Effects of Vildagliptin Add-on Insulin Therapy on Nocturnal Glycemic Variations in Uncontrolled Type 2 Diabetes
To investigate whether vildagliptin add-on insulin therapy improves glycemic variations in patients with uncontrolled type 2 diabetes (T2D) compared to patients with placebo therapy.
This was a 24-week, single-center, double-blind, placebo-controlled trial. Inadequately controlled T2D patients treated with insulin therapy were recruited between June 2012 and April 2013. The trial included a 2-week screening period and a 24-week randomized period. Subjects were randomly assigned to a vildagliptin add-on insulin therapy group (n = 17) or a matched placebo group (n = 16). Scheduled visits occurred at weeks 4, 8, 12, 16, 20, and 24. Continuous glucose monitoring (CGM) was performed before and at the endpoint of the study.
A total of 33 subjects were admitted, with 1 patient withdrawing from the placebo group. After 24 weeks of therapy, HbA1c values were significantly reduced at the endpoint in the vildagliptin add-on group. CGM data showed that patients with vildagliptin add-on therapy had a significantly lower 24-h mean glucose concentration and mean amplitude of glycemic excursion (MAGE). At the endpoint of the study, patients in the vildagliptin add-on group had a significantly lower MAGE and standard deviation compared to the control patients during the nocturnal period (0000–0600). A severe hypoglycemic episode was not observed in either group.
Vildagliptin add-on therapy to insulin has the ability to improve glycemic variations, especially during the nocturnal time period, in patients with uncontrolled T2D.
KeywordsGlycemic variations Insulin Type 2 diabetes Vildagliptin
Insulin therapy is frequently administered to many patients with type 2 diabetes (T2D) to help them to achieve their treatment targets . However, in nearly three-quarters of such patients, treatment with basal insulin and an oral hypoglycemic agent (OAD) fails to decrease their HbA1c to <7% . Concerns about hypoglycemia may be an important factor in this inability of patients to achieve better glucose control . A study demonstrated that complications also affect the efficacy of insulin therapy and increase the risk of hypoglycemia .
Sustained chronic hyperglycemia has been shown to play a role in the development of complications in patients with diabetes [5, 6, 7]. It has been recognized that hypoglycemia and postprandial hyperglycemia, especially the 2 h postprandial glucose (2 h PG) concentration, are associated with deaths from all causes [8, 9]. Importantly, glucose variability has been identified as an indicator of diabetic complications . Patients may require combinational therapy with insulin to avoid hypoglycemia and improve their glycemic variability (GV).
Vildagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, exerts glucose-lowering effects by covalently binding to DPP-4 . Studies indicate that DPP-4 inhibitors may have a glucose-independent beneficial effect in diabetes-related complications, particularly renal complications. In renal ischemia–reperfusion injured and nondiabetic rats with 5/6 nephrectomy, DPP4 inhibition conferred protective effects against tubular damage  and decreased chronic kidney disease progression . The renoprotective effects of DPP-4 inhibitors may be due to the increased half-lives of DPP-4 substrates such as glucagon-like peptide-1 (GLP-1) and stromal derived factor-1α (SDF-1α) . When used in conjunction with self-monitoring of blood glucose (SMBG), vildagliptin add-on insulin therapy can lead to improved glycemic control without an increased risk of hypoglycemia [15, 16, 17]. In addition, this combination therapy leads to a reduction in the number of insulin injections needed and the bolus insulin dose [18, 19]. Furthermore, the vildagliptin add-on to insulin treatment was found to be well tolerated and safe, even when administered for 24 months . However, there was a potential issue with blood glucose levels measured via SMBG : they were usually obtained at fasting or 2 h after meals . Such point-to-point glimpses of blood glucose miss 24-h blood glucose excursions. Continuous glucose monitoring (CGM) allows these 24-h glucose excursions to be examined .
Studies using CGM have demonstrated that vildagliptin add-on therapy leads to a significant improvement in the 24-h mean amplitude of glycemic excursion (MAGE) in patients with T2D who do not receive insulin therapy [24, 25, 26]. In a Japanese population assessed by CGM, the MAGE and the incremental area under the curve (<70 mg/dL) in patients who received vildagliptin plus insulin therapy were found to be significantly reduced compared to those of the patients in a control group .
