Research Article. , Keiko Kondo

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1 Research Article Sitagliptin Add-On Therapy to Avoid Starting Insulin Therapy in Type 2 Diabetes Patients with Secondary Failure to Sulfonylurea: A 24-Week Prospective Study Satoshi Ugi 1 *, Katsutaro Morino 1, Keiko Kondo 2, Katsuyuki Miura 2, Katsuya Egawa 3, Ken-ich Kodama 3, Tomoya Fuke 3, Takaaki Nakamura 4, Masataka Nishimura 5, Shu Yamada 6, Yasushi Omura 6, Akio Kishi 7, Yasuo Kida 7, Noriko Takahara 8, Toshiyuki Obata 8, Yoshihiko Nishio 9 and Hiroshi Maegawa 1 1 Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan 2 Department of public Health, Shiga University of Medical Science, Otsu, Shiga, Japan 3 Nagahama Red Cross Hospital, Japan 4 Omihachiman Community Medical Center, Japan 5 Nagahama City Hospital, Japan 6 Kohka Public Hospital, Japan 7 Okamoto Hospital, Japan 8 Ako City Hospital, Japan 9 University of Kagoshima, Japan *Corresponding Author: Satoshi Ugi, Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan; Tel: ; Fax: ; address: sugi@belle.shiga-med.ac.jp Published: December 30, 2015 Abstract: Aim: To investigate the potential of sitagliptin, a dipeptidyl peptidase-4 inhibitor, as add-on therapy to avoid or delay insulin therapy in type 2 diabetes mellitus (T2DM) patients with secondary failure to sulfonylurea derivatives (SUs). Methods: In this prospective single-arm 24-week intervention study, 19 T2DM patients poorly controlled by SU were hospitalized for 14 days. After diet therapy, sitagliptin (50 mg/day) was started at day 6. Insulin therapy was started if fasting blood glucose was >140 mg/dl and/or 2-h blood glucose >250 mg/dl after starting sitagliptin. Daily glucose excursions were assessed simultaneously by continuous glucose monitoring (CGM). Results: Eighteen patients completed the study and one withdrew because of severe hypoglycemia after starting sitagliptin. Initiation of insulin therapy was avoided during hospitalization. At 12 weeks after discharge, one patient started insulin therapy, while 17 managed without insulin at 24 weeks. Mean glycosylated hemoglobin decreased significantly from 8.39±0.25% at baseline to 6.85±0.17% (P <0.0001) at 12 weeks, and 6.92±0.18% (P <0.0001) at 24 weeks. Add-on sitagliptin rapidly ameliorated pre- and post-prandial glucose levels as assessed by CGM. The 24- h mean glucose levels decreased from 181.1±10.2 mg/dl to 162.0±9.2 mg/dl (P <0.0001), and daily glucose fluctuations assessed by standard deviation of the 24-h glucose levels were decreased from 49.0±3.3 mg/dl to 38.9±3.4 mg/dl (P = 0.001). Conclusion: These results suggest that sitagliptin add-on therapy represents a suitable choice before starting insulin therapy in patients with secondary failure to SU. Abbreviations: BMI: Body Mass Index; CGM: Continuous Glucose Monitoring; FPG: Fasting Plasma Glucose; OHA: Oral Hypoglycemic Agents; SMBG: Self-Monitoring of Blood Glucose

2 Page 2 of 8 Introduction: Type 2 diabetes mellitus (T2DM) is a progressive disease in which the β-cell function of patients declines gradually, as shown in the UK Prospective Diabetes Study (UKPDS) [1]. The Diabetes Outcome Progression Trial (ADOPT) study also showed that anti-diabetic agents did not prevent the deterioration of β-cell function [2]. As a consequence, good glycemic control in T2DM patients often requires insulin supplementation therapy [2-4]. However, despite the known benefits of insulin, many patients delay insulin treatment because of the hesitations of both patients and physicians as revealed in the Diabetes Attitudes, Wishes, and Needs (DAWN) Study [5,6]. As a consequence, unfortunately, many T2DM patients do not receive insulin therapy in a timely manner [5,6]. Sulfonylurea derivatives (SUs), which are widely used in the treatment of T2DM, are long-acting and potent insulin secretagogues. However, SU efficacy diminishes over time, an effect known as secondary failure to SU [7,8]. There is an apprehension that this effect may be due to SU-mediated impairment of β- cell function over time through their potent stimulatory effect on insulin secretion [2,8]. It has been reported that early addition of insulin, when SU therapy is inadequate, can improve glycemic control [4,9]. Thus, it is important for timely initiation of insulin therapy when the patients cannot be adequately controlled by SU. Dipeptidyl peptidase-4 (DPP-4) inhibitors are also widely used for the treatment of T2DM patients. Several studies showed that combination therapy with DPP-4 inhibitors and SU is effective for glycemic control [7,10-12]. Furthermore, basic experiments have shown the synergistic effect of this combination therapy. Using an in situ perfused rat pancreas model, insulin secretion was augmented 3- fold by co-infusion of glucagon-like peptide-1 (GLP- 1) and tolbutamide compared with the responses to GLP-1 and tolbutamide alone [13]. Furthermore, unexpected hypoglycemia has been reported during combination therapy even in patients who had exhibited secondary failure to SU after the launch of sitagliptin in Japan [14]. These observations indicate that combination therapy with these two drugs represents a powerful therapeutic strategy. Therefore, DPP-4 inhibitor addon therapy is expected to avoid or delay the initiation of insulin therapy in patients who are inadequately controlled with SU, or those who deny insulin therapy. In this study, we investigated the potential of add-on therapy with the DPP-4 inhibitor sitagliptin to avoid or delay initiation of insulin therapy in T2DM patients with secondary failure to SU. Meanwhile, we assessed the daily glucose excursion by continuous glucose monitoring (CGM) after the addition of the DPP-4 inhibitor. Methods: Subjects: This study was a prospective single-arm 24-week intervention study conducted at the Shiga University of Medical Science Hospital (Japan) and its affiliated hospitals. Patients with T2DM aged years and poor control of blood glucose levels (glycosylated hemoglobin %) taking SU with or without other oral anti-diabetic treatment for longer than 2 months, were included in this study. Exclusion criteria were: 1) insulin treatment; 2) type 1 diabetes mellitus; 3) severe ketosis, coma; 4) severe infection, pre- or post-operative, or severe trauma; 5) clinically relevant history of gastrointestinal disease, with prolonged nausea and vomiting during the previous 6 months; 6) pregnancy, possible pregnancy; 7) renal dysfunction (the estimated glomerular filtration rate [GFR] <60 ml/min); 8) severe hepatic dysfunction (alanine aminotransferase) greater than three times the upper limit of the normal laboratory range; 9) history of hypersensitivity to any of the ingredients of the study drugs; and 10) judged to be unsuitable for participation for medical reasons. All patients gave written informed consent prior to participation in the study. The study protocol was approved by the Ethics Committee of the Shiga University of Medical Science (#22-84) and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Study Design: Patients were hospitalized for 14 days (Figure 1). After a diet therapy (28 kcal/kg/day) runin period of 3 days to minimize the interference of the effect of diet therapy with the effect of sitagliptin add-on therapy, blood glucose levels were measured for 4 consecutive days (days 4-7) using CGM (CGMS-gold; Medtronic Minimed, Northridge, CA, USA) to compare the values before and after administration of sitagliptin. Patients continued selfmonitoring of blood glucose (SMBG) throughout hospitalization.

3 Page 3 of 8 Patients were hospitalized for 14 days. After dietary therapy for the first 3 days, CGM data were obtained from day 4 to 7. Sitagliptin was administered from day 6 after hospitalization. The decision to start insulin therapy was based on SMBG throughout the period of hospitalization. Follow-up was continued for 24 weeks. Sitagliptin (50 mg/day) was first administered on day 6 at 08:00 hours before breakfast and continued thereafter. The dose of SU was not reduced when sitagliptin was added, but the adjustment of the dose of SU based on the physician s decision was allowed. Figure 1: Study Design and Procedure Flow Chart. and C-reactive immunoreactivity (CPR) levels were measured with a chemiluminescent enzyme immunoassay. Twenty-four-hour urine samples were collected for determination of the CPR content at baseline. Criteria for Starting Insulin Therapy: When fasting blood glucose on each morning during hospitalization exceeded 140 mg/dl and/or 2-h blood glucose exceeded 250 mg/dl as assessed by SMBG after starting sitagliptin (from day 9), insulin therapy was initiated. Endpoint and Assessment: The primary efficacy endpoint was the number of patients who avoided starting insulin