Article: Treatment Effect of sitagliptin on glucose control in adult patients with Type 1 diabetes: a pilot, double-blind, randomized, crossover trial

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1 DIABETICMedicine Article: Treatment Effect of sitagliptin on glucose control in adult patients with Type 1 diabetes: a pilot, double-blind, randomized, crossover trial S. L. Ellis*, E. G. Moser*, J. K. Snell-Bergeon*, A. S. Rodionova*, R. M. Hazenfield* and S. K. Garg* *Barbara Davis Center for Childhood Diabetes, Department of Clinical Pharmacy, University of Colorado Denver and Department of Internal Medicine and Pediatrics, University of Colorado Denver, Aurora, CO, USA Accepted 2 May 2011 DOI: /j x Abstract Aims Patients with Type 1 diabetes have significantly elevated postprandial glucagon secretion. Dipeptidyl peptidase IV inhibitors improve HbA 1c by several mechanisms, including increasing glucagon-like peptide 1 and glucose-dependent insulinotropic peptide concentrations, which decreases postprandial rises in glucagon in both Type 1 and Type 2 diabetes. This study evaluates the clinical implications of sitagliptin in adult patients with Type 1 diabetes. Methods This investigator-initiated, double-blind, randomized, crossover, 8-week, pilot study enrolled 20 adult subjects with Type 1 diabetes. Subjects received sitagliptin 100 mg day or placebo for 4 weeks and then crossed over. Outcomes included 2-h postprandial blood glucose and 24-h area under the curve changes in glucose measurements from continuous glucose monitoring, HbA 1c, fructosamine and insulin dose. Results Sitagliptin significantly reduced blood glucose (2-h postprandial and 24-h area under the curve) despite reduced total and prandial insulin dose. Based on continuous glucose monitor findings, sitagliptin improved measures of glycaemic control, including mean blood glucose ()0.6 mmol l; P = 0.012) and time in euglycaemic range mmol l( h; P = 0.046). Significant reductions were also observed in M100, Glycemic Risk Assessment Diabetes Equation (GRADE) and J-index. After controlling for period, treatment and insulin dose, the HbA 1c was also significantly reduced [) % () mmol mol); P = 0.025] when patients were taking sitagliptin. Conclusions Sitagliptin significantly improved overall glucose control, including postprandial and 24-h glucose control, in adult patients with Type 1 diabetes, while significantly reducing prandial insulin requirements. Further investigation is warranted in patients with Type 1 diabetes in a larger cohort designed to assess both clinical outcomes and mechanism of action. Diabet. Med. 28, (2011) Keywords dipeptidyl peptidase IV inhibitor, glucagon-like peptide 1, HbA 1c, sitagliptin, Type 1 diabetes Abbreviations AUC, area under the curve; GRADE, Glycemic Risk Assessment Diabetes Equation; MAGE, mean amplitude of glycaemic excursion Introduction There are approximately 24 million people in the USA with diabetes, of which approximately 5 10% are diagnosed with Type 1 diabetes [1]. Over the past two decades the incidence Correspondence to: Satish K. Garg MD, Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Mail Stop A140, 1775 Aurora Court, Aurora, CO 80045, USA. Satish.garg@ucdenver.edu (Clinical Trials Registry No; NCT ) of Type 1 diabetes has been increasing in the USA [2]. It is well recognized that improving HbA 1c values with multiple daily injections of insulin during the Diabetes Control and Complication Trial (DCCT) significantly reduced microvascular complication; however, the majority of adults with Type 1 diabetes remains above currently recognized HbA 1c targets of < 53 mmol mol (7%) (reference standards of care) [3 5]. Despite knowledge of the relationship between tight glycaemic control and reduced complications, many barriers interfere with 1176 Diabetic Medicine ª 2011 Diabetes UK

