POSTGRADUATE MEDICINE, 2017 http://dx.doi.org/10.1080/00325481.2017.1315290

CLINICAL FOCUS: ORIGINAL RESEARCH Effect of bromocriptine-QR therapy on glycemic control in subjects with type 2 diabetes mellitus whose dysglycemia is inadequately controlled on Bindu Chamarthia,b,c and Anthony H. Cincottaa aVeroScience LLC, Tiverton, RI, USA; bDivision of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, MA, USA; cDepartment of Medicine, Harvard Medical School, Boston, MA, USA

ABSTRACT ARTICLE HISTORY Objective: The concurrent use of an insulin sensitizer in type 2 diabetes mellitus (T2DM) patients with Received 18 February 2017 inadequate glycemic control on basal-bolus insulin may help improve glycemic control while limiting Accepted 31 March 2017 further insulin requirement. Bromocriptine-QR (B-QR), a quick release, sympatholytic, dopamine D2 receptor KEYWORDS agonist therapy for T2DM, is a postprandial insulin sensitizer. This study evaluated the effect of B-QR on Bromocriptine; dopamine; dysglycemia in T2DM subjects with suboptimal glycemic control on basal-bolus insulin plus . circadian; insulin sensitizer; Methods: The effect of once-daily morning administration of B-QR on dysglycemia was evaluated in 60 type 2 diabetes mellitus; T2DM subjects derived from the Cycloset Safety Trial, with HbA1c >7% on basal-bolus insulin plus insulin resistance metformin at baseline, randomized to B-QR (N = 44) versus placebo (N = 16) and completed 12 weeks of study drug treatment. The analyses also included a subset of subjects on high-dose insulin (total daily insulin dose (TDID) ≥70 units; N = 36: 27 B-QR; 9 placebo). Results: Subjects were well matched at baseline. After 12 weeks of B-QR treatment, mean % HbA1c decreased by -0.73% relative to baseline (p < 0.001) and by -1.13 relative to placebo (p < 0.001). In the high-dose insulin subset, B-QR therapy resulted in % HbA1c reductions of -0.95 and -1.49 relative to baseline (p < 0.001) and placebo (p = 0.001) respectively. Secondary analyses of treatment effect at 24 and 52 weeks demonstrated similar influences of B-QR on HbA1c. The fasting plasma (FPG) and TDID changes within each treatment group were not significant. More subjects achieved HbA1c ≤7at 12 weeks with B-QR relative to placebo (36.4% B-QR vs 0% placebo, Fisher’s exact 2-sided p = 0.003 in the entire cohort and 37% vs 0%, 2-sided p = 0.039 in the high-dose insulin subset). Conclusion: B-QR therapy improves glycemic control in T2DM subjects whose glycemia is poorly controlled on metformin plus basal-bolus insulin, including individuals on high-dose basal-bolus insulin. This glycemic impact occurred without significant change in FPG, suggesting a postprandial glucose lowering mechanism of action.

Cycloset Safety Trial registration: ClinicalTrials.gov Identifier: NCT00377676

1. Introduction control while limiting further insulin requirement but safe, effective options for such agents are limited. The thiazolidine- The natural progression of disease in type 2 diabetes mellitus diones (TZDs) such as pioglitazone and rosiglitazone are effec- (T2DM) is marked by progressive decline in pancreatic beta- tive insulin sensitizers but the use of these agents in insulin- cell function resulting in the need for exogenous insulin ther- treated patients can be associated with significantly increased apy in a large proportion of patients, particularly with increas- risk of adverse effects such as congestive heart failure (CHF), ing duration of the disease [1]. The declining beta-cell function weight gain, edema, and bone fractures [8–16]. Bromocriptine- along with the presence of longstanding and often severe QR (B-QR), a quick-release, high absorbing formulation of the insulin resistance results in the need for exogenous basal as potent dopamine D2 receptor agonist bromocriptine, well as prandial insulin and often escalating doses of insulin to approved in the United States for the treatment of T2DM, is achieve adequate glycemic control. Chronic high-dose insulin a unique insulin sensitizer with a good safety profile [17–23]. therapy can be difficult to manage due to the potential risks of Circadian-timed administration (within 2 h of waking) of this such therapy such as and weight gain [2–7]. quick-release formulation of bromocriptine results in a discrete This sequence of disease progression with increasing insulin and brief daily interval of circulating bromocriptine, thereby requirements and difficulty achieving adequate glycemic con- providing a timed pulse of increased dopaminergic activity trol occurs frequently even in patients on high-dose insulin centrally at the time of day that studies suggest is the natural therapy. The concurrent use of an insulin sensitizer in such daily peak of central dopaminergic activity in healthy indivi- patients whose glycemia is not adequately controlled on high- duals [24] which studies suggest is diminished in insulin-resis- dose insulin therapy may offer a strategy to improve glycemic tant individuals [25,26].

