Cytokeratin-18 and enhanced liver fibrosis scores in type 1 and type 2 diabetes and effects of two different insulins.

Data on cytokeratin-18 (K-18) and enhanced liver fibrosis (ELF) score in insulin-treated diabetes patients with non-alcoholic fatty liver disease (NAFLD) are limited. This study analyzed phase III data comparing basal insulin peglispro (BIL) and insulin glargine in type 1 (T1D), and type 2 diabetes (T2D) (insulin-naïve and insulin-treated). Alanine aminotransferase (ALT), K-18, ELF scores and liver fat content (LFC), measured by MRI, were obtained longitudinally. Baseline K-18 (U/L) was higher in T2D (range: 207‒247) than T1D (range: 148‒183), correlated with ALT in all populations (r (range) 0.264‒0.637, p<0.05), but with LFC only in T2D (r (range) 0.474‒0.586, p<0.05). K-18 increased significantly from baseline in BIL-treated, but not glargine-treated patients. Change from baseline (CFB) K-18 was significantly correlated with CFB in ALT in BIL-treated T2D populations. Baseline ELF scores were higher in T2D (range: 9.12‒9.20) than T1D (range: 8.24‒8.36), correlated with ALT in T1D only (0.209, p<0.05), and not correlated with LFC in any population. ELF scores increased significantly from baseline in BIL-treated but not glargine-treated patients. There were no correlations between CFB in LFC and ELF score at week 52 in any treatment group/population. In all BIL-treated populations, CFB in ALT and CFB in ELF score at week 52 were positively correlated. These data characterize associations of K-18 and ELF score with ALT and LFC in insulin-treated patients with T1D and T2D. Hepatopreferential insulins may be associated with increased K-18 and ELF scores but mechanisms and clinical significance are unknown. ClinicalTrials.gov identifiers are NCT01481779, NCT01435616, NCT01454284 and NCT01582451.

The Sustained Effects of a Dual GIP/GLP-1 Receptor Agonist, NNC0090-2746, in Patients with Type 2 Diabetes.

Unimolecular dual incretins derived from hybridized glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) sequences have demonstrated synergistic reduction of adiposity in animal models and reductions of hyperglycemia in short-duration human trials. Here, we extend the characterization of NNC0090-2746 (also known as RG7697), a fatty-acylated dual agonist possessing in vitro balanced GIPR and GLP-1R agonism. In this 12-week, randomized, placebo-controlled, double-blind phase 2a trial, patients with type 2 diabetes inadequately controlled with metformin received 1.8 mg of NNC0090-2746 or placebo subcutaneously once daily. Liraglutide 1.8 mg (Victoza), starting with 2-week dose escalation, was administered subcutaneously once daily as an open-label reference arm. Measurements were collected at regular intervals after randomization. NNC0090-2746 significantly improved glycemic control and reduced body weight compared with placebo. Total cholesterol, alone among a range of lipid parameters, and leptin were both significantly reduced compared with placebo. Treatment with NNC0090-2746 was generally safe and well tolerated.

Lipid changes during basal insulin peglispro, insulin glargine, or NPH treatment in six IMAGINE trials.

Basal insulin peglispro (BIL) is a novel basal insulin with hepato-preferential action resulting from reduced peripheral effects. This report provides an integrated summary of lipid changes at 26 weeks with BIL and comparator insulins (glargine, NPH) from phase III studies in type 1 diabetes (T1D), insulin-naïve patients with type 2 diabetes (T2D), patients with T2D on basal insulin only and patients with T2D on basal-bolus therapy. BIL treatment had little effect on HDL cholesterol and LDL cholesterol in all patients. The effect of both BIL and glargine treatment on triglycerides (TG) depended on whether patients had been previously treated with insulin. When BIL replaced conventional insulin glargine or NPH treatments, increases in TG levels were observed. When BIL or comparator insulins were given for 26 weeks to insulin-naïve patients with T2D, TG levels were unchanged from baseline with BIL but decreased with either glargine or NPH. The decreased peripheral action of BIL may reduce suppression of lipolysis in peripheral adipose tissue resulting in increased free fatty acid delivery to the liver and, hence, increased hepatic TG synthesis and secretion.

