Edward J. Bastyr

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 (rI ∼ 0.7–0.85) approached that in the epidemiologic cohort (rI ∼ 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 (Σ 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.

Corrected Q-T Interval Prolongation as Diagnostic Tool for Assessment of Cardiac Autonomic Neuropathy in Diabetes Mellitus

A simple method for evaluating alterations in cardiac sympathetic innervation may be measurement of the Q-T interval. Seventy-three diabetic patients (46 insulin dependent and 27 non–insulin dependent) were separated into four groups based on the presence and degree of cardiac autonomic neuropathy (CAN) with noninvasive cardiovascular reflexes and blood pressure responses. None of the patients had evidence of ischemic heart disease, kidney disease, or the idiopathic long Q-T–interval syndrome. The corrected Q-T interval (Q-Tc) was determined at rest with Bazetts formula. As a group, diabetic patients with ≥2 abnormalities of cardiac autonomic function had a longer Q-Tc interval than those with no evidence of CAN. Diabetic patients with ≥1 abnormality had a prolonged Q-Tc interval compared with a control group of 96 healthy nondiabetic subjects (mean ± SD 397 ± 18). The frequency of prolonged (>433 ms, normal mean + 2SD) resting Q-Tc intervals increased with the increasing number of abnormalities (0, 1, 2, ≥ 3): 11, 25, 41, and 75%, respectively. Twenty-three of 25 (92%) patients with a Q-Tc >433 ms had evidence of CAN. However, 57% (31 of 54) of the patients with CAN had a normal Q-Tc interval. These data provide further evidence of a relationship between the presence and severity of CAN and degree of Q-Tc interval prolongation. Compared with cardiovascular reflexes and blood pressure tests for CAN, the Q-Tc interval in the group of diabetic patients studied without evidence of heart or kidney disease was an insensitive but specific marker. An abnormal Q-Tc interval may be an additional diagnostic tool for evaluating CAN in patients with diabetes mellitus.

Insulin lispro in the treatment of patients with type 2 diabetes mellitus after oral agent failure

This study assessed the safety profile and efficacy of a new combination therapy (insulin lispro plus sulfonylurea) in patients with type 2 diabetes mellitus experiencing secondary oral agent failure. A total of 423 patients were randomly assigned to 3 treatment groups: preprandial insulin lispro plus sulfonylurea (L + S), bedtime neutral protamine Hagedorn (NPH) insulin plus sulfonylurea (N + S), and preprandial insulin lispro plus bedtime NPH insulin (L + N). Mean decreases in glycosylated hemoglobin from baseline were 1.60%+/-1.27% for patients receiving L + S, 1.21%+/-1.21% for those receiving N + S, and 1.40%+/-1.46% for those receiving L + N (within treatment, P<0.001; for L + S vs. N + S, P = 0.003). Fasting blood glucose level was higher in patients receiving L + S (171+/-46.5 mg/dL) or L + N (166+/-52.5 mg/dL) than in those receiving N + S (144+/-48.2 mg/dL) (P<0.001, for both comparisons). Conversely, postprandial blood glucose level was lower in patients receiving L + S (165+/-41.6 mg/dL) or L + N (165+/-46.3 mg/dL) than in those receiving N + S (213+/-58.3 mg/dL) (P<0.001, for both comparisons). The overall rate of hypoglycemia (episodes per 30 days) was not statistically significant when the L + S, N + S, and L + N therapies were compared (0.99+/-1.74 vs. 0.87+/-2.31 vs. 1.16+/-2.38, respectively). The rate of nocturnal hypoglycemia was lowest in the L + S group (0.00+/-0.00 vs. 0.10+/-0.37 for the N + S group vs. 0.15+/-0.54 for the L + N group; P = 0.004). L + S, which has a safety profile equal to those of N + S and L + N, is an effective treatment for patients with type 2 diabetes who experience oral sulfonylurea agent failure. L + S offers an alternative to these established combination therapies in patients whose type 2 diabetes cannot be controlled with a sulfonylurea alone.