therapy until either discharge or at 24 weeks. Secondary Endpoint: The following values were calculated using CGM data: 1) mean 24-h blood glucose levels; 2) standard deviation (SD) of 24-h blood glucose levels as the index of daily glucose fluctuations; and 3) lowest pre-prandial and highest post-prandial blood glucose levels. Changes in HbA and body weight from baseline to week 24 were observed. Safety was evaluated with hypoglycemia accompanied by plasma glucose <60 mg/dl based on CGM and SMBG data. Laboratory Assays: Levels of HbA were measured at a National Glycohemoglobin Standardization Program Level 1 certified central laboratory (Covance Central Laboratory Services), using a highperformance liquid chromatography method. Plasma glucose levels were measured with the hexokinase G6PD UV method. Serum immunoreactive insulin Statistical Analysis: Statistical analyses were performed with SPSS version 22.0 (Tokyo, Japan). The distribution of variables was analyzed by assessing histograms and normal plots of the data, and the normality was tested using the Kolmogorov Smirnov and Shapiro Wilk tests. For normally distributed data, repeated measures analysis of variance (RM-ANOVA) was performed for comparisons of different periods of determinations. In addition, post hoc testing was performed using Dunnett s test. For variables with non-normal distributions, the nonparametric Friedman test or Wilcoxon test was used as a post hoc test with Bonferroni correction. Paired t-test was used to compare the levels of blood glucose before and after the treatment. Unpaired Student s t-test was used to compare the change of HbA levels by baseline characteristics. All data except for baseline characteristics are expressed as the mean ± SE. P- values of <0.05 were considered statistically significant, unless specifically described. Results: Baseline Characteristics: Nineteen patients were enrolled in this study. Patients had a mean age of 62.5 years, diabetes duration of 15.2 years, body mass index of 24.5 kg/m 2, and baseline HbA of 8.4% (Table 1). All patients were taking SUs; 14 patients were taking glimepiride (2.1±0.8 mg/day),

4 Page 4 of 8 four were taking glibenclamide (8.4±1.0 mg/day), and one was taking gliclazide (60 mg/day). Nine patients were taking biguanide and six patients were taking thiazolidine and α-glucosidase inhibitor. plasma glucose (180 mg/dl) at 12 weeks. Overall, 17 patients were managed without insulin at 24 weeks. Characteristics Value Age (years) 62.5±44.1 Sex (M/F) 10-Sep Body Weight (kg) 63.2±14.1 BMI (kg/m 2 ) 24.5±4.2 Diabetes duration (years) 15.2±10.1 HbA (%) 8.4±1.1 FPG (mg/dl) 160.4±47.8 Fasting IRI (µu/ml) 4.7±2.4 Fasting CPR (ng/ml) 2.0±1.2 Urinary UPR (µg/day) 80.2±71.7 OHA n (%) Sulfonylurea 19 (100) Biguanide 9 (47.4) Thiazolidine 6 (31.6) α-glucosidase inhibitor 6 (31.6) Table 1: Subject Characteristics at Baseline. Values are expressed as mean±sd for continuous variables. Primary Endpoint: Eighteen patients completed the study (Figure 2). Of the 19 patients enrolled, one patient experienced severe hypoglycemia after the addition of sitagliptin and withdrew from the study. Although all patients exceeded 2-h blood glucose levels of 250 mg/dl before the addition of sitagliptin, fasting blood glucose levels <140 mg/dl and 2-h blood glucose levels <250 mg/dl were maintained in 18 patients, thus avoiding the initiation of insulin therapy during hospitalization. At 12 weeks, one patient started insulin because of no improvement in HbA (8.6% at baseline to 8.3%) and elevated fasting Figure 2: Results of Primary Outcome Secondary Endpoint: CGM Data: One patient was not evaluated by CGM because of technical problems (sensor failure). Thus, CGM data were evaluated in 17 patients. Surprisingly, the blood glucose level after breakfast following the first dose of sitagliptin was significantly decreased compared with that of the previous day (Figure 3). The 24-h mean glucose level before adding sitagliptin (day 5) was 181.1±10.3 mg/dl, and it decreased to 162.0±9.2 mg/dl (P <0.0001) and 158.8±9.0 mg/dl (P <0.0001) on the following days after addition of sitagliptin (days 6 and 7). The SD of blood glucose levels was also significantly decreased from 49.0±3.3 mg/dl to 38.9±3.4 mg/dl (P = 0.001) and 39.7±3.3 mg/dl (P = 0.003) at days 6 and 7, demonstrating reduced fluctuation in the blood glucose levels.