Reduced nocturnal hypoglycaemia with basal insulin peglispro compared with insulin glargine: pooled analyses of five randomized controlled trials.

Basal insulin peglispro (BIL) is a novel basal insulin with hepato-preferential action, resulting from reduced peripheral effects. This report summarizes hypoglycaemia data from five BIL phase III studies with insulin glargine as the comparator, including three double-blind trials. Prespecified pooled analyses (n = 4927) included: patients with type 2 diabetes (T2D) receiving basal insulin only, those with T2D on basal-bolus therapy, and those with type 1 diabetes (T1D). BIL treatment resulted in a 36-45% lower nocturnal hypoglycaemia rate compared with glargine, despite greater reduction in glycated haemoglobin (HbA1c) and higher basal insulin dosing. The total hypoglycaemia rate was similar in patients with T2D on basal treatment only, trended towards being higher (10%) in patients with T2D on basal-bolus treatment (p = .053), and was 15% higher (p < .001) with BIL versus glargine in patients with T1D, with more daytime hypoglycaemia in the T1D and T2D groups who were receiving basal-bolus therapy. In T1D, during the maintenance treatment period (26-52 weeks), the total hypoglycaemia rate was not significantly different. There were no differences in severe hypoglycaemia in the T1D or T2D pooled analyses. BIL versus glargine treatment resulted in greater HbA1c reduction with less nocturnal hypoglycaemia in all patient populations, higher daytime hypoglycaemia with basal-bolus therapy in the T1D and T2D groups, and an associated increase in total hypoglycaemia in the patients with T1D.

Performance of an Electronic Diary System for Intensive Insulin Management in Global Diabetes Clinical Trials.

BACKGROUND: This report describes the performance of a wireless electronic diary (e-diary) system for data collection and enhanced patient-investigator interactions during intensive insulin management in diabetes clinical trials. MATERIALS AND METHODS: We implemented a customized electronic communication system featuring an e-diary and a Web portal in three global, randomized, controlled Phase 3 clinical trials testing basal insulin peglispro compared with insulin glargine, both combined with prandial insulin lispro, in patients with type 1 or type 2 diabetes mellitus (T1DM and T2DM, respectively). We collected data during 28 weeks of study e-diary use for the report. RESULTS: Patients (n=2,938) in 31 countries used e-diaries to transmit 2,439,087 blood glucose (BG) values, 96% of which were associated by the patient with a protocol time point during the 72-h response window. Of 208,192 hypoglycemia events captured, 96% had a BG value, and 95% had treatments and outcomes entered by patients within the 72-h window. Patients recorded administration of 1,964,477 insulin doses; 93% of basal insulin doses were adherent with the investigator prescription. Investigators adjusted 13 basal and 92 bolus insulin prescriptions per patient-year using the e-diary system. After 26 weeks of treatment and e-diary use in the combined study arms, hemoglobin A1c values decreased by 0.6% or 1.6% and fasting BG decreased by 7.8 or 28 mg/dL in patients with T1DM or T2DM, respectively. CONCLUSIONS: The e-diary system enabled comprehensive data collection and facilitated communication between investigators and patients for intensive insulin management in three global clinical trials testing basal insulins.

Lower glucose variability and hypoglycemia measured by continuous glucose monitoring with novel long-acting insulin LY2605541 versus insulin glargine.