CONTACT Bindu Chamarthi [email protected] © 2017 Informa UK Limited, trading as Taylor & Francis Group 2 B. CHAMARTHI AND A. CINCOTTA

Based on preclinical study findings [27–33], it is postulated by site-specific or central institutional review boards and all that appropriately circadian-timed B-QR administration subjects provided written informed consent to participate in restores the diminished circadian peak of dopaminergic activ- the study before enrollment. ity present in insulin resistant states, to thereby improve cen- The CST protocol required that subjects maintained a tral fuel-sensing mechanisms and insulin sensitivity [34]. stable diabetes treatment regimen for ≥30 days prior to ran- Available evidence from preclinical and clinical studies sug- domization and subjects had to remain on their established gests that B-QR is a postprandial-weighted insulin sensitizer baseline antihyperglycemic treatments without any changes promoting glucose disposal following a meal [21–23,35–39]. to the regimen (including no changes to the insulin regimen Hyperinsulinemic–euglycemic clamp studies indicate that type) except adjustments in the dosages of their baseline B-QR improves maximally insulin-stimulated glucose disposal diabetes medications if needed during the first 12 weeks of [21]. Moreover, consistent with B-QR’s meal-time insulin sensi- the study. However, the CST protocol allowed for changes to tizing properties, the HbA1c-lowering effect of B-QR has been the baseline regimen (including changes shown to correlate with the postprandial insulin level [26]. In a to the composition/type of insulin regimen and/or adding or previous small open-label pilot study [38], B-QR therapy in stopping medication(s) including insulin) after week 12 of the T2DM subjects with inadequate glycemic on metformin plus study though without employing a specific algorithm for such high-dose basal–bolus insulin resulted in a significant mean % adjustments. Therefore, due to the inability to accurately HbA1c reduction of −1.76 with a concurrent 27% reduction in account for all such insulin changes occurring after the initial total daily insulin dose (TDID) and a 32% decrease in post- 12-week study period, the primary analysis for the present prandial glucose response to a mixed-meal tolerance test with study evaluated the treatment effects of B-QR versus placebo no significant change in fasting plasma glucose (FPG) level. from baseline to week 12 of therapy. As a secondary analysis, Given the import of these findings highlighting a potential the treatment effects of B-QR versus placebo were analyzed at potent method of improving glycemic control in these very study weeks 24 and 52 (end of study), during which time difficult to manage T2DM patients, in the present study, we changes in both insulin dose and insulin regimen were sought to evaluate the reproducibility of the above pilot study allowed. All analyses in the current study are original and within a double-blind, placebo-controlled study design utiliz- different from any previously reported results from the CST. ing a cohort of subjects derived from a randomized, placebo- HbA1c levels, FPG levels, and TDID were assessed at base- controlled safety study of B-QR therapy in T2DM subjects line and week 12 for the primary analysis and at weeks 24 and (Cycloset Safety Trial [CST]) [17]. 52 for the secondary analyses. FBG and HbA1c assays were performed at a central lab. HbA1c was measured using high- performance liquid chromatography. Insulin dose information 2. Methods was as obtained and recorded in the case report forms col- lected at the baseline and weeks-12, 24 and 52 study visits. 2.1. Study subjects and design Study subjects were derived from the CST. The total CST study population had included subjects whose T2DM was managed 2.2. Statistical analysis with either lifestyle interventions alone, oral antihyperglyce- mic agents (≤2), or insulin either alone or in combination with The primary statistical analyses were performed to assess (a) 1 oral antihyperglycemic agent. The present study is a post- between study group (B-QR vs. placebo) differences in the hoc analysis limited to a subset (N = 60) of the CST study changes from baseline to week 12 in HbA1c, FPG, and TDID; population that was not prespecified in the original CST study (b) within-group changes in HbA1c, FPG, and TDID from base- protocol and included only those CST subjects on metformin line to week 12; and (c) between group comparison of percent and basal plus prandial insulin therapy (including mixed insu- of subjects achieving goal HbA1c of ≤7% after 12 weeks of lin regimens) with HbA1c >7% at baseline, randomized to treatment. These analyses were performed in the entire cohort B-QR therapy (N = 44) versus placebo (N = 16) and completing of 60 subjects (44 B-QR, 16 placebo), which included all subjects 12 weeks on the study drug with a 12-week HbA1c on basal–bolus insulin plus metformin regardless of their base- measurement. line TDID. In addition, to more closely mimic the study subjects The study design and protocol for the CST have been in the previous pilot study[38] discussed above, the between- previously described [17]. Briefly, the CST was a 12-month, group and within-group changes in HbA1c, FPG, and TDID multicenter, randomized, placebo-controlled, double-blind, were analyzed in a subset of the cohort limited to subjects parallel-group safety and efficacy study in outpatient T2DM who were on high-dose insulin defined as TDID ≥ 70 units at subjects between the ages of 30 and 80 years, with body mass baseline (N = 36:27 B-QR, 9 placebo). Further, a sensitivity index <43 kg/m2 and HbA1c ≤10.0%. Subjects were rando- analysis of the treatment effect was conducted in both the mized 2:1 to B-QR therapy versus placebo added on to their total and high-dose insulin study populations wherein the baseline diabetes treatment regimen as described above. The analysis was restricted to subjects with TDID change within study drug was titrated by adding 1 tablet (0.8 mg B-QR per ≤5 units/day from baseline. Secondary statistical analyses tablet) per week until a maximum