Postprandial serum C-peptide is a useful parameter in the prediction of successful switching to liraglutide monotherapy from complex insulin therapy in Japanese patients with type 2 diabetes

AimsLiraglutide improves glycemic control in patients with type 2 diabetes. However, no information is available about an indicator of successful switching to liraglutide monotherapy from complex insulin therapy in Japanese patients with type 2 diabetes.MethodsWe studied 69 patients with type 2 diabetes, including 39 consecutive successful patients and 30 consecutive unsuccessful patients from insulin therapy to liraglutide monotherapy. Before switching, we measured urinary C-peptide, fasting C-peptide and postprandial C-peptide at 30, 60 and 120 min loading a test meal. In successful patients, HbA_1c and body weight were measured at 4, 8, and 12 weeks after switching.ResultsUsing univariate analysis, duration of disease was significantly higher in unsuccessful patients than in successful patients. Urinary C-peptide, fasting C-peptide, and postprandial C-peptides were significantly higher in successful patients than in unsuccessful patients. Multiple logistic regression analysis showed that postprandial C-peptide at 60 min was an independent predictor of successful switching to liraglutide monotherapy from insulin therapy (odds ratio, 7.28; 95% confidence interval, 2.89–18.36). In the receiver operating characteristic analyses, 2.9 ng/mL of postprandial C-peptide at 60 min was the best cut-off value, providing that sensitivity and specificity were 95% and 93%, respectively. In the follow-up period, successful patients showed a sustained reduction in HbA_1c and body weight without hypoglycemia.ConclusionsPostprandial C-peptide at 60 min is a useful parameter in the prediction of successful switching from insulin therapy to liraglutide monotherapy in Japanese patients with type 2 diabetes.     

Efficacy and safety of adding liraglutide to existing insulin regimens in Japanese patients with type 2 diabetes mellitus: A post‐hoc analysis of a phase 3 randomized clinical trial

Aims/Introduction

To determine the efficacy and safety of adding liraglutide to three different insulin regimens in Japanese patients with type 2 diabetes mellitus.

Materials and Methods

In this post‐hoc analysis, results from a 36‐week, randomized, double‐blind, placebo‐controlled, parallel‐group trial are reported. Individuals with type 2 diabetes mellitus were stratified according to their pre‐trial insulin regimen (basal, basal–bolus and premix). The primary objective was to determine whether adding liraglutide (0.9 mg/day) to fixed‐dose insulin therapy was superior vs fixed‐dose insulin monotherapy, assessed by the effect on glycemic control after 16 weeks of treatment.

Results

The treatment effect on glycated hemoglobin reduction was independent of the pre‐trial insulin regimen. Comparing liraglutide with a placebo, liraglutide was associated with glycated hemoglobin reduction in all insulin regimens, with placebo‐corrected reductions at 16 weeks ranging from ?1.45 to ?1.17%, and maintained at 36 weeks. Liraglutide resulted in a greater reduction in mean plasma glucose obtained from seven‐point self‐monitoring, and greater proportions of patients achieved target glycated hemoglobin. With liraglutide, slightly higher proportions of patients receiving basal and basal–bolus insulin reported confirmed hypoglycemia from 0 to 16 weeks.

Conclusions

The efficacy and safety of adding liraglutide to insulin therapy was confirmed, regardless of pre‐trial insulin regimen.

     

Defining criteria for the introduction of liraglutide using the glucagon stimulation test in patients with type 2 diabetes

Aims/Introduction

To define a set of criteria using indices of β‐cell function, including results from the glucagon stimulation test, for liraglutide introduction in patients with type 2 diabetes.

Materials and Methods

In the present retrospective cohort study, patients were included in our analysis if their β‐cell function had been evaluated with a glucagon stimulation test and a 24‐h urinary C‐peptide (U‐CPR) excretion test before switching from insulin therapy to liraglutide monotherapy. The efficacy of liraglutide was determined by the extent to which glycemic control was achieved or if glycated hemoglobin levels were maintained at <7.0% after liraglutide monotherapy for 24 weeks.

Results

Liraglutide was effective in 36 of 77 patients. In the liraglutide‐effective cases, the following parameters were higher: fasting C‐peptide (CPR0) levels, C‐peptide levels 6 min after glucagon stimulation (CPR6), the C‐peptide index (CPI; CPR0 × 100/fasting plasma glucose) and stimulated C‐peptide index (S‐CPI; CPR6 × 100/plasma glucose 6 min after glucagon stimulation). U‐CPR did not differ between liraglutide‐effective and liraglutide‐ineffective cases. Using receiver operating characteristic analysis adjusted for baseline characteristics, the independent cut‐off value for effective liraglutide introduction was 0.72 for CPI and 1.92 for S‐CPI.