OBJECTIVE: To use continuous glucose monitoring (CGM) to evaluate the impact of the novel, long-acting basal insulin analog LY2605541 on hypoglycemia and glycemic variability in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Hypoglycemia and glucose variability were assessed with CGM of interstitial glucose (IG) in a subset of patients with type 2 diabetes from a phase II, randomized, open-label, parallel study of LY2605541 (n = 51) or insulin glargine (GL) (n = 25). CGM was conducted on 3 consecutive days (72-84 h) during the week before week 0, 6, and 12 study visits. RESULTS: Measured by CGM for 3 days prior to the 12-week visit, fewer LY2605541-treated patients experienced hypoglycemic events overall (50.0 vs. 78.3%, P = 0.036) and nocturnally (20.5 vs. 47.8%, P = 0.027) and spent less time with IG ≤70 mg/dL than GL-treated patients during the 24-h (25 ± 6 vs. 83 ± 16 min, P = 0.012) and nocturnal periods (11 ± 5 vs. 38 ± 13 min, P = 0.024). These observations were detected without associated differences in the average duration of individual hypoglycemic episodes (LY2605541 compared with GL 57.2 ± 5.4 vs. 69.9 ± 10.2 min per episode, P = NS). Additionally, LY2605541-treated patients had lower within-day glucose SD for both 24-h and nocturnal periods. CONCLUSIONS: By CGM, LY2605541 treatment compared with GL resulted in fewer patients with hypoglycemic events and less time in the hypoglycemic range and was not associated with protracted hypoglycemia.

Factors that impact symptomatic diabetic peripheral neuropathy in placebo-administered patients from two 1-year clinical trials.

OBJECTIVE: The purpose of this study was to evaluate the change in neuropathy symptoms and disease progression in placebo-administered patients from two 1-year studies in which the impact of ruboxistaurin (RBX) in mild diabetic peripheral neuropathy (DPN) was tested. RESEARCH DESIGN AND METHODS: Data from 262 placebo-administered patients from two identical phase 3, randomized, double-blind trials were combined and analyzed. RESULTS: After 1 year, change in the neuropathy impairment score of lower limbs [NIS(LL)] (-0.63 points; P = 0.005), vibration detection threshold (VDT) (-0.42 just noticeable difference units; P = 0.003), and Neuropathy Total Symptom Score-6 (NTSS-6) questionnaire (-3.73 points; P < 0.001) improved, whereas some electrophysiology measures and heart rate deep breathing (HRDB) (-0.78 beats; P = 0.003) worsened compared with baseline values. There was a small but significant worsening of A1C (0.28%; P < 0.001), and a greater percentage of patients were using analgesics at the end of the trials (33.6%; P = 0.003). At 1 year, the change in NTSS-6 directly correlated with changes in NIS(LL) and VDT and inversely correlated with the peroneal nerve conduction velocity. On logistic regression analyses, a > or = 50% reduction in NTSS-6 score was less likely in patients who used antihypertensive or chronic symptom medication at baseline. CONCLUSIONS: In placebo-administered patients with mild symptomatic DPN, there was a progressive improvement in symptoms over 12 months, whereas nerve conduction studies and HRDB declined, and clinically significant worsening of DPN would require > 1 year of observation.

Challenges in design of multicenter trials: end points assessed longitudinally for change and monotonicity.

OBJECTIVE: Assessing clinimetric performance of diabetic sensorimotor polyneuropathy (DSPN) end points in single and multicenter trials. RESEARCH DESIGN AND METHODS: Assessed were placebo-treated patients with DSPN in the Viatris and Eli Lilly trials and an epidemiologic cohort. RESULTS: Test reproducibility in clinical trial cohorts (r(I) approximately 0.7-0.85) approached that in the epidemiologic cohort (r(I) approximately 0.85-0.95). Associations between pairs of end points explained <10% of the variability of data (sometimes 15-35%), being higher in the epidemiologic cohort and the Viatris trial than in the Lilly trial. Most end points did not show monotonic worsening over 4 years. However, sural nerve amplitude and peroneal motor conduction velocity did. A nerve conduction score (Sigma 5 NC nds [5 attributes of nerve conduction expressed as normal deviates]) did not show monotonic worsening in established DSPN. In the epidemiologic cohort followed for 9.5 years, monotonic worsening of small magnitude occurred for sural amplitude, vibration detection threshold, and especially for composite quantitative sensation. CONCLUSIONS: The main reason why it is difficult to demonstrate monotonic worsening of neuropathic end points appears to be a very slow worsening of DSPN, a placebo effect for symptoms and signs, and measurement noise. Demonstrating disease progression in controlled trials of DSPN is more likely when 1) patients with developing rather than established DSPN are selected, 2) type 1 diabetic patients are preferentially recruited, 3) patients are selected who cannot or will not achieve ideal glycemic control, 4) end points chosen are known to show monotonic worsening, and 5) a restricted number of centers and expert examiners (trained, certified, using standard approaches, and reference values and interactive surveillance of tests) are used.