2 Original article DIABETICMedicine achieving target HbA 1c in patients with Type 1 diabetes [6]. Monnier et al. demonstrated that, when HbA 1c values are < 62 mmol mol (7.8%), the greater postprandial blood glucose has a greater influence on overall glucose control, suggesting the need for more aggressive management of postprandial hyperglycaemia [7]. Patients with Type 1 diabetes also experience a paradoxical increase in glucagon, similar to Type 2 diabetes, which contributes to increased hepatic glucose output, resulting in worsening HbA 1c values, postprandial blood glucose control and increased glucose variability [8 11]. Pörksen et al. demonstrated that glucagon levels increase significantly in the first year after diagnosis of Type 1 diabetes and that this increase is highly correlated to increasing postprandial blood glucose levels. In this study, they determined that every 10-mmol l increase in blood glucose corresponded to a 20% increase in glucagon release [11]. This suggests that alternative strategies to help reduce elevated postprandial glucagon release could have important therapeutic benefits in patients with Type 1 diabetes. Sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, increases endogenous glucagon-like peptide 1 levels by inhibiting its rapid metabolism through the dipeptidyl peptidase IV enzyme. It is currently Food and Drug Administration (FDA) approved for the treatment of Type 2 diabetes as monotherapy or in combination with insulin or other oral hypoglycaemic agents. Increasing endogenous glucagon-like peptide 1 levels in patients with Type 2 diabetes has been shown to significantly improve postprandial glucose levels by both increasing glucose-dependent insulin release and reducing glucagon levels. The purpose of this investigator-initiated, pilot study was to assess the clinical benefit of sitagliptin in adult patients with Type 1 diabetes. Patients and methods This 8-week, double-blind study, randomized subjects to either sitagliptin 100 mg day (group A) or matching placebo (group B) for 4 weeks and then crossed over to the opposite treatment for 4 weeks. Patients were eligible to participate in the study if they were years old, had documented Type 1 diabetes, were on stable multiple daily injection or continuous subcutaneous insulin infusion therapy and had an HbA 1c value between 69 and 108 mmol mol (8.5 12%). Subjects were excluded if they were on pramlintide, metformin or a glucagon-like peptide 1 agonist, had known allergy to adhesives or dipeptidyl peptidase IV inhibitors, creatinine >0.1mmol L or a calculated creatinine clearance of <50ml min. Blinded continuous glucose monitoring was carried with the SEVEN PLUS Ò CGM system (DexCom Inc., San Diego, CA, USA) throughout the entire 8-week study. Only self-monitoring of blood glucose results were used to make insulin dosing decisions. Patients were educated on proper use, insertion (every 7 days) and calibration of the continuous glucose monitor. Subjects were instructed to continue their current insulin dosing regimen and attempt to maintain their current diet and exercise regimen. No insulin titration schedule was used during this study. Patients were instructed to make changes to their insulin dose as they felt necessary based on their blood glucose readings as it was a double-blind study. A diary was provided to each subject where they recorded blood glucose readings, mealtimes, insulin dose and comments about missed meals, exercise and illness. These data were used along with continuous glucose monitor downloads to determine the effects of sitagliptin on blood glucose at 2-h post-meal, daytime, night-time and 24-h area under the curve (AUC). This study was approved by the Colorado Multiple Institutional Review Board Western Institutional Review Board (COMIRB WIRB) and each subject provided informed consent and was registered under clinicaltrials.gov identifier: NCT The primary outcome was to compare the 2-h postprandial blood glucose and the 24-h glucose AUC in adult subjects with Type 1 diabetes on sitagliptin and placebo. Secondary outcomes included comparing markers of glucose control [mean continuous glucose monitor glucose, M100, J-index, Glycemic Risk Assessment Diabetes Equation (GRADE), High and Low Blood Glucose Index and time spent in hyper, hypo and euglycaemic ranges] and glucose variability [mean amplitude of glycaemic excursion (MAGE), per cent coefficient of variation and standard deviation]. In addition, changes to HbA 1c, fructosamine and insulin dose were recorded. Statistical analysis Characteristics of study participants at screening were examined by randomization to determine whether there were differences in demographic variables or screening laboratory values by crossover sequence. A Student t-test was used to compare continuous screening