Conclusions

Evaluation of β‐cell function using the glucagon stimulation test is useful for determining the efficacy of liraglutide introduction in patients with type 2 diabetes.     

Efficacy of liraglutide therapy in Japanese type 2 diabetic patients insufficiently controlled with basal‐supported oral therapy

(J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00223.x, 2012) Aims/Introduction: We assessed the efficacy of liraglutide therapy in Japanese type 2 diabetic patients insufficiently controlled with basal‐supported oral therapy (BOT). Materials and Methods: We retrospectively analyzed the data of 37 patients who had postprandial hyperglycemia (≥10.0 mmol/L) with BOT (long‐acting insulin plus glimepiride) with their insulin titrated enough to keep preprandial glycemia <7.2 mmol/L, and who had their treatment changed to liraglutide monotherapy, with the subsequent addition of glimepiride, when required. Those who achieved the glycemic target at all points (preprandial glycemia <7.2 mmol/L and postprandial glycemia <10.0 mmol/L) were regarded as responders and the efficacy of liraglutide therapy was assessed. We also explored the predictive clinical characteristics associated with its efficacy. Results: Daily doses of insulin and glimepiride with BOT were 14 ± 9 units and 1.5 ± 0.9 mg, respectively. After the change to liraglutide therapy, 37% of the patients appeared to be responders to the therapy, whereas 12% had their glycemic control rather deteriorated. Efficacy of liraglutide therapy was significantly associated with baseline insulin dosage and post‐breakfast glycemia with BOT. The C‐statistic of the model was calculated to be 0.90. Conclusions: There were responders and non‐responders to liraglutide therapy in Japanese BOT failures. It is likely that baseline insulin dosage and post‐breakfast glycemia with BOT are clinically useful indicators for the efficacy of liraglutide therapy.     

Effect of renal impairment on cognitive function during a 3‐year follow up in elderly patients with type 2 diabetes: Association with microinflammation

Aims/Introduction

We investigated the effect of renal impairment on cognitive function during a 3‐year follow up in elderly type 2 diabetic patients, and an association with microinflammation.

Materials and Methods

Four cognitive function tests – Mini‐Mental State Examination (MMSE), word recall, Digit Symbol Substitution (DSS) and Stroop Color Word – were carried out in 67 patients. Renal impairment was defined as the presence of albuminuria and a decline in estimated glomerular filtration (eGFR) <60 mL/min/1.73 m². Inflammatory markers, such as highly sensitive C‐reactive protein (hs‐CRP), tumor necrotizing factor‐α (TNF‐α), interleukin (IL)‐1β and IL‐6, were measured at baseline.

Results

At baseline, cognitive decline was found in patients with renal impairment. The DSS test was independently associated with eGFR decline, whereas MMSE tended to be associated with albuminuria after adjusting for confounding factors. Regarding changes in cognitive function and renal impairment, changes in urinary albumin to creatinine ratios were strongly and independently associated with changes in word recall scores. In patients with persistent eGFR decline, there was a tendency toward a greater decrease in MMSE and DSS scores, whereas in those with newly detected albuminuria, there was a tendency toward a greater decrease in word recall scores. Increased baseline levels of hs‐CRP, TNF‐α and IL‐6 were associated with renal impairment and cognitive function, especially DSS tests, respectively. However, the increased levels were not independent predictors for cognitive decline.

Conclusions

The present study showed a reciprocal relationship between cognitive decline and renal impairment, especially progression of albuminuria. Thus, monitoring treatment using renal biomarkers will be important for preserving both renal and cognitive function.     

The once‐daily human glucagon‐like peptide‐1 analog,liraglutide, improves β‐cell function in Japanese patients with type 2 diabetes

