Louis Vignati

Reduction of Postprandial Hyperglycemia and Frequency of Hypoglycemia in IDDM Patients on Insulin-Analog Treatment

Insulin lispro, an insulin analog recently developed particularly for mealtime therapy, has a fast absorption rate and a short duration of action. We compared insulin lispro and regular human insulin in the mealtime treatment of 1,008 patients with IDDM. The study was a 6-month randomized multinational (17 countries) and multicenter (102 investigators) clinical trial performed with an open-label crossover design. Insulin lispro was injected immediately before the meal, and regular human insulin was injected 30–45 min before the meal. Throughout the study, the postprandial rise in serum glucose was significantly lower during insulin lispro therapy. At the endpoint, the postprandial rise in serum glucose was reduced at 1 h by 1.3 mmol/l and at 2 h by 2.0 mmol/l in patients treated with insulin lispro (P < 0.001). The rate of hypoglycemia was 12% less with insulin lispro (6.4 ± 0.2 vs. 7.2 ± 0.3 episodes/30 days, P < 0.001), independent of basal insulin regimen or HbA1c level. The reduction was observed equally in episodes with and without symptoms. When the total number of episodes for each patient was analyzed according to the time of occurrence, the number of hypoglycemic episodes was less with insulin lispro than with regular human insulin therapy during three of four quarters of the day (P < 0.001). The largest relative improvement was observed at night. In conclusion, insulin lispro improves postprandial control, reduces hypoglycemic episodes, and improves patient convenience, compared with regular human insulin, in IDDM patients.

Unimolecular Dual Incretins Maximize Metabolic Benefits in Rodents, Monkeys, and Humans

Compared to best-in-class GLP-1 mono-agonists, unimolecular co-agonists of GLP-1 and GIP with optimized pharmacokinetics enhance glycemic and metabolic benefits in mammals. “Twincretins”: Two Is Better than One Despite obesity-linked diabetes approaching worldwide epidemic proportions and the growing recognition of it as a global health challenge, safe and effective medicines have remained largely elusive. Pharmacological options targeting multiple obesity and diabetes signaling pathways offer greater therapeutic potential compared to molecules targeting a single pathway. Finan et al. now report the discovery, characterization, and translational efficacy of a single molecule that acts equally on the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). In rodent models of obesity and diabetes, this dual incretin co-agonist more effectively lowered body fat and corrected hyperglycemia than selective mono-agonists for the GLP-1 and GIP receptors. An enhanced insulinotropic effect translated from rodents to monkeys and humans, with substantially improved levels of glycosylated hemoglobin A1c (HbA1c) in humans with type 2 diabetes. The dual incretin was engineered with selective chemical modifications to enhance pharmacokinetics. This, in combination with its inherent mixed agonism, lowered the drug dose and ameliorated the dose-limiting nausea that has plagued selective GLP-1 therapies. These dual incretin co-agonists signify a new direction for unimolecular combination therapy and represent a new class of drug candidates for the treatment of metabolic diseases. We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co-agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1–mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1–based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.

Health-Related Quality-of-Life Results From Multinational Clinical Trials of Insulin Lispro: Assessing benefits of a new diabetes therapy

OBJECTIVE To compare health-related quality of life (HRQOL) in patients with diabetes receiving insulin lispro with patients receiving regular human insulin (Humulin R). RESEARCH DESIGN AND METHODS We performed two randomized comparative studies over a 6-month period (3 months per treatment). Primary analyses used crossover baseline to 3-month changes in HRQOL scores. Ninety-three principal investigators in Canada, France, Germany, and the U.S. participated in these studies. One HRQOL crossover study included 468 patients with type I diabetes; the other HRQOL crossover study included 474 patients with type II diabetes. In both studies, patients were taking insulin at least 2 months before enrollment. Primary outcomes included two generic HRQOL domains, energy/fatigue and health distress, and two diabetes-specific domains, treatment satisfaction and treatment flexibility. Thirty secondary outcomes included both generic and diabetes-specific measures. Secondary outcome domains were controlled for multiplicity in the analyses. RESULTS Primary analyses showed that treatment satisfaction scores (P < 0.001) and treatment flexibility scores (P = 0.001) were higher for insulin lispro in type I diabetic patients. No other significant treatment differences were detected using the data from these 6-month crossover studies. CONCLUSIONS Treatment satisfaction and treatment flexibility were significantly improved in patients with type I diabetes using insulin lispro. Other HRQOL findings were comparable for insulin lispro and regular human insulin. Insulin lispro appears to have a measurable impact on lifestyle benefits in patients with type I diabetes, as demonstrated by increased treatment satisfaction and treatment flexibility.