A 6-month, randomized, double-masked, placebo-controlled study evaluating the effects of the protein kinase C-beta inhibitor ruboxistaurin on skin microvascular blood flow and other measures of diabetic peripheral neuropathy.

OBJECTIVE: Diabetes leads to protein kinase C (PKC)-beta overactivation and microvascular dysfunction, possibly resulting in disordered skin microvascular blood flow (SkBF) and other changes observed in diabetic peripheral neuropathy (DPN) patients. We investigate the effects of the isoform-selective PKC-beta inhibitor ruboxistaurin mesylate on neurovascular function and other measures of DPN. RESEARCH DESIGN AND METHODS: Endothelium-dependent and C fiber-mediated SkBF, sensory symptoms, neurological deficits, nerve fiber morphometry, quantitative sensory and autonomic function testing, nerve conduction studies, quality of life (using the Norfolk Quality-of-Life Questionnaire for Diabetic Neuropathy [QOL-DN]), and adverse events were evaluated for 20 placebo- and 20 ruboxistaurin-treated (32 mg/day) DPN patients (aged > or =18 years; with type 1 or type 2 diabetes and A1C < or =11%) during a randomized, double-masked, single-site, 6-month study. RESULTS: Endothelium-dependent (+78.2%, P < 0.03) and C fiber-mediated (+56.4%, P < 0.03) SkBF at the distal calf increased from baseline to end point. Significant improvements from baseline within the ruboxistaurin group were also observed for the Neuropathy Total Symptom Score-6 (NTSS-6) (3 months -48.3%, P = 0.01; end point -66.0%, P < 0.0006) and the Norfolk QOL-DN symptom subscore and total score (end point -41.2%, P = 0.01, and -41.0, P = 0.04, respectively). Between-group differences in baseline-to-end point change were observed for NTSS-6 total score (placebo -13.1%; ruboxistaurin -66.0%, P < 0.03) and the Norfolk QOL-DN symptom subscore (placebo -4.0%; ruboxistaurin -41.2%, P = 0.041). No significant ruboxistaurin effects were demonstrated for the remaining efficacy measures. Adverse events were consistent with those observed in previous ruboxistaurin studies. CONCLUSIONS: In this cohort of DPN patients, ruboxistaurin enhanced SkBF at the distal calf, reduced sensory symptoms (NTSS-6), improved measures of Norfolk QOL-DN, and was well tolerated.

Diagnosis of diabetic peripheral neuropathy among patients with type 1 and type 2 diabetes in France, Italy, Spain, and the United Kingdom.

AIMS: The objective of this study was to describe the proportion and characteristics of patients with type 1 and type 2 diabetes diagnosed with diabetic peripheral neuropathy (DPN) in France, Italy, Spain, and the United Kingdom (UK). METHODS: A cross-sectional survey was administered to general practitioners and diabetes specialists. Existing physicians' records were used to quantify the frequency of DPN diagnoses, and notes from patients' medical charts were used to characterize symptoms. RESULTS: The average number of physicians per country was 41 (range of 34-49). The proportion of diabetes patients diagnosed with DPN ranged from 9.6% (95% CI, 7.1-12.2) in Spain to 23.1% (95% CI, 15.4-30.7) in Italy. Of 913 DPN study patients, 55.0% were male, and 78.5% had type 2 diabetes. Mean age was 64.5+/-12.5 years. A DPN diagnosis was based primarily on symptoms. Approximately 27% of patients had no documented neurological examination. "Prickling" was the most common DPN symptom recorded in France, Italy, and Spain, and "numbness" was the most common in the UK. CONCLUSIONS: Country-specific estimates of DPN diagnosis may reflect clinical management of diabetes and DPN. A substantial number of diagnoses were not associated with a record of a neurological examination.