5 Page 5 of 8 Arrows indicate the time of sitagliptin administration. The 24-h mean and standard deviation (SD) of glucose levels measured by CGM are shown in Table. Data represent the mean±se. CGM: continuous glucose monitoring. a P < vs. day 5, b P = vs. day 5, c P = vs. day 5 Figure 3: CGM data were obtained from day 4 to day 7 of the hospital stay (n = 17). One patient was excluded because of a technical issue. Pre-prandial glucose level (just before meal ingestion) and post-prandial glucose level (peak value after meal ingestion) on days 5 and 7 (before and after the addition of sitagliptin) were compared using CGM data. Both the pre- and post-prandial (breakfast, lunch, and dinner) glucose levels were significantly decreased after the addition of sitagliptin (Figure 4), with pre-prandial blood glucose levels decreased from 19 mg/dl to 26 mg/dl, and the post-prandial levels decreased from 26 mg/dl to 51 mg/dl. weeks was 8.3% (8.6% at baseline). The body weight of patients was significantly reduced from baseline at 2, 12, and 24 weeks ( 1.2±0.5 kg, 1.8±0.6 kg, and 2.2±0.6 kg, respectively) (Figure 5B). Data represent the mean±se. B: breakfast; L: lunch; D: dinner Figure 4: Change in pre- and post-prandial blood glucose levels before (day 4) and after (day 7) the addition of sitagliptin as assessed by CGM data. HbA and Body Weight: HbA significantly decreased from 8.39±0.25% at baseline to 6.85±0.17% at 12 weeks (P <0.0001) and 6.92±0.18% at 24 weeks (P <0.0001) (Figure 5A). The number of patients with HbA below 7% at 12 and 24 weeks was 10 and eight, respectively. In contrast, HbA in patients who started insulin at 12 Changes in body weight are expressed as the change from baseline. Data represent the mean±se. *P <0.05 vs. 0 week, ** P <0.001 vs. 0 week, ** P < vs. 0 week Figure 5: Changes in HbA (A) and body weight (B) Hypoglycemia: Severe hypoglycemia occurred in only one patient. According to CGM data analysis, hypoglycemia ( 60 mg/dl) was recorded in four patients with a total frequency of nine episodes before the addition of sitagliptin, and in three patients with a total frequency of five episodes after the addition of sitagliptin.

6 Page 6 of 8 SU Dosage: The SU dosage was reduced in three patients and stopped in one patient at 2 weeks. At 12 weeks, the dosage was reduced in three patients and stopped in one patient. Finally, at 24 weeks, the dosage was reduced in eight patients and stopped in three patients. The final dosages of glimepiride, glibenclamide, and gliclazide were 1.4±0.8 mg, 6.7±1.2 mg, and 0 mg, respectively. Discussion: We demonstrated that sitagliptin add-on therapy improved glycemic control in patients with T2DM for whom there was inadequate glycemic control with SU. Insulin therapy was avoided in most of the participating patients (N=17) over the 6-month period. Furthermore, we observed rapid effects of sitagliptin in the reduction of both pre- and postprandial glucose levels. Of the 18 patients who completed the study, insulin therapy was avoided in all patients prior to discharge from the hospital. Initiation of insulin therapy was based on the criteria of fasting blood glucose and 2-h blood glucose below 140 mg/dl and 250 mg/dl, respectively. The Japan Diabetes Association as well as the American Diabetes Association recommend lowering HbA to 7.0% in most patients to reduce the incidence of microvascular disease [15,16]. In this study, the number of patients with HbA below 7% at 12 weeks and at 24 weeks was 10 (56%) and 8 (44%). These results suggest that approximately 50% of patients have the potential to be managed by the sitagliptin add-on therapy over 6 months. However, the remainder of the patients may need insulin therapy. Interestingly, we observed a highly acute response to sitagliptin. The addition of sitagliptin before breakfast rapidly lowered the postprandial glucose on that occasion. CGM data showed that both the preand post-prandial glucose levels were significantly decreased after the addition of sitagliptin. As a result, both the mean and SD of the 24-h blood glucose levels were significantly improved, which is consistent with previous reports showing that administration of sitagliptin alone or in combination with another drug decreased both the mean and glucose fluctuations [17]. These results suggest that sitagliptin effectively ameliorates blood glucose fluctuations. One patient experienced severe hypoglycemia after the addition of sitagliptin and withdrew from the study. However, the incidence of hypoglycemia did not increase in other patients during the study. Serious hypoglycemic side effects were frequently encountered in patients receiving combination therapy with sitagliptin and high-dose SU after the launch of sitagliptin in Japan [14]. Consequently, a safety alert was issued by the Japan Diabetes Association [18], which recommended that glycemic control should be monitored closely when adding sitagliptin to ongoing SU therapy, and down-titration of the SU dose should be considered to prevent hypoglycemia [14,18]. Our protocol did not automatically reduce the dose of SU when sitagliptin was added because the patients were hospitalized with continuous close observation. However, based on the physician s decision, the SU dosage was