Improved mealtime treatment of diabetes mellitus using an insulin analogue

The absorption of regular human insulin from subcutaneous injection sites is delayed due to the self-association of insulin to multimeric forms. The insulin analogue insulin lispro has a weak self-association and a fast absorption rate. We examined the safety and efficacy of insulin lispro in the premeal treatment of patients with diabetes mellitus. A 12-month study was performed in 336 patients with insulin-dependent diabetes mellitus (IDDM) and 295 patients with non-insulin-dependent diabetes mellitus (NIDDM). The patients were randomized to inject either regular human insulin 30 to 45 minutes before eating, or insulin lispro immediately before each meal, in addition to basal insulin. The postprandial rise in serum glucose was lower in patients receiving insulin lispro than in those receiving regular human insulin therapy. At end point the increment was significantly lower at 1 hour (35%) and at 2 hours (64%) after the meal in IDDM patients; in NIDDM patients, the increment was nonsignificantly lower at 1 hour (19%) and significantly lower at 2 hours (48%). IDDM patients receiving insulin lispro achieved significantly lower glycated hemoglobin (HbA1c) levels in patients receiving regular human insulin (8.1% vs 8.3%). In NIDDM patients, HbA1c levels decreased equally in both treatment groups. Due to its fast absorption rate, insulin lispro improves postprandial control in diabetes. Insulin lispro can be considered one step toward optimal insulin therapy and improved patient convenience.

The Antidiabetogenic Effect of GLP-1 Is Maintained During a 7-Day Treatment Period and Improves Diabetic Dyslipoproteinemia in NIDDM Patients

OBJECTIVE To investigate the long-term antidiabetogenic effect of glucagon-like peptide 1 (GLP-1) and its influence on diabetic dyslipoproteinemia, patients with NIDDM were treated with GLP-1 subcutaneously for 1 week. RESEARCH DESIGN AND METHODS Twelve patients participated in the study. The 1st week of the study, all of them were on intensive insulin treatment and from day 8, four were randomized to a control group continuing with insulin, and eight to a treatment group where GLP-1 was given at meals together with regular insulin from day 8 to 12. On days 13 and 14, they were only given GLP-1 at meals. NPH insulin at bedtime was given throughout the study. RESULTS In the GLP-1-treated patients, the doses of regular insulin, given to keep a satisfactory blood glucose control, were reduced compared with treatment with insulin only. GLP-1 virtually inhibited the early increase in blood glucose after the meals, whereas an increase of ∼ 2 mmol was seen during an optimized insulin treatment. In agreement with the short half-life of the peptide, 2-h postprandial plasma insulin levels were significantly decreased both at day 12 and 14, suggesting that there was not enough GLP-1 left to stimulate endogenous insulin release and compensate for the decrease in the dose of exogenous insulin. Therefore, the effect of GLP-1 was lost before the next meal, resulting in increased preprandial blood glucose values at lunch and dinner. The concentration of VLDL triglycerides decreased already during the 1st week. This decrease persisted during the 2nd week when GLP-1 was included in the treatment. No changes were observed in the levels of LDL and HDL cholesterol. The LDL particle diameter increased from a mean of 22.3 to 22.6 nm (P < 0.01) in response to insulin treatment. A further increment to 22.9 nm (P < 0.05) was seen after GLP-1 treatment. The LDL particle size did not change in the control group. Lipoprotein lipase activity was decreased by 27% and hepatic lipase was reduced by 13% in the GLP-1-treated group. CONCLUSIONS We confirm the antidiabetogenic effect of GLP-1 in NIDDM patients. This effect was maintained during 7 days, which implies that the patients did not develop tolerance during this treatment period. Intensive insulin treatment, leading to normotriglyceridemia, increased the mean LDL particle diameter, which is likely to lower the risk of future coronary heart disease in patients with NIDDM. Furthermore, an additive effect of GLP-1 is indicated. Hence, this study gives additional evidence that GLP-1 may be useful as an agent for treating NIDDM.

