1c was not associated with lower SD of 24-h glucose values, but may result in increased hypoglycemia. Trial Registration Current controlled trials UMIN000019190.

Can Fasting Glucose Levels or Post-Breakfast Glucose Fluctuations Predict the Occurrence of Nocturnal Asymptomatic Hypoglycemia in Type 1 Diabetic Patients Receiving Basal-Bolus Insulin Therapy with Long-Acting Insulin?

OBJECTIVE: To investigate whether the occurrence of nocturnal asymptomatic hypoglycemia may be predicted based on fasting glucose levels and post-breakfast glucose fluctuations. PATIENTS AND METHODS: The study subjects comprised type 1 diabetic patients who underwent CGM assessments and received basal-bolus insulin therapy with long-acting insulin. The subjects were evaluated for I) fasting glucose levels and II) the range of post-breakfast glucose elevation (from fasting glucose levels to postprandial 1- and 2-hour glucose levels). The patients were divided into those with asymptomatic hypoglycemia during nighttime and those without for comparison. Optimal cut-off values were also determined for relevant parameters that could predict nighttime hypoglycemia by using ROC analysis. RESULTS: 64 patients (mean HbA1c 8.7 ± 1.8%) were available for analysis. Nocturnal asymptomatic hypoglycemia occurred in 23 patients (35.9%). Fasting glucose levels (I) were significantly lower in those with hypoglycemia than those without (118 ± 35 mg/dL vs. 179 ± 65 mg/dL; P < 0.001). The range of post-breakfast glucose elevation (II) was significantly greater in those with hypoglycemia than in those without (postprandial 1-h, P = 0.003; postprandial 2-h, P = 0.005). The cut-off values determined for relevant factors were as follows: (I) fasting glucose level < 135 mg/dL (sensitivity 0.73/specificity 0.83/AUC 0.79, P < 0.001); and (II) 1-h postprandial elevation > 54 mg/dL (0.65/0.61/0.71, P = 0.006), 2-h postprandial elevation > 78 mg/dL (0.65/0.73/0.71, P = 0.005). CONCLUSIONS: Nocturnal asymptomatic hypoglycemia was associated with increases in post-breakfast glucose levels in type 1 diabetes. Study findings also suggest that fasting glucose levels and the range of post-breakfast glucose elevation could help predict the occurrence of nocturnal asymptomatic hypoglycemia.

Comparing postprandial efficacy in type 2 diabetic patients receiving mitiglinide and sitagliptin by using continuous glucose monitoring: a pilot study.

OBJECTIVE: To compare postprandial efficacy in type 2 diabetic patients given mitiglinide and sitagliptin, both of which are known to improve postprandial hyperglycemia, by using continuous glucose monitoring (CGM). METHODS: Eleven patients with type 2 diabetes were given mitiglinide 10 mg three times a daily or sitagliptin 50 mg once a day for 1 month and were hospitalized for 4 days and evaluated by CGM. On discharge, they were crossed over to the other regimen for 1 month of treatment/4 days of evaluation. The CGM data were used to compare each parameter for glycemic variability. RESULTS: The patients were 60 ± 10 (mean ± SD) years old, and had HbA1c value 7.3 ± 0.9%. The pre-meal glucose levels before lunch were significantly lower with mitiglinide than with sitagliptin (116 ± 26/131 ± 34 mg/dl, p = 0.022). The AUC measuring over 140 mg/dl 3 h after breakfast (mitiglinide 4812 ± 4219/sitagliptin 7807 ± 6391 mg/dl·min, p = 0.042) and lunch (mitiglinide 5658 ± 5856/sitagliptin 8492 ± 7161, p = 0.050) was significantly lower with mitiglinide than with sitagliptin. CONCLUSIONS: A CGM-based comparison showed that mitiglinide and sitagliptin were different in their glucose-lowering effects, where mitiglinide significantly improved hyperglycemia after breakfast and lunch, and significantly lowered pre-meal glucose levels before lunch, compared to sitagliptin.

24-hour glycemic variations in drug-naïve patients with type 2 diabetes: a continuous glucose monitoring (CGM)-based study.

OBJECTIVE: To investigate a 24-hour glycemic variation in drug-naïve, type 2 diabetic patients by using CGM. METHODS: A total of 30 inpatients with type 2 diabetes were included in the study to analyze the 24-hour CGM data. RESULTS: The patients' median age was 58 years old (interquartile range: 42-66 years), and their median HbA1c value was 7.6 (6.7-8.8)%. The median time to postprandial peak glucose levels(Peak Time) for each meal was 70-85 minutes, with the range of postprandial glucose increases(Increase Range) for each meal being 83-109 mg/dL. There was a significant positive correlation between the HbA1c values and Increases Range, Peak Time observed after breakfast and dinner, respectively. When the patients were stratified by a median HbA1c value of 7.6% into 2 groups, Increases Range and Peak Time, after breakfast, were shown to be significantly higher in the high-HbA1c group (H) than in the low-HbA1c (L) group. When the subjects were divided into four groups according to HbA1c levels:1 (<7.0%, n = 8), 2 (7.0-7.9%, n = 8), 3 (8.0-8.9%, n = 8), and 4 (≥9%, n = 6), the average glucose level, pre-meal glucose level and postprandial peak glucose level increased steadily from group 1 to 4 in a stepwise manner. CONCLUSIONS: In drug-naïve, Japanese type 2 diabetic patients, the Peak Time and the Increase Range were maximal after dinner. It was shown that the greater the HbA1c values, the longer Peak time and the higher Increase Range after breakfast and dinner. The average glucose level, pre meal glucose level and postprandial peak glucose level increased steadily as HbA1c level increased.