tolerated daily dose included analysis of the within and between group changes between 2 and 6 tablets (1.6–4.8 mg/day) was achieved. The in HbA1c, FPG, and TDID at study week 24 and study week 52. study drug was taken once daily with the morning meal, Between-group differences were analyzed using 2-tailed within 2 h of waking. The CST study protocol was approved Student’s t-tests and within-group comparisons were analyzed POSTGRADUATE MEDICINE 3 using paired samples t-tests. Fisher’s exact tests were per- 3.2. Effect of B-QR versus placebo on glycemic control in formed to evaluate the between-group differences in the the total study population percent of subjects reaching HbA1c goal of ≤7.0. Statistical After 12 weeks of study drug treatment, mean HbA1c analyses were performed using SPSS version 19.0 (Armonk, NY: decreased significantly in the B-QR treated group from IBM Corp). The significance level was set at p < 0.05. Data are 8.31 ± 0.13 at baseline to 7.58 ± 0.19 at week 12 presented as mean ± standard error of the mean (SEM) except (p < 0.001) and trended up in the placebo-treated group categorical variables shown as numbers and percent. from 8.10 ± 0.19 at baseline to 8.5 ± 0.30 at week 12 Safety analyses were conducted as previously described for (p = 0.14) yielding a significant between group difference the CST [17]. As per the CST study protocol, hypoglycemia was in mean change in % HbA1c of −1.13 (p <0.001)(Table 2). defined as characteristic symptoms of hypoglycemia with When stratified by gender, the between group difference blood glucose 59 mg/dL or less or if blood glucose was not in the change in HbA1c from baseline held in favor of checked, prompt resolution of symptoms with treatment (food B-QR for both males (N =50,−1.03, p = 0.007) and females intake, subcutaneous glucagon, or intravenous glucose) or any (N =10,−1.4, p = 0.008). Similarly, the results remained glucose measurement of 49 mg/dL or less, with or without significant in favor of B-QR when stratified by age for both symptoms. The intensity of hypoglycemia was defined as age <60 (N =33,−1.4, p =0.01)andage≥60 (N =27, severe if all three of the following criteria were met including −0.85, p = 0.006). Within each treatment arm, differences patient being unable to treat himself/herself, exhibiting neu- inthechangein%HbA1cwerenot statistically signifi- roglycopenic symptoms, and either a blood glucose of 49 mg/ cantly between men versus women or age <60 versus ≥60. dL or less or if the blood glucose was not measured, reversal The within-group change in FPG from baseline to week 12 of clinical manifestations with oral carbohydrates, subcuta- was −12.2 ± 9.1 mg/dL (from 161.8 ± 8.6 at baseline to neous glucagon, or intravenous glucose. Events that did not 149.7 ± 7.8 at week 12, p = 0.19) in the B-QR group and meet all three criteria for severe hypoglycemia were charac- 27.1 ± 16.1 mg/dL (from 144.8 ± 13.6 at baseline to 171.9 mg/ terized as mild–moderate. dL ± 20.6 at week 12, p = 0.11) in the placebo group, with neither of these within-group changes being statistically signifi- cant but yielding a statistically significant between-group differ- 3. Results ence of −39.2 ± 17.9 mg/dL (p = 0.03) in favor of B-QR (Table 2). The sensitivity analysis restricted to subjects with 3.1. Baseline characteristics ≤5 units TDID change from baseline (N = 39:25 B-QR; 14 The baseline characteristics of the study population are placebo) yielded similar findings as the primary analysis shown in Table 1. The study subjects in the B-QR and placebo (Table 2). In this subset, mean % HbA1c decreased signifi- treatment arms were well matched at baseline with no sig- cantly in the B-QR-treated group by −0.85 from 8.07 ± 0.19 nificant differences in average age, BMI, duration of diabetes, at baseline to 7.22 ± 0.18 at week 12 (p <0.001)and blood pressure, lipids, renal function, and gender or race trended up in the placebo-treated group by 0.43 from distributions (p > 0.05 for all). There were also no significant 8.13 ± 0.22 at baseline to 8.56 ± 0.34 at week 12 differences between the two groups in baseline HbA1c (p = 0.16), yielding a significant between-group difference (p =0.40),FPG(p = 0.31), or TDID (p = 0.48). The character- in mean change in % HbA1c of −1.28 (p = 0.001) associated istics of the subset of the study cohort limited to those on with B-QR therapy relative to placebo (Table 3). The within- high-dose insulin defined as TDID ≥70 units at baseline were group change in FPG from baseline to week 12 was similar to the whole cohort except for higher mean TDID −23.6 ± 12.2 mg/dL (from 167.5 ± 11.4 at baseline to doses with no significant between treatment group differ- 143.9 ± 8.0 at week 12, p = 0.06) in the B-QR group and ences within this subset (see Table 1 for details). 27.9 ± 17.98 mg/dL (from 144.5 ± 15.1 at baseline to

Table 1. Baseline characteristics. Subjects on basal–bolus insulin (any dose) + metformin and Subjects on high-dose basal–bolus insulin (≥70 U/ baseline HbA1c >7.0 day) + metformin and baseline HbA1c >7.0 B-QR (N = 44) Placebo (N = 16) B-QR (N = 27) Placebo (N =9) Age (years) 59 ± 1 58 ± 3 58 ± 1 59 ± 3 Gender – n (%) male 38/44 (86%) 12/16 (75%) 26/27 (96%) 7/9 (78%) Race – n (%) Caucasian 27/44 (61%) 11/16 (69%) 18/27 (67%) 6/9 (67%) BMI (kg/m2) 33.7 ± 0.7 32.6 ± 0.9 34.7 ± 0.9 31.8 ± 1.0 Heart rate (bpm) 74.4 ± 2.0 70.4 ± 3.1 76.4 ± 2.6 72.4 ± 2.6 Systolic BP (mmHg) 133.8 ± 2.2 135.5 ± 3.2 132.4 ± 2.5 133.6 ± 3.9 Diastolic BP (mmHg) 74.9 ± 1.5 76.7 ± 2.2 72.9 ± 1.7 77.4 ± 2.9 Serum creatinine (mg/dL) 1.19 ± 0.02 1.19 ± 0.05 1.17 ± 0.03 1.18 ± 0.07 eGFR (mL/min) 67.9 ± 1.8 66.2 ± 3.9 69.4 ± 2.1 67.8 ± 6.5 Duration of diabetes (years) 14.2 ± 1.3 14.4 ± 1.7 13 ± 1.3 16.0 ± 2.3 Fasting plasma glucose (mg/dL) 161.8 ± 8.6 144.8 ± 13.6 157.9 ± 11.2 169.2 ± 20.2 HbA1c (%) 8.3 ± 0.1 8.1 ± 0.2 8.4 ± 0.2 8.4 ± 0.2 Total daily insulin dose (units) 91 ± 7 82 ± 8 119 ± 8 98 ± 11 Data shown as means ± SEM except categorical variables shown as numbers and percentages. p > 0.05 for all between treatment group comparisons. B-QR: Bromocriptine-QR. 4 .CAATIADA CINCOTTA A. AND CHAMARTHI B.