Aims/Introduction: β‐cell function was evaluated by homeostasis model assessment of β‐cell function (HOMA‐B) index, proinsulin:insulin and proinsulin:C‐peptide ratios in adult, Japanese type 2 diabetes patients receiving liraglutide. Materials and Methods: Data from two randomized, controlled clinical trials (A and B) including 664 Japanese type 2 diabetes patients (mean values: glycated hemoglobin [HbA_1c] 8.61–9.32%; body mass index [BMI] 24.4–25.3 kg/m²) were analyzed. In two 24‐week trials, patients received liraglutide 0.9 mg (n = 268) or glibenclamide 2.5 mg (n = 132; trial A), or liraglutide 0.6, 0.9 mg (n = 176) or placebo (n = 88) added to previous sulfonylurea therapy (trial B). Results: Liraglutide was associated with improved glycemic control vs sulfonylurea monotherapy or placebo. In liraglutide‐treated groups in trials A and B, area under the curve (AUC) _{insulin 0–3 h} was improved (P < 0.001 for all) and the AUC_{insulin 0–3 h}:AUC_{glucose 0–3 h} ratio was increased (estimated treatment difference [liraglutide–comparator] 0.058 [0.036, 0.079]). HOMA‐B significantly increased with liraglutide relative to comparator in trial B (P < 0.05), but not in trial A. The reduction in fasting proinsulin:insulin ratio was 50% greater than in comparator groups. Conclusions: In Japanese type 2 diabetes patients, liraglutide was associated with effective glycemic control, restoration of prandial insulin response and indications of improved β‐cell function. This trial was registered with Clinicaltrials.gov (trial A: no. NCT00393718/JapicCTI‐060328 and trial B: no. NCT00395746/JapicCTI‐060324). (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00193.x, 2012)     

Accuracy of flash glucose monitoring in insulin‐treated patients with type 2 diabetes

The present study evaluated the accuracy of interstitial glucose measurements by flash glucose monitoring (FGM) and continuous glucose monitoring (CGM). Five diabetes patients simultaneously underwent FGM (FreeStyle Libre Pro) and CGM (iPro?2), and their glucose levels were compared with venous blood and capillary blood glucose levels. The range of daily venous blood glucose levels (30 measurements) was 70–245 mg/dL, with a median of 138 mg/dL. There were good correlations of glucose levels measured by FGM (r² = 0.90, mean absolute relative difference 8.2 ± 5.6%), CGM (r² = 0.86, mean absolute relative difference 9.2 ± 9.1%) and capillary blood (r² = 0.87, mean absolute relative difference 7.2 ± 7.2%) with venous blood glucose levels. The accuracy of FGM measurements was also shown against CGM, with 99.9% of the FGM values (1,279 measurements) being within the Parkes error grid zones A and B. The results suggest that the accuracy of FGM is similar to that of CGM, and that FGM is a useful tool for determining daily glucose profile.     

Glucagon‐like peptide‐1 analog liraglutide in combination with sulfonylurea safely improves blood glucose measures vs sulfonylurea monotherapy in Japanese patients with type 2 diabetes: Results of a 52‐week,randomized, multicenter trial

Aims/Introduction:  Sulfonylurea (SU) agents are the most effective drugs at lowering blood glucose when used alone. However, their effectiveness declines after a certain period. The addition of liraglutide to existing SU therapy might reverse some of the known drawbacks of SU.Materials and Methods:  This multicenter, randomized, 52‐week study assessed the long‐term efficacy and safety of adding liraglutide at 0.6 or 0.9 mg/day to existing SU therapy in Japanese patients with inadequately controlled type 2 diabetes.Results:  In total, 264 patients were enrolled and received treatment. At week 52, HbA_1c in the liraglutide 0.6 mg, liraglutide 0.9 mg and placebo groups was reduced from 9.00 to 7.91%, from 8.61 to 7.33%, and from 8.85 to 8.79%, respectively. The mean difference of HbA_1c (95% CI) in the liraglutide 0.6 and 0.9 mg groups vs the placebo group was 0.96 (−1.25 to −0.67) and −1.33 (−1.62 to −1.04), respectively. For the liraglutide 0.6 mg, 0.9 mg and placebo groups, the Japanese Diabetes Society target HbA_1c of <6.9% was achieved by 15.1, 39.1 and 4.5% of patients, respectively. Mean fasting plasma glucose at week 52 was lower in the liraglutide groups compared with the placebo group, and mean bodyweight remained unchanged in the liraglutide groups. Most subjects in all three treatment groups reported mild adverse events. No major hypoglycemic episode was reported.Conclusions:  Once‐daily administration of liraglutide in combination with SU for 52 weeks provided favorable metabolic control, a safety profile and did not alter bodyweight. This trial was registered with ClinicalTrial.gov (no. {"type":"clinical-trial","attrs":{"text":"NCT00395746","term_id":"NCT00395746"}}NCT00395746). (J Diabetes Invest,doi: 10.1111/j.2040‐1124.2011.00103.x, 2011)     

Impact of primary aldosteronism on renal function in patients with type 2 diabetes