Clinical safety of the selective PKC-beta inhibitor, ruboxistaurin.

The aim of this manuscript is to report the safety profile of patients treated with ruboxistaurin mesylate (RBX; LY333531), a selective protein kinase C-beta (PKC-beta) inhibitor, for up to 4 years. Data from patients with diabetes (1396 RBX 32 mg/day; 1408 placebo) were combined from 11 placebo-controlled, double-masked studies. The proportion of patients who reported one or more serious adverse events was greater in the placebo group than in the RBX-treated group (23.2 versus 20.8%, respectively). There were 51 deaths (21 RBX; 30 placebo) reported in this patient cohort; none of the deaths was attributed to study drug by the investigators. Common adverse drug reactions (> or = 1/100 - < 1/10 patients) that were reported in the RBX-treated patients were dyspepsia and increased blood creatine phosphokinase. In controlled, randomised clinical trials, RBX had an adverse event profile comparable to placebo, and was well tolerated.

Treatment of symptomatic diabetic peripheral neuropathy with the protein kinase C beta-inhibitor ruboxistaurin mesylate during a 1-year, randomized, placebo-controlled, double-blind clinical trial.

OBJECTIVE: The aim of this study was to assess the effects of ruboxistaurin (RBX) mesylate on nerve function and sensory symptoms in patients with diabetes mellitus (DM) and diabetic peripheral neuropathy (DPN). METHODS: Patients were enrolled in a multinational, randomized, Phase II, double-blind, placebo-controlled parallel-group trial comparing 32 mg/d or 64 mg/d RBX with placebo for 1 year. DPN was identified by abnormal measurable vibration detection threshold (VDT) and verified by abnormal neurologic examination and nerve electrophysiology measures. Baseline patient characteristics (eg, sex, type of DM, age, body mass index, glycosylated hemoglobin, and duration of DM and DPN) were measured. The primary end point was the change in VDT. Secondary end point measures included effects of RBX versus placebo on Neuropathy Total Symptom Score-6 (NTSS-6), neurologic examination, electrophysiologic nerve conduction studies, Neuropathy Impairment Score, Clinical Global Impressions, and safety. A post-hoc analysis was performed on patients with less severe DPN (sural sensory nerve action potential > or =0.5 microV and NTSS-6 total score >6). RESULTS: Two hundred five patients were assessed: 66 were assigned to the RBX 32 mg/d group, 71 to the RBX 64 mg/d group, and 68 to the placebo group. The demographic and baseline characteristics of the treatment groups were well matched between the RBX 32 mg/d, RBX 64 mg/d, and placebo groups: mean (SD) age, 45.6 (8.41) years; 122 (60%) men, 83 (40%) women; 110 (54%) with type 1 DM, 95 (46%) with type 2 DM; mean (SD) duration of DPN, 3.4 (4.21) years. The RBX 32 mg/d group had slightly more patients with type 1 DM (P = 0.05). Eighty-three patients had clinically significant symptoms at baseline (defined as NTSS-6 total score >6: RBX 32 mg/d, n = 22; RBX 64 mg/d, n = 26; placebo, n = 35); 122 patients had NTSS-6 total scores < or =6. No treatment differences were observed for change in VDT. Among the 83 patients with significant symptoms at baseline, there was a reduction from baseline at 12 months in the NTSS-6 total score in the RBX 32 mg/d (P = NS) and RBX 64 mg/d (P = 0.015) groups compared with placebo. In a subgroup of patients with clinically significant symptoms and less severe DPN (n = 50), there was a significantly greater reduction in the NTSS-6 total score with RBX 64 mg/d (P = 0.006 vs placebo). Furthermore, in these patients, there was a statistically significant improvement in VDT for both RBX 32 mg/d (P = 0.012) and RBX 64 mg/d (P = 0.026) compared with placebo. CONCLUSIONS: RBX appeared to be well tolerated in the patients with DPN who participated in this study. Overall, changes in VDT and NTSS-6 total scores did not differ among treatment groups at end point. However, RBX treatment appeared to be of benefit for the subgroup of patients with less severe symptomatic DPN by relieving sensory symptoms and improving nerve fiber function, as indicated by reductions in VDT and NTSS-6 total score.