Table 2. Effect of bromocriptine-QR as add-on therapy in subjects with suboptimal glycemic control (HbA1c >7%) on treatment with metformin plus basal–bolus insulin. Basal–bolus insulin + metformin Basal–bolus insulin + metformin B-QR versus + B-QR (N = 44) + placebo (N = 16) placebo After 12 weeks of Within-group change from After 12 weeks of Within-group change from Between-group difference in change from Baseline treatment baseline Baseline treatment baseline baseline Panel A: All subjects on metformin and basal–bolus insulin (any dose) at baseline HbA1c (%) 8.31 ± 0.13 7.58 ± 0.19 −0.73 ± 0.16 (−1.05, −0.41)a 8.10 ± 0.19 8.50 ± 0.30 +0.40 ± 0.25 (−0.14, 0.94) −1.13 ± 0.30 (−1.73, −0.53)a Fasting plasma 161.8 ± 8.6 149.7 ± 7.8 −12.2 ± 9.1 (−30.4, 6.1) 144.8 ± 13.6 171.9 ± 20.6 27.1 ± 16.1 (−7.2, 61.4) −39.2 ± 17.9c (−75.0, −3.4) glucose (mg/dL) Total daily insulin 90.8 ± 7.4 88.5 ± 7.8 −2.4 ± 2.5 (−7.4, 2.6) 81.5 ± 7.4 81.5 ± 7.8 0.0 ± 1.2 (−2.6, 2.6) −2.4 ± 2.8 (−7.9, 3.1) dose (units) Basal–bolus insulin + metformin Basal–bolus insulin + metformin B-QR versus + B-QR (N = 25) + placebo (N = 14) placebo After 12 weeks of Within-group change from After 12 weeks of Within-group change from Between-group difference in change from Baseline treatment baseline Baseline treatment baseline baseline Panel B: Subjects on metformin and basal–bolus insulin (any dose) at baseline and ≤5 units insulin dose change from baseline to week 12 HbA1c (%) 8.07 ± 0.19 7.22 ± 0.18 −0.85 ± 0.12a (−1.10, −0.61) 8.13 ± 0.22 8.56 ± 0.34 0.43 ± 0.29 (−0.19, 1.05) −1.28 ± 0.31b (−1.94, −0.63) Fasting plasma glucose 167.5 ± 11.4 143.9 ± 8.0 −23.6 ± 12.2 (−48.8, 1.5) 144.5 ± 15.1 172.4 ± 23.6 27.9 ± 17.98 (−10.9, 66.8) −51.6 ± 21.1c (−94.3, −8.8) (mg/dL) Total daily insulin dose 86.9 ± 9.8 86.8 ± 9.9 −0.04 ± 0.4 (−0.9, 0.8) 74.6 ± 5.8 74.2 ± 5.6 −0.3 ± 0.5 (−1.4, 0.8) 0.3 ± 0.7 (−1.1, 1.6) (units) Data are shown as means ± SEM with 95% confidence intervals in parenthesis for the within and between group mean HbA1c changes/difference. B-QR: Bromocriptine-QR. ap < 0.001; bp = 0.001; cp < 0.05. Table 3. Effect of bromocriptine-QR as add-on therapy in subjects with suboptimal glycemic control (HbA1c > 7%) on treatment with metformin plus high-dose basal–bolus insulin (total daily insulin dose ≥ 70 units/day) at baseline. High-dose basal–bolus insulin + metformin + B-QR High-dose basal–bolus insulin + metformin + placebo B-QR versus (N = 27) (N =9) placebo After 12 weeks of Within-group change from After 12 weeks of Within-group change from Between-group difference in change from Baseline treatment baseline Baseline treatment baseline baseline Panel A: All subjects on metformin and high-dose basal–bolus insulin (≥70 units/day) at baseline HbA1c(%) 8.42 ± 0.17 7.47 ± 0.23 −0.95 ± 0.20(−1.35, −0.55)a 8.36 ± 0.24 8.90 ± 0.49 0.54 ± 0.39(−0.37, 1.65) −1.49 ± 0.41b(−2.32, −0.67) Fasting plasma glucose 157.9 ± 11.2 146.9 ± 8.7 −10.96 ± 10.4(−32.4, 10.5) 169.2 ± 20.2 212.6 ± 27.9 43.3 ± 26.6(−18.0, 104.7) −54.3 ± 23.6c(−102.2, −6.4) (mg/dL) Total daily insulin dose 119.3 ± 7.8 118.2 ± 8.4 −1.1 ± 3.8(−8.9, 6.7) 98.1 ± 11.1 97.7 ± 10.3 −0.4 ± 2.1 (−5.4,4.5) −0.67 ± 6.8(−14.4, 13.1) (units) B-QR versus High-dose basal–bolus insulin + metformin + B-QR (N = 13) High-dose asal-bolus insulin + metformin + placebo (N =7) placebo After 12 weeks of Within-group change from After 12 weeks of Within-group change from Between-group difference in change from Baseline treatment baseline Baseline treatment baseline baseline Panel B: Subjects on metformin and high-dose basal–bolus insulin (≥70 units/day) at baseline and ≤5 units insulin dose change from baseline to week 12 HbA1c(%) 8.18 ± 0.28 7.15 ± 0.28 −1.03 ± 0.15a(−1.36, −0.70) 8.49 ± 0.29 9.13 ± 0.597 0.64 ± 0.49(−0.56, 1.84) −1.67 ± 0.41b(−2.53, −0.81) Fasting plasma glucose 158.9 ± 17.1 147.6 ± 9.5 −11.3 ± 13.97(−41.8, 19.1) 175.6 ± 24.7 225.3 ± 34.8 49.7 ± 33.3(−31.7, 131.1) −61.0 ± 30.7(−125.4, 3.4) (mg/dL) Total daily insulin dose 127.9 ± 8.4 128.4 ± 8.3 0.5 ± 0.6(−0.8, 1.8) 89.0 ± 8.6 87.9 ± 8.6 −1.1 ± 0.8(−3.0, 0.7) 1.7 ± 0.99(−0.4, 3.8) (units) Data are shown as means ± SEM with 95% confidence intervals in parenthesis for the within and between group mean HbA1c changes/difference. B-QR: Bromocriptine-QR. ap < 0.001; bp = 0.001; cp < 0.05. OTRDAEMEDICINE POSTGRADUATE 5 6 B. CHAMARTHI AND A. CINCOTTA

172.4 ± 23.6 mg/dL at week 12, p =0.14)intheplacebo 3.5. Secondary analyses of B-QR versus placebo treatment group, with neither of these within-group changes being effect on glycemic control at study weeks 24 and 52 statistically significant but yielding a statistically significant After 24 weeks of study drug treatment (N = 59:43 B-QR, 16 between-group difference of −51.6 ± 21.1 mg/dL (p = 0.02) placebo), mean HbA1c decreased significantly in the B-QR- in favor of B-QR. There were no significant within-group treated group from 8.27 ± 0.13 at baseline to 7.76 ± 0.25 at changes or between-group difference in the change in week 24 (p = 0.03) and trended up in the placebo-treated TDID (see Table 2 for details). group from 8.10 ± 0.19 at baseline to 8.64 ± 0.29 at week 24 (p = 0.03), yielding a significant between-group difference in mean change in % HbA1c of −1.05 (p = 