Effect of Ruboxistaurin on the Visual Acuity Decline Associated with Long-standing Diabetic Macular Edema

PURPOSE To compare relationships between severity and duration of diabetic macular edema (DME) and visual acuity (VA) observed in the PKC-DRS2 with those from the Early Treatment Diabetic Retinopathy Study (ETDRS) and to assess the effect of the orally administered PKC beta inhibitor ruboxistaurin (RBX) on these parameters. METHODS In the PKC-DRS2, patients with moderately severe to very severe nonproliferative diabetic retinopathy (n = 685) were randomly assigned to 32 mg/d RBX or placebo and followed up for 36 months with ETDRS VA measurements and fundus photographs (FP) every 3 to 6 months. Mean VA was calculated across all FP visits for eyes in each level of the ETDRS DME severity scale at those visits. For eyes with baseline VA > or = 20/40, relationships between change in VA from baseline to last visit and duration of severe DME were analyzed with linear regression. RESULTS Mean VA decreased by approximately 22 letters between the mildest and most severe levels of the DME scale in the PKC-DRS2, compared with 27 letters in the ETDRS. In the placebo group, the rate of decrease in VA over time associated with duration of severe DME was 0.67 letters per month (24 letters over 36 months, compared with 20 letters over 28-36 months in the ETDRS). This rate was 30% less in the RBX group (0.47 letter per month, P = 0.022). CONCLUSIONS The VA decrease in the PKC-DRS2 associated with long-standing DME agrees well with estimates from the ETDRS. RBX appears to ameliorate this decrease, an effect that could be important clinically. (ClinicalTrials.gov number, NCT00604383.).

Efficacy of insulin lispro in combination with NPH human insulin twice per day in patients with insulin-dependent or non—insulin-dependent diabetes mellitus

A common treatment regimen for patients with either insulin-dependent diabetes mellitus (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM) is a combination of rapid-acting insulin and intermediate-acting insulin administered twice each day. It is usually recommended that regular human insulin be injected 30 to 45 minutes before a meal. In practice, patients often inject regular human insulin closer to mealtime, causing a higher post-prandial serum glucose level and an increased potential for hypoglycemia in the postabsorptive period. Insulin lispro, a rapid-acting insulin analogue, is best injected just before a meal because of its more rapid absorption and shorter duration of action. In 707 randomized patients, 379 with IDDM and 328 with NIDDM, we studied the effect of twice-daily insulin lispro or regular human insulin in combination with NPH human insulin (isophane insulin) on premeal, 2-hour postprandial, and bedtime glycemic control. Assessments were based on the results of a seven-point blood glucose profile, the insulin dose (by formulation and time of administration), the incidence and frequency of hypoglycemic episodes, and the glycated hemoglobin value. Treatment with insulin lispro resulted in lower postprandial glucose levels and smaller increases in glucose level after the morning and evening meals compared with treatment with regular human insulin. Overall glycemic control, frequency of hypoglycemic events, and total insulin dose were not different between the two groups. Insulin lispro in combination with NPH human insulin in a twice-per-day regimen allows injection closer to mealtime and improves post-prandial glycemic control without increasing the risk of hypoglycemia.

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.

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.

Sustained moderate visual loss as a predictive end point for visual loss in non-proliferative diabetic retinopathy.

PurposeIn PKC-DRS2, the efficacy of the oral PKC-β inhibitor, ruboxistaurin 32 mg/day, was measured by the primary end point of sustained moderate visual loss (SMVL: a ⩾15 letter decrease from baseline on the ETDRS (Early Treatment Diabetic Retinopathy Study) chart sustained at least for the last 6 months of study participation). We now evaluate whether SMVL is more accurate than moderate visual loss (MVL: a single occurrence of a decrease from baseline of ⩾15 ETDRS letters) for predicting future visual loss.MethodsStudy eyes with moderately severe to very-severe non-proliferative diabetic retinopathy, best-corrected visual acuity of at least 45 letters on the ETDRS chart (∼Snellen 20/125), and no prior pan retinal photocoagulation were evaluated in 506 patients (869 eyes) who completed 36 months of treatment.ResultsSixty-five percentage (26/40) of study eyes with the onset of SMVL within 24 months of enrolment still had SMVL at study completion (36 months). In comparison, only 24% (30/126) with MVL within 24 months had SMVL at study completion. Analyses based on data from 6, 12, and 18 months of treatment were similar.ConclusionsSMVL is a more predictable measure of subsequent visual loss than is a single time point measure of MVL.