variables by randomization group. Linear mixed models were fitted to examine the effect of treatment on AUC, HbA 1c, total daily insulin dose and continuous glucose monitor measures of glycaemic variability and control, controlling for the time period and randomized sequence for the crossover design. The variance structure used was compound symmetry, which uses the assumption that the correlation between all pairs of measures are the same. Data were included for AUC analyses if more than 70% of continuous glucose monitor readings were available during the evaluation period. Area under the curve values were adjusted for pre-meal blood glucose readings. Least-square means were calculated for the difference in the variables of interest on placebo compared with treatment. A P-value < 0.05 was considered to be significant for all analyses. Results Twenty-three patients were screened and 20 met inclusion criteria and were enrolled into this study. Subjects were randomized to sitagliptin (n = 10; sitagliptin fi placebo, Diabetic Medicine ª 2011 Diabetes UK 1177

3 DIABETICMedicine Sitagliptin in Type 1 diabetes S. L. Ellis et al. group A) or placebo (n = 10; placebo fi sitagliptin, group B). One subject withdrew after 1 week of enrolment (group A) and another (group B) was discontinued at week 3 after experiencing severe hypoglycaemia while on placebo. Baseline demographics were similar between randomization groups (group A vs. group B; Table 1). Glucose area under the curve When combining all meals, there was a significant reduction in 2-h postprandial blood glucose AUC. Individual meal postprandial blood glucose AUC was not statistically different. There was a significant decrease in 24-h AUC during sitagliptin use (Table 2). The reduction in both daytime ()452.9 mmol l 16 h) and overnight ()234.1 mmol l 8 h) AUC contributed to the significant reduction in 24-h AUC. However, neither one was statistically significant, with P-values of 0.08 and 0.14, respectively. HbA 1c, glucose control and glucose variability Table 2 Changes to measures of glucose control: differences between sitagliptin and placebo groups Measure of glucose control Estimated difference: sitagliptin vs. placebo (mean sd) P-value 2-h postprandial ) * glucose AUC (mmol l 2h) 24-h glucose AUC ) * (mmol l 24 h) HbA 1c (mmol mol) ) HbA 1c (%) ) Fructosamine ) *Change in least-square means ( se) 2-h postprandial blood glucose and 24-h area under the curve (AUC) (controlled for period, treatment and pre-meal blood glucose) was significantly lower when patients were on sitagliptin. HbA 1c was significantly improved while on sitagliptin after controlling for period, treatment, baseline HbA 1c and insulin dose. After 4 weeks, there was a significant reduction in HbA 1c values in both groups. After 8 weeks, there was a further reduction in HbA 1c values in group B (placebo fi sitagliptin) compared with a small increase in HbA 1c in group A (sitagliptin fi placebo). After controlling for period, treatment and insulin dose, there was a significant reduction in HbA 1c values with sitagliptin compared with placebo (Fig. 1). As expected, there was a higher decline in HbA 1c values in patients with higher baseline HbA 1c c Table 1 Baseline demographics (mean sd) HbA 1c, mmol/mol (%) 84 (9.8) 81 (9.6) 79 (9.4) 77 (9.2) 75 (9.0) 73 (8.8) 70 (8.6) 68 (8.4) 66 (8.2) Group A Group B Group A: sitagliptin placebo Group B: placebo sitagliptin P = Crossover Treatment fi placebo (group A) Placebo fi treatment (group B) (n = 10) (n =9) P-value* Age (years) Duration (years) HbA 1c (mmol mol) HbA 1c (%) Fructosamine (lmol) BMI (kg m 2 ) Total daily dose (units) Insulin dose (units kg day) Systolic blood pressure (mmhg) Diastolic blood pressure (mmhg) *Student s t-test comparing subjects randomized to sitagliptin 100 mg daily vs. placebo reveals no differences in baseline demographics between group A (randomized to sitagliptin) and group B (randomized to placebo). 