0.01) (Figure 1,Panel 3.3. Effect of B-QR versus placebo on glycemic control in A). Similar to the primary analysis at week 12, there was a the subset of subjects on high-dose insulin (TDID ≥70 units non-statistically significant decrease in mean FPG from base- at baseline) line in the B-QR group (−13.6 ± 9.96 mg/dL, p =0.18)andan increase in FPG from baseline in the placebo group When the above analyses were limited to only subjects within (23.6 ± 9.9 mg/dL, p = 0.03), yielding a statistically signifi- the study cohort who were on ≥70 units TDID at baseline cant between-group difference in the mean change in FPG (N = 36:27 B-QR; 9 placebo), the mean HbA1c decreased sig- from baseline of −37.18 (p = 0.04). The mean TDID change nificantly from 8.42 ± 0.17% at baseline to 7.47 ± 0.23 was −4.5 ± 3.4 units in the B-QR group and 4.2 ± 6.9 units in (p < 0.001) in the B-QR group and trended up from the placebo group, yielding a between-group difference of 8.36 ± 0.24 at baseline to 8.90 ± 0.49 at week 12 (p =0.2)in −8.7 units (95% CI −22.5, 5.1) in favor of lower TDID in the the placebo group, yielding a significant between-group differ- B-QR group but neither of the within group changes nor the ence in the change in HbA1c of −1.49 (p =0.001)(Table 3). between-group difference in TDID were statistically The mean FPG change from baseline was −11 ± 10 mg/dL significant. (from 157.9 ± 11.2 at baseline to 146.9 ± 8.7 at week 12, p =0.30) When the above analyses were limited to subjects within in the B-QR group and 43 ± 27 mg/dL (from 169.2 ± 20.2 at the study cohort who were on ≥70 units TDID at baseline and baseline to 212.6 ± 27.9 at week 12, p = 0.1) in the placebo group completed 24 weeks of study drug treatment (N = 36:27 B-QR; with neither of these within-group changes being statistically significant but yielding a significant between-group difference of −54 mg/dL (p = 0.028) in favor of B-QR (Table 3). The mean TDID change from baseline was not statistically A B-QR vs Placebo Add-on to Met + BB Insulin, any dose significant within or between the two treatment groups (see 9.5 Table 3 for details). Baseline HbA1c > 7 Sensitivity analysis restricted to a subset of subjects within this 9 Placebo ≤ high-dose insulin cohort that had 5 units TDID change from B-QR baseline (N = 20:13 B-QR; 7 placebo) revealed similar findings 8.5 (Table 3) with the mean % HbA1c decreasing significantly by −1.03 in the B-QR-treated group from 8.18 ± 0.28 at baseline to 8 7.15 ± 0.28 at week 12 (p < 0.001) and trending up by 0.64 in the placebo-treated group from 8.49 ± 0.29 at baseline to 9.13 ± 0.6 at Mean HbA1c (%) 7.5 p week 12 ( = 0.24), yielding a significant between-group difference Δ HbA1c† -1.13 -1.05 -1.11 in the change in %HbA1c of −1.67 (p = 0.001). In this subgroup, the 7 p=<.001 p=0.01 p=0.027 within-group change in FPG from baseline to week 12 was Week 0 Week 12 Week 24 Week 52 −11.3 ± 13.97 mg/dL (from 158.9 ± 17.1 at baseline to 147.6 ± 9.5 Duration of Study Dug Treatment at week 12, p = 0.43) in the B-QR group and 49.7 ± 33.3 mg/dL B B-QR vs Placebo Add-on to Met + BB Insulin, ≥70 U/day (from 175.6 ± 24.7 at baseline to 225.3 ± 34.8 mg/dL at week 12, p = 0.19) in the placebo group, with neither of these within-group 10 Baseline HbA1c > 7 changes being statistically significant and yielding a relative 9.5 between-group difference of −61.0 ± 30.7 mg/dL which was also Placebo 9 not statistically significant (p=0.06). B-QR 8.5 8 3.4. Effect of B-QR versus placebo in percent of subjects

Mean HbA1c (%) 7.5 achieving goal HbA1c ≤7% 7 Δ HbA1c† -1.49 -1.36 -1.89 Among subjects treated with B-QR, 16 out of the 44 (36.4%) p=0.001 p=0.007 p=0.005 ≤ 6.5 subjects achieved HbA1c 7% at week 12 compared to 0 of Week 0 Week 12 Week 24 Week 52 the 16 subjects in the placebo group (Fisher’s exact 2-sided Duration of Study Dug Treatment p = 0.003). In the high-dose insulin subgroup, 10 out of the 27 B-QR-treated (37%) versus 0 of the 9 placebo-treated subjects Figure 1. Effect of B-QR vs Placebo on HbA1c in Subjects on Basal-Bolus (BB) achieved HbA1c ≤7% (Fisher’s exact 2-sided p = 0.039). Insulin Plus Metformin (Met). POSTGRADUATE MEDICINE 7

9 placebo), the mean HbA1c decreased significantly from hypoglycemia each compared to 2 out of the 16 subjects 8.33 ± 0.17% at baseline to 7.46 ± 0.25 (p = 0.001) in the (12.5%) treated with placebo with one episode each of mild– B-QR group and trended up from 8.36 ± 0.24 at baseline to moderate hypoglycemia during the 12-week study period. 