Development and validity testing of the neuropathy total symptom score-6: questionnaire for the study of sensory symptoms of diabetic peripheral neuropathy.

OBJECTIVE: The aim of this study was to develop and validate a neuropathy sensory symptom scale, the Neuropathy Total Symptom Score-6 (NTSS-6), which evaluates individual neuropathy sensory symptoms in patients with diabetes mellitus (DM) and diabetic peripheral neuropathy (DPN) in clinical trials, with the intent of distinguishing a response to therapy. METHODS: The NTSS-6 questionnaire was developed to evaluate the frequency and intensity of individual neuropathy sensory symptoms identified frequently by patients with DPN (ie, numbness and/or insensitivity; prickling and/or tingling sensation; burning sensation; aching pain and/or tightness; sharp, shooting, lancinating pain; and allodynia and/or hyperalgesia). The NTSS-6 was administered 8 times over a 1-year period to DPN patients. The NTSS-6's reliability (determined by internal consistency and test-retest reproducibility), construct validity, convergent validity, and minimally clinically important differences (MCIDs) were determined. RESULTS: The NTSS-6 was administered to a total of 205 patients at 10 centers in the United States, Canada, Belgium, Germany, Hungary, Croatia, Slovenia, and the United Kingdom. Internal consistency was demonstrated at all 8 visits (Cronbach's alpha > 0.7). Test-retest reproducibility (intraclass correlation coefficient >0.9) was observed during the baseline period and at end point. Construct validity was demonstrated by statistically significant correlations between the NTSS-6 total score and the Neuropathy Symptoms and Change (NSC) score (r = 0.773-0.885, P < 0.001). Convergent validity was demonstrated by statistically significant correlations between the change in NTSS-6 total scores and the following: change in NSC scores (r = 0.519-0.708, P < 0.001); change in Neuropathy Impairment Score of the Lower Limbs and composite nerve function scores (r = 0.188-0.202, P < 0.007), and categories of the Clinical Global Impressions (r = 0.402, P < 0.001). The within- and between-groups MCIDs for the total NTSS-6 total scores were -1.26 and 0.97 points, respectively. The mean (SD) within-group MCID for all patients who improved on the Clinical Global Impression was -2.29 (3.4) points. CONCLUSIONS: The NTSS-6 provided a valid assessment of neuropathy sensory symptoms in this sample of patients with DM and DPN, which suggests that it may be useful for symptom evaluation in clinical trials and practice. The NTSS-6 showed internal consistency, test-retest reliability, and construct validity. There was also convergent validity of the scores, indicating that the NTSS-6 may be a suitable questionnaire for clinical trials that evaluate symptoms of DPN in this well-defined patient population.

Sural sensory action potential identifies diabetic peripheral neuropathy responders to therapy.

Identifying patients with diabetic peripheral neuropathy (DPN) amenable to therapy is a challenge. To determine whether the amplitude of the sural sensory nerve action potential (sural SNAP) reflects the severity of DPN, an analysis was performed on 205 patients with DPN, identified by an abnormal vibration detection threshold (VDT), who were enrolled in a multinational clinical trial investigating ruboxistaurin (RBX) mesylate. Nerve conduction velocity and response amplitude and latency were measured and compared. VDT was significantly lower in those with preserved sural SNAPs (n = 128) than in those in whom they were absent (n = 77; 21.5 vs. 22.7 JND units, P = 0.002). Thus, preserved sural SNAP denoted less severe DPN. Logistic regression analyses evaluating baseline characteristics, HbA(1c), and baseline symptom scores identified only DPN duration as a factor that might contribute to the presence of sural SNAP (P = 0.004; OR = 0.896). For patients with abnormal VDT, preserved sural SNAP identifies a patient population with less severe DPN who may respond to therapeutic intervention in clinical trials.