64 (8.0) Baseline Month1 Month2 FIGURE 1 HbA 1c (mean se) MANOVA controlling for period (period 1 vs. 2), treatment (sitagliptin 100 mg daily vs. placebo) and insulin dose. Group A ( ) initially received sitagliptin for 4 weeks and then was crossed over for 4 weeks of placebo. There was a significant reduction in HbA 1c within this group, but a slight worsening of HbA 1c between weeks 5 and 8 while on placebo. Group B (n) initially received placebo for 4 weeks and then was crossed over for 4 weeks of sitagliptin. There was a significant reduction in HbA 1c within this group during the initial 4 weeks, but a continued decline in HbA 1c between weeks 5 and 8 after switching to sitagliptin. A significant difference in HbA 1c was observed when controlling for period, treatment and insulin dose. values. No difference was seen in fructosamine levels between groups. Measures of overall glucose, including mean glucose, (Fig. 2a) time spent in euglycaemic range ( mmol l), M100, J-index and GRADE (Table 3) control, were significantly improved with sitagliptin. These measures evaluate overall glucose control using both linear and non-linear methodologies. Measures of within-day and between-day 1178 Diabetic Medicine ª 2011 Diabetes UK

4 Original article DIABETICMedicine Table 3 Changes to measures of glucose control and glucose variability: differences between sitagliptin and placebo groups Glycaemic control parameters Overall glucose control glucose variability were not different between groups. These measures included standard deviation, per cent coefficient of variation and MAGE (Table 3). There was a trend for spending less time in the hyperglycaemic range and more time in the hypoglycaemic ranges (Fig. 2c), but neither was statistically significant. There were no serious adverse events reported while on sitagliptin. Insulin dose and weight Estimated difference sitagliptin vs. placebo (mean sd) P-value Mean glucose (mmol l) ) * Time spent in * mmol l (h) M100 ) * J-index ) * Glycemic Risk Assessment ) * Diabetes Equation (GRADE) Insulin dose Total daily insulin ) dose (units kg) Total daily basal ) insulin dose (units kg) Total daily bolus ) insulin dose (units kg) Glycaemic variability Glucose sd (mmol l) ) à Glucose coefficient à of variation (%) Mean amplitude of ) à glycaemic excursions (MAGE) Hyperglycaemia Time spent ) > 13.3 mmol l (h) High blood glucose index ) Hypoglycaemia Low blood glucose index à Time spent < 3.1 mmol l (h) à *Mean blood glucose, time spent in euglycaemic range, M100, J-index, and GRADE were significantly improved while on sitagliptin using the linear mixed model test and controlling for period, treatment and insulin dose. While on treatment there was a significant decrease in total and prandial insulin dose. àmeasures of glycaemic variability and hypoglycaemia were no different in the two groups. Total daily insulin dose (units kg) was significantly reduced in subjects while on sitagliptin compared with placebo (leastsquare means sd = ) , P = 0.012; Table 3). A significant (13.8%; P < 0.01, Fig. 2d) reduction in daily bolus insulin dose was observed. There was no difference in weight (P = 0.7) between groups throughout the study. Discussion To the best of our knowledge, this is the first study that evaluates the clinical efficacy of sitagliptin on glucose control and variability in adult patients with Type 1 diabetes. This study demonstrated that sitagliptin significantly reduced blood glucose; both 2-h and 24-h AUC in patients with Type 1 diabetes. Sitagliptin also significantly reduced total daily insulin dose and HbA 1c values while improving mean glucose from continuous glucose monitor downloads and time spent in the euglycaemic range ( mmol l). There was an overall downward shift in glucose profiles while receiving sitagliptin, but there was no significant effect on measures of glucose variability or hypoglycaemia. There were no reported serious adverse events in patients taking sitagliptin, including hypoglycaemia. A trend was identified during this study showing that patients on sitagliptin may spend more time in the low glucose range. This finding, although not statistically significant, suggests that hypoglycaemia needs to be further assessed in a larger clinical study designed to evaluate safety in this patient population. This study did not perform glucagon-like peptide 1, glucagon or C-peptide concentrations so it cannot make conclusions as to why these clinical improvements were observed. However, a recent study using vildagliptin in Type 1 diabetes reported a significant decrease in 4-h postprandial glucagon levels, suggesting a possible mechanism of action in patients with Type 1 diabetes of reducing postprandial glucose