Aims/IntroductionRenal dysfunction might quickly progress in patients with type 2 diabetes mellitus, when accompanied by hypertension. However, whether primary aldosteronism (PA), which autonomously over‐secretes aldosterone, causes additional renal damage in patients with type 2 diabetes mellitus is unclear. We evaluated the impact of PA on renal function in patients with type 2 diabetes mellitus.Materials and MethodsA retrospective review of all patients with type 2 diabetes mellitus who visited Yokohama Rosai Hospital’s (Yokohama Japan) outpatient department between April 2017 and March 2018 was carried out. Records of patients with PA who underwent PA treatment by adrenalectomy or mineralocorticoid receptor antagonists (PA group) and those without PA (non‐PA group) were extracted, and renal function was compared between the two groups. Untreated PA patients were excluded, as their renal function might be overestimated as a result of glomerular hyperfiltration.ResultsThere were 83 patients in the PA group and 1,580 patients in the non‐PA group. The PA group had significantly lower estimated glomerular filtration rates than the non‐PA group (66.3 [52.4–78.2] vs 70.5 [56.0–85.6] mL/min/1.73 m², P = 0.047). Multiple regression analysis showed that PA was a factor for decreased estimated glomerular filtration rate, independent of age, sex, glycated hemoglobin, diuretic use and hypertension (P = 0.025). PA induced a 3.7‐mL/min/1.73 m² (95% confidence interval 0.47–6.9) decrease in estimated glomerular filtration rate, equivalent to that induced by 4.4 years of aging.ConclusionsOur results show that in patients with type 2 diabetes mellitus, PA is an independent risk factor for renal dysfunction. To prevent the progression of renal failure, PA should not be overlooked.     

Utility of indices using C‐peptide levels for indication of insulin therapy to achieve good glycemic control in Japanese patients with type 2 diabetes

Aims/Introduction: Type 2 diabetes is progressive in that therapy must be altered over time, which is partly as a result of the progressive loss of pancreatic β‐cell function. To elucidate the relationship between residual endogenous insulin secretion and the necessity of insulin therapy to achieve good glycemic control, indices using serum C‐peptide immunoreactivity (CPR) were analyzed in patients with type 2 diabetes. Materials and Methods: The data of 201 Japanese patients with type 2 diabetes who achieved the target of glycemic control during admission were analyzed retrospectively. Indices using CPR including fasting CPR (FCPR), CPR 6 min after intravenous injection of glucagon (CPR‐6 min), increment of CPR (ΔCPR), secretory unit of islet in transplantation index (SUIT) and C‐peptide index (CPI) were compared between the group requiring insulin (insulin group) and the group not requiring insulin (non‐insulin group). A receiver–operator characteristic (ROC) curve was made, and optimal cut‐off point and likelihood ratio were determined for each index. Results: All indices of CPR were lower in the insulin group compared with those in the non‐insulin group. Likelihood ratios at the optimal point of FCPR, CPR‐6 min, ΔCPR, SUIT, and CPI were 2.0, 2.1, 1.6, 2.3 and 2.8, respectively. Optimal cut‐off point of CPI was 1.1 ng/mg. Sensitivity and specificity at optimal point of CPI were 61 and 78%, respectively. Conclusions: The advantage of CPI of the indices of CPR to select insulin therapy to achieve good glycemic control was shown, but limitations of the predictive abilities of the indices using CPR should be taken into account. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00096.x, 2011)     

Renal threshold for glucose reabsorption predicts diabetes improvement by sodium‐glucose cotransporter 2 inhibitor therapy

In the present study we examined the efficacy of sodium‐glucose cotransporter 2 inhibitors on improvement of glycated hemoglobin (HbA1c) in comparison with the renal threshold for glucose reabsorption in patients with type 2 diabetes mellitus. Patients visited the hospital once a month for a regular follow‐up examination with the determination of blood glucose and HbA1c levels, and urinary glucose concentration from spot urine samples. Patient samples were compared before and after ipragliflozin administration. We defined the renal threshold for glucose reabsorption as the lowest blood glucose level that correlated with the first detectable appearance of urine glucose. These data showed a significant negative correlation between improvement of HbA1c level and renal threshold for glucose reabsorption in patients treated with the sodium‐glucose cotransporter 2 inhibitor. These findings show that patients who have a higher renal threshold for glucose reabsorption can be expected to more effectively respond to sodium‐glucose cotransporter 2 inhibitor therapy in terms of lowering HbA1c levels.