8.84 ± 0.46 at week 24 (p = 0.19) in the placebo group, Between study weeks 12 and 24, there were 2 episodes of yielding a significant between-group difference in the change mild hypoglycemia in the B-QR group and one episode of in % HbA1c of −1.36 (p = 0.007) (Figure 1, Panel B). The hypoglycemia, considered moderate, in the placebo group. change in FPG was −14.9 ± 13.2 (p = 0.27) in the B-QR group From 24 to 52 weeks, there were 3 episodes of mild–moderate and 7.8 ± 14.1 (p = 0.6) in the placebo group, yielding a hypoglycemia in the B-QR group, but 2 of these were asso- between-group difference of −22.7 ± 19.3 mg/dL, which was ciated with other reasons for hypoglycemia, including one not statistically significant (p = 0.36). The TDID change was subject who developed mild hypoglycemia after having −3.4 ± 5 units in the B-QR group and 4.4 ± 12.3 units in the taken AM insulin dose while fasting and another patient with placebo, yielding a between-group difference of an episode of moderate hypoglycemia in the setting of having −7.8 ± 11.1 units (95% CI −30.4, 14.8) in favor of lower dose not eaten the night before. Overall, between baseline to week in the B-QR group but neither of the within group changes nor 52, there were a total of 9 episodes of hypoglycemia occurring the between-group difference were statistically significant. in 8 subjects in the B-QR group, but with 2 of the episodes Among subjects completing 52 weeks of study drug treat- likely due to other reasons as described above and a total of 3 ment (N = 45: 32 B-QR, 13 placebo), mean HbA1c trended episodes in 2 subjects in the placebo group. There were no down in the B-QR treated group from 8.25 ± 0.16 at baseline severe/serious episodes of hypoglycemia in either treatment to 7.81 ± 0.29 at week 52 (p = 0.13) and trended up in the group. placebo-treated group from 8.15 ± 0.21 at baseline to 8.82 ± 0.42 at week 52 (p = 0.045), yielding a significant between-group difference in the mean change in HbA1c 4. Discussion from baseline of −1.11 (p = 0.027) (Figure 1, Panel A). The changes in FPG from baseline to week 52 were not statistically The results of this study demonstrate that in T2DM subjects significant within either treatment groups (−7.8 ± 11.3 mg/dL, whose glycemia was poorly controlled on metformin plus p = 0.5 in the B-QR group and 25 ± 13.9 mg/dL, p = 0.096 in basal–bolus insulin therapy, the addition of B-QR resulted in the placebo group) and the between-group difference in the significant improvement of glycemic control (−1.13 reduction in mean change in FPG (−32.8 ± 19.8 mg/dL, p = 0.1) was also HbA1c with B-QR relative to placebo [p <0.001];–0.73 reduc- not statistically significant. The within-group changes and tion in HbA1c from baseline of 8.3% within the B-QR group [p < between-group difference in the change in TDID from baseline 0.001]). This B-QR effect was even more pronounced in subjects were not statistically significant (mean change in TDID whose glycemia was poorly controlled on high dose (≥70 U/ 0.3 ± 5.5 units in the B-QR group; 4.2 ± 7 units in the placebo day) basal–bolus insulin therapy (−1.49 reduction in HbA1c with group; between-group difference −3.8 ± 9.7 units). B-QR relative to placebo [p =0.001];−0.95 reduction in HbA1c Among subjects in the high-dose insulin subset (≥70 units from baseline of 8.4% within the B-QR group [p <0.001]). TDID at baseline) completing 52 weeks of study drug (N = 28: Moreover, 36% of B-QR treated versus 0% of placebo-treated 21 B-QR, 7 placebo), HbA1c decreased significantly from subjects achieved an HbA1c ≤7.0. No significant within or 8.31 ± 0.2 to 7.42 ± 0.26 (p = 0.01) in the B-QR treated between-group differences were observed in the change from group and trended up in the placebo group from baseline in TDID. Importantly, a sensitivity analysis restricted to 8.46 ± 0.25 to 9.46 ± 0.65 (p = 0.07), yielding a significant individuals with minimal insulin dose change during the study between-group difference in the mean change in % HbA1c of reaffirmed the study findings in the total study population −1.89 (95% CI −3.2, −0.61; p = 0.005) (Figure 1, Panel B). The (both in the any baseline TDID and baseline TDID ≥70 units/ within-group changes in mean FPG from baseline to week 52 day groups). The findings of this randomized, double-blind, and the mean between-group difference in the change in FPG placebo-controlled study corroborate and are in agreement from baseline were not statistically significant with those of a previous open-label, pilot study of B-QR therapy (−17.6 ± 14.7 mg/dL, p = 0.2 in the B-QR group, in T2DM subjects on metformin plus high-dose basal–bolus 35.9 ± 15.9 mg/dL, p = 0.07 in the placebo group, between- insulin [38]. Furthermore, consistent with previous studies of group difference −53.4 ± 27.2 mg/dL, p = 0.06). The within- B-QR therapy impact on glycemic control [23,38,39], the group changes and between-group difference in the change improvement in HbA1c observed within B-QR-treated subjects in mean TDID were not statistically significant (mean change in this study cannot be fully attributed to a reduction in fasting in TDID 1.1 ± 7.6 units in the B-QR group; 0.29 ± 12.5 units in glucose levels (−0.73 and −0.95 percentage points reductions the placebo group, between-group difference 0.86 ± 15 units). from baseline in HbA1c, p < 0.001 for both with −12 and −11 mg/dL reduction from baseline in mean FPG, p =NSfor the any baseline TDID and ≥70 units/day baseline TDID groups, 3.6. Safety respectively) (see Table 2 for details). In the previous pilot study There was no significant difference in adverse events asso- mentioned above, the HbA1c reduction with B-QR was coupled ciated with B-QR therapy compared to placebo. Episodes of with no significant change in FPG levels but a 32% reduction in hypoglycemia were infrequent and mild–moderate in severity. postprandial blood glucose response to a mixed-meal tolerance Between baseline and study week 12, 4 out of the 44 