effect [12]. These data are consistent with clinic benefits observed in this study on 2-h postprandial glucose AUC. The use of metformin (another insulin sensitizer) in subjects with Type 1 diabetes has shown similar results in lowering HbA 1c values and insulin dose [13 15]. The limitations of this study include a large Hawthorne effect, which was seen during period 1 in both the sitagliptin and placebo groups. Taking this into account, we controlled for both period and treatment effects, which indicated sitagliptin had a greater benefit on multiple measures of glucose control, including 2-h and 24-h AUC, mean blood glucose and reduction in time spent in the euglycaemic range. An additional limitation included a small sample size evaluated for a short duration. This did not allow for a full evaluation of the effect on the secondary outcome HbA 1c, which takes 12 weeks to achieve the maximum effect. Another possible limitation was the lack of washout between the two periods. We controlled for this by evaluating the outcomes of this study using only the week 3 4 data in each time period, thus controlling for the lack of washout in the study design. This study did not evaluate the effect of sitagliptin on glucagon-like peptide 1 or glucagon levels, which would allow us to make more correlation between the possible mechanisms of sitagliptin and the clinical findings we found in this study. A much larger multi-centre study for longer duration is warranted, Diabetic Medicine ª 2011 Diabetes UK 1179

5 DIABETICMedicine Sitagliptin in Type 1 diabetes S. L. Ellis et al. (a) (b) (c) (d) FIGURE 2 Mean glucose (a) and HbA 1c (b) values were significantly lower in the sitagliptin-treated group when compared with the placebo group. Time spent in euglycaemia (c) was significantly higher despite a decrease in insulin dose (d) during the sitagliptin exposure when controlled for treatment and period effects. evaluating the effects of dipeptidyl peptidase IV inhibitor on insulin dose, glucose control, variability and mechanisms of action in patients with Type 1 diabetes. Author Contributions Ellis SL researched data, contributed to discussion, wrote manuscript, and reviewed/edited manuscript. Moser EG researched data, contributed to discussion, and reviewed/edited manuscript. Snell-Bergeon JK performed statistical analysis, contributed to discussion, and reviewed/edited manuscript. Rodionova AS researched data, contributed to discussion, and reviewed/edited manuscript. Hazenfield RM contributed to discussion and reviewed/edited manuscript. Garg SK researched data, contributed to discussion, and reviewed/edited manuscript. Competing interests SLE and SKG have received research funding from Merck Inc. SKG has received honoraria for attending the global Advisory board for Merck. JKS-B, EGM, ASR and RMH have nothing to declare. Acknowledgement This investigator-initiated study was sponsored by a grant to the University of Colorado Denver from Merck Inc. (Whitehouse Station, NJ, USA). References 1 American Diabetes Association. Standards of medical care in diabetes Diabetes Care 2010; 33: S11 S61. 2 Vehik K, Hamman RF, Lezotte D, Norris JM, Klingensmith G, Bloch C et al. Increasing incidence of type 1 diabetes in 0- to 17-year-old Colorado youth. Diabetes Care 2007; 30: Diabetes Control and Complications Trial Research Group. The effect of intensive treatment on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: Diabetes Control and Complications Trial Epidemiology of Diabetes Interventions and Complications (DCCT EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with Type 1 diabetes. N Engl J Med 2005; 353: Diabetes Control and Complications Trial Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes 4 years after a trial of intensive therapy. N Engl J Med 2000; 342: Peyrot M, Rubin RR, Lauritzen T, Snoek FJ, Matthews DR, Skovlund SE. Psychosocial problems and barriers to improved diabetes management: results of the Cross-National Diabetes Attitudes, Wishes and Needs (DAWN) Study. Diabet Med 2005; 22: Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients. Diabetes Care 2003; 26: Garg S, Jovanovic L. Relationship of fasting and hourly blood glucose levels to HbA 1c values. Diabetes Care 2006; 29: Diabetic Medicine ª 2011 Diabetes UK

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