A set of metrics obtained from CGM were employed to study GV in patients with type 1 (T1D) and T2D [28, 29, 30]. Studies have demonstrated that the 24-h standard deviation of blood glucose (24 h-SDBG) is strongly correlated with the MAGE [23, 31, 32]. A study also indicated that the SDMG is more strongly correlated with HbA1c than with the MAGE, although both the SDBG and the MAGE were strongly correlated with HbA1c . In addition, the coefficient of variation (CV, in %) should be considered when interpreting the GV [31, 32, 33]. A pilot study using CGM indicated that patients with T2D, even newly diagnosed T2D patients, may have an increased risk of nocturnal hypoglycemia during insulin therapy . Therefore, controlling the GV, especially the GV during the nocturnal period, in uncontrolled T2D patients receiving insulin therapy is of critical importance.
We performed a 24-week, single-center, double-blind, placebo-controlled trial using CGM to determine whether using vildagliptin as an add-on to insulin therapy leads to a significant improvement in GV in T2D patients, especially during the nocturnal period (0000–0600).
Subjects and Methods
This was a 24-week, single-center, randomized, double-blind, placebo-controlled study. This study was approved by the China Food and Drug Administration CSFA (2011L02052). All procedures followed were in accordance with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all patients before they were included in the study.
Beginning in June 2012, and continuing to April 2013, we recruited a total of 33 patients with uncontrolled T2D from Nanjing First Hospital, Nanjing Medical University, China. The study was performed as described previously . Uncontrolled T2D patients who had HbA1c values of 7.5–11.0% and received insulin only (<1 unit/kg/day) or insulin combined with metformin therapy (≥1500 mg daily or the maximally tolerated dose) for at least 12 weeks before the screening period were enrolled in this study.
According to the clinical protocol (CLAF237A23155), patients, investigators, assessors, and data analysts were blinded to the treatment given to each patient from the time of randomization until the database was locked. The following methods were employed to achieve this: (1) randomization data were kept strictly confidential until unblinding and could not be accessed by anyone else involved in the study (with the following exceptions: Biostatistics Quality Assurance Group, independent data manager, and the investigator and sponsor in the event of a patient emergency); (2) treatment identity was concealed by using study drugs that were all identical in terms of their packaging, labeling, administration schedule, appearance, taste, and odor.
The trial included a 2-week screening period and a 24-week treatment period. Scheduled visits occurred at weeks 4, 8, 12, 16, 20, and 24. HbA1c values were measured at a central laboratory (Eurofins Global Central Laboratory, Shanghai, China) at baseline and the endpoint. The baseline parameters were collected from all subjects 4 days before randomization. The recruited subjects were then randomized 1:1 to receive either vildagliptin (Novartis Pharma AG, Basel, Switzerland) 50 mg bid or a placebo without any oral antidiabetic drugs except for metformin for 24 weeks. For most of the patients, the dose and type of insulin administered were maintained through the course of the study, but the dose of insulin was increased by 10% in some patients. All patients were fitted with a 3-day retrospective CGM (Sof-sensor, CGMS Gold, Medtronic Inc., Northridge, USA) in hospital by a specialist nurse during the study period on two occasions. The first CGM was fitted 3 days before the patient was assigned to a group, and the second CGM was fitted at last 3 days before the endpoint. Briefly, the CGM sensor was subcutaneously embedded on day 0 at around 1600–1700. If the CGM was performing well, the subject was instructed to keep the sensor fixed in place. The study nurse took at least four calibration readings every day. On day 4 at around 1600–1700, the subject had the sensor removed, and the CGM data were saved by the investigator, as described previously [36, 37, 38]. The daily energy intake of each patient was the same during the CGM period. All subjects were instructed to maintain their usual physical activity and received meals that provided a caloric intake of 25 kcal/kg/day. The ratio of carbohydrate to protein to fat was 55:17:28. Patients were instructed to have breakfast, lunch, and dinner at 0700, 1100, and 1700, respectively.
The 24-h MBG, 24-h SDBG, CV%, MAGE, the decreases in the incremental AUCs of plasma glucose >10.0 and <3.9 mmol/L, and the hourly MBG were calculated by software provided by Medtronic Inc., USA. The MAGE was calculated manually for each patient by measuring the arithmetic mean of the ascending and descending excursions between consecutive peaks and nadirs for the same 24-h period; only absolute excursion values >1 SD were considered, as described previously [37, 38]. We also analyzed the intensity of hypoglycemia and the CV% during the daytime and the nocturnal period. In addition, the total daily insulin dose and the change in body weight were recorded at weeks 12 and 24. Hypoglycemia was defined as a glucose concentration of <3.9 mmol/L as measured by CGM.