Comparison of glycemic variability in patients with type 2 diabetes given sitagliptin or voglibose: a continuous glucose monitoring-based pilot study.

OBJECTIVE: This study compared glycemic variability in patients with type 2 diabetes given sitagliptin or voglibose. PATIENTS AND METHODS: Seventeen type 2 diabetes patients were given sitagliptin 50 mg/day or voglibose 0.9 mg/day for 2 months and were hospitalized for a 4-day evaluation by continuous glucose monitoring (CGM). On discharge, they were crossed over to the other regimen for 2 months of treatment/4 days of evaluation. The CGM data were used to compare each parameter for glycemic variability. RESULTS: The average glucose levels with sitagliptin and voglibose were significantly different at 138.6 and 152.6 mg/dL for 24 h (P=0.014) and 147.2 and 160.9 mg/dL for during daytime (P=0.050), respectively. The patients' glucose levels with sitagliptin and voglibose were significantly different at 125.3 and 139.7 mg/dL before breakfast (P=0.015) and 112.7 and 131.4 mg/dL before lunch (P=0.049), respectively. The time from before meal to postprandial peak glucose levels was significantly longer after dinner with voglibose than with sitagliptin (91.5 and 122.3 min, respectively; P=0.012). All of the slopes of glucose elevation were significantly lower with voglibose after each meal, with that after breakfast, lunch, and dinner being 1.16 and 0.86 mg/dL/min (P=0.031), 0.70 and 0.45 mg/dL/min (P=0.048), and 1.06 and 0.73 mg/dL/min (P=0.028), respectively. CONCLUSIONS: This CGM-based pilot study revealed that sitagliptin significantly lowered 24-h and daytime mean glucose levels and glucose levels before breakfast and lunch compared with voglibose, whereas the time from before dinner to peak postprandial glucose levels was significantly longer, and the slope of postprandial elevation of glucose level was significantly lower after each meal, with voglibose compared with sitagliptin.

Comparison of vildagliptin twice daily vs. sitagliptin once daily using continuous glucose monitoring (CGM): crossover pilot study (J-VICTORIA study).

BACKGROUND: No previous studies have compared the DPP-4 inhibitors vildagliptin and sitagliptin in terms of blood glucose levels using continuous glucose monitoring (CGM) and cardiovascular parameters. METHODS: Twenty patients with type 2 diabetes mellitus were randomly allocated to groups who received vildagliptin then sitagliptin, or vice versa. Patients were hospitalized at 1 month after starting each drug, and CGM was used to determine: 1) mean (± standard deviation) 24-hour blood glucose level, 2) mean amplitude of glycemic excursions (MAGE), 3) fasting blood glucose level, 4) highest postprandial blood glucose level and time, 5) increase in blood glucose level after each meal, 6) area under the curve (AUC) for blood glucose level ≥180 mg/dL within 3 hours after each meal, and 7) area over the curve (AOC) for daily blood glucose level <70 mg/dL. Plasma glycosylated hemoglobin (HbA1c), glycoalbumin (GA), 1,5-anhydroglucitol (1,5AG), immunoreactive insulin (IRI), C-peptide immunoreactivity (CPR), brain natriuretic peptide (BNP), and plasminogen activator inhibitor-1 (PAI-1) levels, and urinary CPR levels, were measured. RESULTS: The mean 24-hour blood glucose level was significantly lower in patients taking vildagliptin than sitagliptin (142.1 ± 35.5 vs. 153.2 ± 37.0 mg/dL; p = 0.012). In patients taking vildagliptin, MAGE was significantly lower (110.5 ± 33.5 vs. 129.4 ± 45.1 mg/dL; p = 0.040), the highest blood glucose level after supper was significantly lower (206.1 ± 40.2 vs. 223.2 ± 43.5 mg/dL; p = 0.015), the AUC (≥180 mg/dL) within 3 h was significantly lower after breakfast (484.3 vs. 897.9 mg/min/dL; p = 0.025), and urinary CPR level was significantly higher (97.0 ± 41.6 vs. 85.2 ± 39.9 µg/day; p = 0.008) than in patients taking sitagliptin. There were no significant differences in plasma HbA1c, GA, 1,5AG, IRI, CPR, BNP, or PAI-1 levels between patients taking vildagliptin and sitagliptin. CONCLUSIONS: CGM showed that mean 24-h blood glucose, MAGE, highest blood glucose level after supper, and hyperglycemia after breakfast were significantly lower in patients with type 2 diabetes mellitus taking vildagliptin than those taking sitagliptin. There were no significant differences in BNP and PAI-1 levels between patients taking vildagliptin and sitagliptin. TRIAL REGISTRATION: UMIN000007687.