reduced in three patients and stopped in one patient at 2 weeks. The patient who experienced severe hypoglycemia was receiving 10 mg of highdose glibenclamide, which should have been reduced when sitagliptin was added. Thus, as recommended, our study confirms that the changes in blood glucose should be monitored closely during the add-on therapy. Persuasive mechanisms have been proposed regarding unexpected hypoglycemia as a result of combination therapy. SUs induce insulin secretion by directly closing the ATP-sensitive potassium channels, which are affected by intracellular adenosine triphosphate (ATP) levels [19]. Chronic hyperglycemia impairs glucose metabolism and ATP production in the cells, which then impairs insulin secretion [19]. Additionally, it has been reported that incretin increases ATP levels through improving glucose metabolism in the cells, which may improve the SU-induced insulin secretion [20]. It is important to note that this study was conducted in hospitalized patients. It has been reported that near normalization of glycemic control with insulin before starting sitagliptin improves the efficacy of sitagliptin in poorly controlled T2DM patients [21]. This phenomenon is supported by the report that the incretin receptor expression in β cells in diabetic mice was downregulated, and recovered after improvement of glycemic control [22]. Therefore, it can be speculated that dietary intervention after hospitalization might underlie the beneficial effect of sitagliptin observed in our study. Thus, it is possible that these results might not be generalized to apply to outpatients. In fact, body weight was reduced throughout the study, suggesting that lifestyle intervention during hospitalization was successful in

7 Page 7 of 8 our patients. Since DPP-4 inhibitor is known to be weight-neutral [23], it is unlikely that weight reduction was due to the administration of DPP-4 inhibitor. There are several limitations to this study; principally it only consisted of a small number of subjects. It is also limited by its relatively short duration and the possibility that the exact criteria used to determine the insulin requirement was inadequate over the time frame. Long-term glycemic control is the aim of diabetes therapy; therefore, a greater number of subjects and a longer period of observation are required for the precise evaluation of therapeutic efficacy. Second, this was a single-arm prospective study. In order to make clear the effectiveness of the combination therapy, it should be compared with a control group. Finally, this study was conducted with hospitalized patients who received intensive diet and lifestyle interventions. Therefore, our results cannot be generalized to be representative of outpatients. References: 1. U.K. prospective diabetes study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. (1995) Diabetes 44: Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, et al. (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355: Riddle MC, Ambrosius WT, Brillon DJ, Buse JB, Byington RP, et al. (2010) Epidemiologic relationships between A1C and all-cause mortality during a median 3.4- year follow-up of glycemic treatment in the ACCORD trial. Diabetes Care 33: Dailey GE 3 rd (2005) Early insulin: an important therapeutic strategy. Diabetes Care 28: Peyrot M, Rubin RR, Lauritzen T, Skovlund SE, Snoek FJ, et al. (2005) Resistance to insulin therapy among patients and providers: results of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study. Diabetes Care 28: Ishii H, Iwamoto Y, Tajima N (2012) An exploration of barriers to insulin initiation for physicians in Japan: findings from the Diabetes Attitudes, Wishes And Needs (DAWN) JAPAN study. PLoS One 7: e Harashima SI, Ogura M, Tanaka D, Fukushima T, Wang Y, et al. (2012) Sitagliptin add-on to low dosage sulphonylureas: efficacy and safety of combination therapy on glycaemic control and insulin secretion capacity in type 2 diabetes. Int J Clin Pract 66: Nichols GA, Alexander CM, Girman CJ, Kamal-Bahl SJ, Brown JB (2007) Contemporary analysis of secondary failure of successful sulfonylurea therapy. Endocr Pract 13: Wright A, Burden AC, Paisey RB, Cull CA, Holman RR, et al. (2002) Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care 25: Aaboe K, Knop FK, Vilsboll T, Vølund A, Simonsen U, et al. (2009) KATP channel closure ameliorates the impaired insulinotropic effect of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. J Clin Endocrinol Metab 94: Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, et al. (2007) Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab 9: Tajima N, Kadowaki T, Odawara M, Nishii M, Taniguchi T, et al. (2011) Addition of sitagliptin to ongoing glimepiride therapy in Japanese patients with type 2 diabetes over 52 weeks leads to improved glycemic control. Diabetol Int 2: de Heer J, Holst JJ (2007) Sulfonylurea compounds uncouple the glucose dependence of the insulinotropic effect of glucagon-like peptide 1. Diabetes 56: Sato D, Sato Y, Masuda S, Kimura H (2012) Impact of the sitagliptin alert on prescription of oral antihyperglycemic drugs in Japan. Int J Clin Pharm 34: Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013.

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