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.

Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans.

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.

Oral protein kinase c ß inhibition using ruboxistaurin: efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with diabetic retinopathy in the Protein Kinase C ß Inhibitor-Diabetic Retinopathy Study and the Protein Kinase C ß Inhibitor-Diabetic Retinopathy Study 2.

PURPOSE: To evaluate efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with moderately severe to very severe nonproliferative diabetic retinopathy from the Protein Kinase C ß Inhibitor-Diabetic Retinopathy Study and Protein Kinase C ß Inhibitor-Diabetic Retinopathy Study 2 ruboxistaurin (RBX) protein kinase C ß inhibitor trials. METHODS: Patients in these 3-year, randomized, placebo-controlled, double-masked, Phase 3 trials had best-corrected Early Treatment Diabetic Retinopathy Study visual acuity ≥45 letters (∼20/125 Snellen), Early Treatment Diabetic Retinopathy Study retinopathy level 47A/B-53E, and no previous panretinal photocoagulation in ≥1 eye. Patients received placebo (N = 401) or RBX 32 mg/day (N = 412). Data from the 2 studies were combined and masked evaluation of retinal photographs was performed for cause of visual decline in all patients experiencing sustained moderate visual loss (≥15-letter loss sustained for the last 6 months of study). RESULTS: In the studies combined, sustained moderate visual loss occurred in 10.2% of placebo-treated patients versus 6.1% of RBX-treated patients (P = 0.011). A ≥15-letter gain occurred in 2.4% of placebo versus 4.7% of RBX eyes (P = 0.021) and a ≥15-letter loss occurred in 11.4% versus 7.4%, respectively (P = 0.012). Diabetic macular edema was the probable primary cause of vision loss. Among eyes without focal/grid photocoagulation at baseline, fewer RBX group eyes (26.7%) required initial focal/grid photocoagulation versus placebo (35.6%; P = 0.008). No safety concerns were identified. CONCLUSION: Analysis of data combined from two similar studies adds further statistical significance to RBX's beneficial effects on visual loss, need for focal laser, and vision gain, most likely through effects on macular edema.

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.).

Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy.

OBJECTIVE: To evaluate the effect of ruboxistaurin, an orally administered protein kinase C beta (PKC beta) isozyme-selective inhibitor, on vision loss in patients with diabetes. DESIGN: Thirty-six-month, randomized, double-masked, placebo-controlled, parallel, multicenter trial. PARTICIPANTS: Six hundred eighty-five patients randomized at 70 clinical sites. METHODS: Ophthalmologic examination was performed at screening and at each 3-month visit. Retinopathy status was assessed every 6 months with Early Treatment Diabetic Retinopathy Study (ETDRS) standard 7-field 30 degrees color stereoscopic fundus photography. Levels of diabetic retinopathy and diabetic macular edema were determined by 2 independent graders masked to site and treatment assignment, with additional independent adjudication as required. Eligible patients had a best-corrected visual acuity (VA) score of > or =45 letters, retinopathy level > or = 47A and < or = 53E, and no prior panretinal photocoagulation in at least one eye. MAIN OUTCOME MEASURE: Effect of oral ruboxistaurin (32 mg/day) on reduction of sustained moderate visual loss (> or =15-letter decrease in ETDRS VA score maintained > or = 6 months) in patients with moderately severe to very severe nonproliferative diabetic retinopathy. RESULTS: Sustained moderate visual loss occurred in 9.1% of placebo-treated patients versus 5.5% of ruboxistaurin-treated patients (40% risk reduction, P = 0.034). Mean VA was better in the ruboxistaurin-treated patients after 12 months. Baseline-to-end point visual improvement of > or =15 letters was more frequent (4.9% vs. 2.4%) and > or =15-letter worsening was less frequent (6.7% vs. 9.9%) in ruboxistaurin-treated patients relative to placebo (P = 0.005). When clinically significant macular edema was >100 microm from the center of the macula at baseline, ruboxistaurin treatment was associated with less frequent progression of edema to within 100 microm (68% vs. 50%, P = 0.003). Initial laser treatment for macular edema was 26% less frequent in eyes of ruboxistaurin-treated patients (P = 0.008). CONCLUSION: Oral ruboxistaurin treatment reduced vision loss, need for laser treatment, and macular edema progression, while increasing occurrence of visual improvement in patients with nonproliferative retinopathy.

Diabetic microvascular complications--can the presence of one predict the development of another?

The number of people with diabetes is increasing dramatically worldwide. The rising prevalence of obesity in childhood and adolescence has also been linked to a startling increase in the number of diagnosed cases of type 2 diabetes in these younger age groups. Despite the introduction of treatment strategies, diabetes remains a major cause of new-onset blindness, end-stage renal disease, and lower leg amputation, all of which contribute to the excess morbidity and mortality in people with diabetes. Furthermore, the management of diabetes-related complications generates substantial costs. In order that timely treatment can be given, it is essential that patients at risk for the development of diabetic microvascular complications are identified earlier. Diabetes duration and glycemic, blood pressure, and lipid control have consistently been shown to correlate with diabetic retinopathy, neuropathy, and nephropathy, but to date, the relationship of one diabetic microvascular complication to another has not been clearly described. A review of the literature has raised the question that apart from other known risk factors, there is a possible relationship among the diabetic microvascular complications themselves, and this appears to be much stronger than the sparse published data on it would suggest. A scoring system that can predict the development of diabetic microvascular complications may facilitate the early identification of those patients at risk and, consequently, have a positive impact on patients' quality of life and reduce the economic burden of diabetes and its complications.