Endothelial‐protective effects of a G‐protein‐biased sphingosine‐1 phosphate receptor‐1 agonist, SAR247799, in type‐2 diabetes rats and a randomized placebo‐controlled patient trial

Figures

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  FIGURE 1. Effects of SAR247799 on lymphocytes, heart rate and renal parameters in diabetic rats. Zucker diabetic fatty (ZDF) rats treated for 5 weeks with chow formulated with control (0), low (L; 0.002% w/w), intermediate (I; 0.007% w/w) or high (H; 0.0245% w/w) doses of SAR247799. Age‐matched lean rats treated with control chow (0) for comparison. n = 8, 12, 14, 12 rats in lean, ZDF 0, ZDF L, ZDF I, ZDF H groups, respectively. Bars are mean ± standard error of the mean when Shapiro–Wilks test did not reject normality hypothesis (A, B) and median ± interquartile range otherwise (C–G). # P < .05, ## P < .01, ### P < .001 for lean vs ZDF control group; A and B by Student t test; E, F, G by Wilcoxon test; C and D baseline comparisons of lean vs the 4 ZDF groups by Kruskal–Wallis followed by Wilcoxon posthoc test; C and D treatment comparisons of lean vs ZDF control group by Wilcoxon test. * P < .05, ** P < .01, *** P < .001 for treated groups vs ZDF control group; A and B by 1‐way ANOVA followed by Dunnett's test; E, F, G and C & D (treatment) by Kruskal–Wallis test followed by Wilcoxon posthoc test

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  FIGURE 2. Effects of SAR247799 on plasma biomarkers in diabetic rats. Zucker diabetic fatty (ZDF) rats following 5‐week treatment with chow formulated with control (0), low (L; 0.002% w/w), intermediate (I; 0.007% w/w), or high (H; 0.0245% w/w) doses of SAR247799. Age‐matched lean rats treated with control chow (0) for comparison. n = 8, 12, 14, 12 rats in lean, ZDF 0, ZDF L, ZDF I, ZDF H groups, respectively. Bars represent mean ± standard error of the mean when Shapiro–Wilks test did not reject normality hypothesis (C) and median ± interquartile range otherwise (A, B, D, E, F, G). ## P < .01, ### P < .001 for lean vs ZDF control group; Student t‐test for C, or Wilcoxon test for A, B, D, E, F, G. * P < .05, ** P < .01, for treated groups vs ZDF control group; Kruskal–Wallis test followed by Wilcoxon posthoc test for A, B, D, E, F, G

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  FIGURE 3. Design and patient (pt) progress through randomized, double‐blinded clinical trial to evaluate SAR247799 on flow‐mediated dilation in type‐2 diabetes patients. (A) Study design. (B) Flow chart of patient progress through trial. of the 122 patients not meeting inclusion criteria, 14 were because flow‐mediated dilation (FMD) was >7%. # 1 patient excluded for unusable FMD data and 1 patient withdrawn. DSM, dose selection meeting; PK, pharmacokinetics; B, baseline; EOS, end of study; BAD, brachial artery diameter; HR, heart rate; BP, blood pressure; PK, pharmacokinetics

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  FIGURE 4. Effect of SAR247799 (1 and 5 mg), sildenafil (50 mg), or placebo on heart rate (A) and lymphocytes (B) in type‐2 diabetes patients. Heart rate and lymphocytes expressed on each day (D1–D28) at time points associated with maximal pharmacodynamic effects (4 and 6.5 h, respectively). Mean ± standard error of the mean; P values shown when < .05 (repeated‐measure model as described under Methods)

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  FIGURE 5. Effect of SAR247799 (1 and 5 mg), sildenafil (50 mg), or placebo on % flow‐mediated dilation (FMD) in type‐2 diabetes patients. FMD data expressed as change from baseline (A), or change from baseline, placebo corrected (B). Bars are mean ± standard error of the mean. Variation in the placebo groups in B (placebo‐corrected FMD change) illustrated by retaining error bars with mean zero (first group at each time point). Precise P‐values for difference vs placebo shown when P < .05; repeated‐measure model as described under Methods. Number of patients with FMD data in each histogram was as follows for placebo/1 mg SAR247799/5 mg SAR247799/50 mg sildenafil, respectively; 12/15/15/10 (D14, D21, D28 and D42) and 12/15/13/10 (D35)