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.

Randomized, double-blind clinical trial comparing basal insulin peglispro and insulin glargine, in combination with prandial insulin lispro, in patients with type 1 diabetes: IMAGINE 3.

To evaluate the efficacy and safety of basal insulin peglispro (BIL) with those of insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (T2D).

Factors associated with nocturnal hypoglycaemia among patients with type 2 diabetes new to insulin therapy: experience with insulin lispro

Aim: To identify factors associated with nocturnal hypoglycaemia in patients with type 2 diabetes who were new (< 2 months therapy) to insulin therapy.

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.

Effect of Ruboxistaurin on Albuminuria and Estimated GFR in People With Diabetic Peripheral Neuropathy: Results From a Randomized Trial

Support: The eGFR Study was funded by the National Health and Medical Research Council (NHMRC; project grant 545202), with additional support from Kidney Health Australia, NHMRC#320860, the Colonial Foundation, Diabetes Australia Research Trust, and the Rebecca L. Cooper Foundation. LM-B is supported by anNHMRCEarlyCareer Fellowship inAboriginal and Torres Strait Islander Health Research (605837); JH, by NHMRC Scholarship 490348, Rio Tinto Aboriginal Fund, and the Centre of Clinical Research Excellence in Clinical Science of Diabetes, University of Melbourne; PL, by NHMRC Scholarship 1038529. AC holds NHMRC Principal Research Fellowship 1027204; WH, NHMRC Australia Fellowship 511081. We thank Roche Diagnostics for enzymatic creatinine reagents, Melbourne Pathology for technical support in enzymatic creatinine analysis, SeaSwift for in-kind support in transportation of the DEXA to Thursday Island, and MeasureUp for assisting in having their mobile bone densitometry vehicle present on Thursday Island. Funding bodies had no role in the study design; collection, analysis, or interpretation of data; or the writing or decision to submit the manuscript. Financial Disclosure: LCW consults for Impedimed Ltd, which had no involvement in the concept, design, or execution of this study or preparation of this manuscript. The remaining authors declare that they have no other relevant financial interests. Contributions: Research idea and study design: LMB, JH, LCW, LSP, PDL, GRDJ, AGE, WH, AC, KOD, RJM, GJ; data acquisition: LMB, JH; laboratory measurement of mGFR: AGE; data analysis/interpretation: LMB, MC; statistical analysis: MC; supervision or mentorship: LMB, KOD, GJ. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. LMB takes responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted, and that any discrepancies from the study as planned have been explained.

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.

Time-Averaged Self-Monitored Blood Glucose Values Estimate Hemoglobin A1c Outcomes in Patients With Type 1 Diabetes

Hemoglobin A1c (HbA1c) reflects average glucose control over 2-3 months and is predictive for diabetes-related complications but is also limited by the turnover rate of red blood cells. Self-monitored blood glucose (SMBG) measurements provide earlier assessments of glycemic response. The A1c-derived average glucose (ADAG) study demonstrated a strong relationship between estimated average blood glucose (BG) and HbA1c in subjects with stable BG. The ADA recommends ADAG as an adjunct for determining glucose control in clinical practice. We used 24-hour 5-point SMBG profiles from patients receiving stable daily insulin dosing (after 8 weeks of treatment in the IMAGINE 3 trial) to determine how to use timeaveraged BG (TABG) to estimate HbA1c. Patients were Type 1 diabetes (T1D) adults with HbA1c <12% (mean 7.9%), treated with prandial insulin lispro and either basal insulin peglispro or insulin glargine. Patients included in the analyses (N = 977; treatment groups were combined) had ≥1 complete 5-point SMBG profile in the period of interest and HbA1c values at weeks 4 and 18 (study weeks 12 and 26). Patients monitored BG at least 4 times daily (pre–morning meal, pre–midday meal, pre–evening meal, bedtime). We calculated TABG for each 5-point SMBG profile collected during weeks 1-4 (fasting BG [FBG]-to-next-dayFBG) as follows: