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  • In type diabetic subjects with mean

    2022-05-13

    In type-2 diabetic subjects with mean baseline glycated hemoglobin A (HbA) of 8.4%, q.d. administration of MK-0893 for 12weeks as a monotherapy resulted in dose-dependent decreases in HbA and FPG. Administration of MK-0893 q.d. at doses of 20, 40, 60, and 80mg led to observed reductions in HbA of 0.6%, 1%, 1.5%, and 1.8%, respectively, after 12weeks. Elevated alanine aminotransferase (ALT) levels and an apparent dose-dependent increase in body weight were also observed with administration of MK-0893. In this study, increases in LDL-C were observed at all doses of MK-0893. Mu et al. have contrasted the clinical data obtained with MK-0893 to preclinical data generated using a related analog, GRA1 (), . Contrary to the observed lack of an additive effect on glucose lowering with coadministration of MK-0893 and sitagliptin in clinical studies, treatment of high fat diet-streptozotocin-induced diabetic mice expressing the human glucagon receptor (hGCGr) with a combination of GRA1 and des-fluoro-sitagliptin resulted in additive lowering of blood glucose. In this report, treatment of hGCGr diet-induced obese (DIO) mice with GRA1 for 10weeks did not lead to observed elevations in plasma lipid levels, contrasting with the clinical increases in LDL-C observed with MK-0893. Mu et al. posit that these disconnects are due to differences in GCGr signaling and downstream metabolic effects between human and rodents. However, the possibility of compound-specific effects was not ruled out. In experiments described in a recent Merck patent filing on the coadministration of selected GCGr antagonists with an inhibitor of cholesterol absorption, for example ezetimibe, treatment of hGCGr mice maintained on chow diet with GRA1 or either of two GCGr antagonists described in the patent literature from Eli Lilly () and (), , for five days led to increases in plasma total cholesterol and cholesterol absorption, as indicated by increases in plasma phytosterols. In a similar experiment, coadministration of ezetimibe with either MK-0893, MK-3577, or GRA1 did not lead to observed increases in total cholesterol or cholesterol absorption. A dual tracer study in hGCGr mice using p.o. administration of -cholesterol to track changes in cholesterol 2881 receptor and intraperitoneal administration of deuterium oxide to track changes in endogenous cholesterol synthesis demonstrated that treatment with GRA1 led to increased cholesterol absorption without causing significant effects on endogenous cholesterol synthesis. Administration of MK-0893 was shown to increase plasma phytosterols in hGCGr mice, but not in wild-type mice. As the compounds used in these experiments are much weaker antagonists of the mouse GCGr compared to their potency against the hGCGr, these results were interpreted to imply dependence of the observed changes in cholesterol absorption on GCGr blockade. The results of these rodent studies are accompanied by data from a post hoc analysis of plasma samples of the 60mg and 80mg dose groups from the 12-week clinical study with MK-0893 indicating dose-dependent increases in plasma campesterol and sitosterol. A negative correlation between baseline LDL-C and percent change in LDL-C in all dose groups from the 12-week clinical study with MK-0893 is also described. Increases in LDL-C were also observed in 9 of the 14 subjects in the 60mg dose group that were on statins during the 12-week study with MK-0893, suggesting a limited potential for inhibition of endogenous cholesterol synthesis to prevent the observed changes in LDL-C. Although the presented clinical data is limited to a post hoc analysis and the utility of plant sterols as a marker of cholesterol absorption in man has been questioned, the implied effect of MK-0893 on cholesterol absorption is an intriguing mechanistic hypothesis to explain the clinically observed changes in cholesterol levels upon administration of MK-0893. In 2012, Merck reported results from clinical experiments using a second GCGr antagonist, MK-3577 (), , designed to assess the effects of partial GCGr blockade and comparing the effects of diurnal versus nocturnal GCGr blockade on glycemic control and circulating lipids. The shorter human half-life of MK-3577 (approximately 4h compared to 60–100h for MK-0893) allowed for selection of dosing regimens modeled to provide >80% blockade of GCGr signaling over 24h (25mg b.i.d.), <50% blockade during daytime (10mg q.d. a.m.), or <50% blockade during nighttime (6mg q.d. p.m.). In this five-period cross-over study, type-2 diabetic subjects were randomized to either one of the three MK-3577 regimens, 1g metformin b.i.d., or placebo for a 4-week period. After 118 patients completed at least two study periods, a planned interim analysis was performed and the study was subsequently stopped.