subjects test. While postprandial blood glucose levels were not available (9%) treated with B-QR had one episode of mild–moderate for analysis in the present study, the similar pattern of 8 B. CHAMARTHI AND A. CINCOTTA significant HbA1c lowering without significant change in fasting Likewise, circadian-timed administration of the dopamine glucose levels within the B-QR-treated group suggests that the agonist, bromocriptine (either systemically or intracerebroven- HbA1c reduction may be mostly driven by lowering of post- tricularly) to insulin resistant rodents at a time of day prece- prandial blood glucose levels. dent to the circadian peak in dopaminergic activity at the The preponderance of available evidence from preclinical and hypothalamic clock (SCN) center observed in normal insulin- clinical mechanistic studies indicates that a majority (but not the sensitive animals (and which is diminished in insulin resistant total) of the improvement in glycemic control observed with B-QR states as mentioned above) improves insulin resistance/glu- therapy in T2DM subjects results from a drug-induced improve- cose intolerance particularly insulin-mediated glucose disposal ment in postprandial glucose metabolism and [21– assessed during a hyperglycemic–euinsulinemic clamp (post- 23,35–39]. Interestingly, this B-QR effect on postprandial hypergly- prandial glucose environment) [28–31,35]. Such circadian- cemia is expressed at meal times across the day [22,23]andwell timed bromocriptine treatment also reduces abnormally ele- after (e.g. 24 h later) the short pulsed duration of bromocriptine vated NA and serotonergic (S) input activity to the VMH into the circulation following its circadian-timed morning admin- [28,31] and CRH and NPY activities at the PVN [30], which istration [37,38], which supports the preclinical data suggesting a are all neuromodulatory activities that, as described above, ‘resetting’ of aberrant neuroendocrine responsiveness to meal- act to potentiate insulin resistance and glucose intolerance time feeding to improve postprandial insulin sensitivity with this [28–31,41–43]. In particular, elevated VMH NA input activity therapy [27–36]. Mechanistic insights into this metabolic phenom- functions to attenuate appropriate glucose and free fatty acid enon can be gained from a series of neurophysiological studies nutrient sensing at meal time [34] that in turn potentiates that established a facilitatory role for the circadian peak in dopa- postprandial insulin resistance and reduced glucose disposal minergic input activity to the body pacemaker clock system [48–50]. Furthermore, such metabolic effects of increased NA (suprachiasmatic nuclei [SCN]) in the maintenance of normal insu- input activity to the VMH can be exacerbated by concurrent lin sensitivity and glucose tolerance in animal models of insulin increased serotonergic input activity to the VMH [42]. resistance [26–34] described as follows. The simple rationale of combining the administration of an The normal circadian peak in neuronal dopaminergic input insulin sensitizer with insulin is an effort to simultaneously activity to the SCN is diminished in insulin-resistant states and treat two main pathologies of T2DM, namely insulin resistance selectively reducing such peak activity in normal animals by and deficient plasma insulin levels, as has been previously targeted biochemical disruption of dopaminergic function at reviewed [51]. While the rationale of such a combination is the SCN induces the insulin-resistant and glucose-intolerant straightforward respecting optimizing glucose control in condition [26,32]. Moreover, high fat feeding that induces insu- T2DM patients with inadequate glycemic control on basal– lin resistance/glucose intolerance results in a marked reduction bolus insulin plus metformin, the options currently available in the circadian peak of dopaminergic activity at the SCN [40]. for an effective and safe insulin sensitizer are very limited. The Importantly, in animals made insulin resistant by such high fat use of TZDs, the only other currently available option for an feeding, a 1-min administration of dopamine to the SCN made insulin sensitizer, is limited by safety concerns particularly once daily for a 2-week period at the time of day that dopamine edema and heart failure leading to the Food and Drug activity peaks at the SCN of normal insulin-sensitive animals Administration including a warning in the prescription infor- reverses the insulin resistance/glucose intolerance while ani- mation for rosiglitazone and pioglitazone [14–16]. Inasmuch as mals are maintained on the high fat diet [27]. Such circadian- improving insulin resistance with TZD therapy is accompanied timed dopamine treatment at the SCN reduces abnormally with increased risk of bone fracture, edema, weight gain, and elevated noradrenergic (NA) input activity to the ventromedial CHF [8–16] and its effects on edema and CHF may be further hypothalamus (VMH) and the paraventricular nuclei (PVN) and exacerbated among insulin-treated T2DM subjects [8,13–16], is coupled to decreases in elevated neuropeptide Y (NPY) and safe and effective therapies are needed in this T2DM patient corticotropin releasing hormone (CRH) at the PVN [25–28,31], population, particularly those patients on high-dose insulin two neurophysiological conditions precipitating the insulin with few treatment options to improve insulin action and resistance syndrome [25,26,28,30,33,41–43]inpartbyinducing hyperglycemia whose diabetes is difficult to manage. The overactivation of sympathetic tone and hypothalamic–pituitary combination of B-QR with basal–bolus insulin represents a axis (HPA) drive to the viscera and vasculature that potentiate rather unique aspect of this therapeutic complementary strat- the syndrome [43–47]. That is, a diminution of the circadian egy in that B-QR therapy appears to induce improvement peak dopaminergic activity at the SCN is a neuromodulatory primarily in postprandial responsiveness to insulin as dis- signal that initiates output signals from the SCN to other cussed above and this effect is combined with a meal-time hypothalamic nuclei (e.g. VMH and PVN) programing them to insulin treatment to improve postprandial dysglycemia. It increase sympathetic drive to the liver and adipose, increase should be appreciated, however, that other meal-time, insu- HPA activity and alter neuroendocrine functions (increase glu- lin-independent, effects of circadian-timed B-QR therapy may cagon secretion, increase plasma leptin levels and resistance) also be operative in its effects to reduce postprandial hyper- that favor increased hepatic glucose production and lipid synth- glycemia, such as affecting glucose-mediated glucose dispo- esis, adipose lipolysis, hyperinsulinemia and decreased periph- sal, gastric absorption, reduction of elevated diurnal plasma eral uptake of glucose (in part from increased triglyceride prolactin level, and/or leptin action [25,26,28]. The results of storage in muscle), ultimately leading to insulin resistance with- this small study suggest that a larger, corroborative trial of B- out a requirement for any change in food consumption QR impact on glycemic control in T2DM subjects on metfor- (reviewed in Refs. [25, 26]). min plus basal/bolus insulin is warranted. POSTGRADUATE MEDICINE 9

Insulin resistance, postprandial dysglycemia, postpran- a financial interest in or financial conflict with the subject matter or dial hyperlipidemia, and elevated sympathetic nervous sys- materials discussed in the manuscript apart from those disclosed. tem activity are each risk factors for cardiovascular disease (CVD) [44–46,52–58]. As discussed above, circadian-timed B-QR therapy improves insulin sensitivity and postprandial References dysglycemia. Circadian-timed bromocriptine therapy also reduces elevated postprandial lipids, sympathetic tone, 1. Ferrannini E, Gastaldelli A, Miyazaki Y, et al. Beta-cell function in subjects spanning the range from normal glucose tolerance to inflammation, and endothelial nitric oxide synthase uncou- overt diabetes: a new analysis. J Clin Endocrinol Metab. – – pling [22,26,28,59], all major risk factors for CVD [44 46,52 2005;90:493–500. 54,58]. B-QR therapy has been associated with a 40–55% 2. Khunti K, Davies M, Majeed A, et al. 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Adding pioglitazone to insulin containing however is limited and further large trials are required to evalu- regimens in type 2 diabetes: systematic review and meta-analysis. ate/confirm this effect and such trials are warranted. PLoS One. 2009;4:e6112. 14. Scheen AJ. Combined thiazolidinedione-insulin therapy: should we be concerned about safety? Drug Saf. 2004;27:841–856. 5. Conclusion 15. Actos (pioglitazone hydrochloride) prescribing information [online]. cited 2017 Jan. Available from: http://www.accessdata.fda.gov/ B-QR therapy for a 12–52-week period in T2DM subjects whose drugsatfda_docs/label/2011/021073s043s044lbl.pdf; http://www. glycemia was poorly controlled on metformin plus basal–bolus actos.com/pi.pdf insulin, including those subjects on daily high-dose insulin (≥70 16. Avandia (rosiglitazone maleate) prescribing information [online] . units/day), improved glycemic control relative to placebo. cited 2017 Jan. Available from: http://www.accessdata.fda.gov/ drugsatfda_docs/label/2008/021071s034lbl.pdf; www.avandia.com 17. Gaziano JM, Cincotta AH, O’Connor CM, et al. Randomized clinical Funding trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes. Diabetes – This study was funded by S2 Therapeutics Inc. and VeroScience LLC. Care. 2010;33:1503 1508. 18. Gaziano JM, Cincotta AH, Vinik A, et al. Effect of bromocriptine-QR (a quick-release formulation of bromocriptine mesylate) on major Declaration of interest adverse cardiovascular events in type 2 diabetes subjects. J Am Heart Assoc. 2012;1:e002279. B Chamarthi is a consultant and part-time employee of VeroScience LLC. 19. Vinik AI, Cincotta AH, Scranton RE, et al. Effect of bromocriptine-QR AH Cincotta serves as the President and Chief Scientific Officer and is a on glycemic control in subjects with uncontrolled hyperglycemia shareholder of VeroScience LLC. The authors have no other relevant on one or two oral anti-diabetes agents. Endocr Pract. affiliations or financial involvement with any organization or entity with 2012;18:931–943. 10 B. CHAMARTHI AND A. CINCOTTA

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