The primary efficacy endpoint was change in MAGE from the baseline to the endpoint, especially during the nocturnal period from 0000 to 0600. Secondary endpoints included the changes in the 24-h MBG, 24-h SDBG, and CV% during the daytime and the nocturnal period from the baseline to the endpoint.
The study was registered with ClinicalTrials.gov (identifier: NCT01582230).
Data were analyzed with the SPSS PASW Statistics 18 Package. The Shapiro–Wilk test was used to assess the distribution of the data. Normally distributed and continuous variables are presented below as the mean ± standard deviation (SD). The independent samples t test was used to analyze the difference between two groups. The two-way ANOVA for repeated measurements was used to compare the groups. Bonferroni correction was performed. Safety data were summarized using descriptive statistics from the safety analysis set (SAF). P values were two-tailed with a significance level of 5%.
Characteristics of the patients at baseline
58.9 ± 9.0
59.9 ± 7.7
8.6 ± 5.1
8.6 ± 2.9
26.1 ± 3.1
26.1 ± 3.4
0.5 ± 0.3
0.4 ± 0.2
8.5 ± 0.8
8.8 ± 0.7
Coronary heart disease
Patient background at baseline
Basal insulin − metformin
Basal insulin + metformin
Pre-mixed insulin analogue
Pre-mixed insulin analogue − metformin
Pre-mixed insulin analogue + metformin
Characteristics of the patients in the vildagliptin and placebo groups before and after therapy
19.47 ± 10.82
21.75 ± 10.61
20.00 ± 6.99
21.18 ± 7.92
19.47 ± 8.46
18.44 ± 5.23
20.00 ± 7.07
18.13 ± 3.58
4.33 ± 0.72
5.36 ± 0.54
4.58 ± 0.78
5.73 ± 0.93
1.91 ± 0.97
2.47 ± 1.40
1.88 ± 0.98
2.62 ± 5.50
1.25 ± 0.31
1.35 ± 0.36
1.20 ± 0.33
1.46 ± 0.98
2.21 ± 0.72
2.96 ± 0.79
2.61 ± 0.73
3.43 ± 0.76
4.77 ± 5.86
4.77 ± 5.86
4.70 ± 7.38
4.70 ± 7.38
98.15 ± 13.64
95.92 ± 14.97
93.17 ± 16.62
97.88 ± 15.29
10.69 ± 3.01
10.23 ± 2.03
8.09 ± 2.52
9.62 ± 2.57
Glucose, Insulin, and Body Weight Profiles
The total insulin dose required by the subjects in the vildagliptin add-on therapy group to maintain euglycemic control was not significantly lower than the corresponding value for the control group at the endpoint (0.41 ± 0.06 vs. 0.33 ± 0.07 U/kg/days, P > 0.05). We also analyzed the change in insulin dose from the baseline to the endpoint. Our data showed that the insulin dose was significantly decreased in the patients receiving vildagliptin add-on therapy compared to the patients in the placebo group (0.13 ± 0.03 vs. 0.17 ± 0.04 U/kg, P = 0.02). There was no significant difference in body weight between the groups (70.7 ± 11.2 vs. 72.9 ± 13.1 kg, P > 0.05), and there was no significant change in body weight from the baseline to the endpoint in the vildagliptin group (68.6 ± 11.2 vs. 70.7 ± 11.2 kg, P > 0.05) or in the control group (72.1 ± 13.3 vs. 72.9 ± 13.1 kg, P > 0.05). In addition, the addition of metformin therapy to vildagliptin or the placebo did not significantly alter the body weight changes observed (all P > 0.05).
Glycemic Variation Profiles
Changes in blood glycemic excursion parameters in the patients in the the vildagliptin and placebo groups before and after therapy
11.58 ± 2.31
11.43 ± 1.83
6.54 ± 1.20
6.98 ± 1.33
6.64 ± 2.89
5.46 ± 2.22
2.47 ± 0.79
3.37 ± 2.17
2.45 ± 1.82
1.86 ± 1.44
0.02 ± 0.07
0.15 ± 0.28
4.08 ± 2.27
3.59 ± 1.73
0.16 ± 0.23
0.61 ± 0.65
0.00 ± 0.02
0.00 ± 0.00
0.02 ± 0.06
0.00 ± 0.02
We did not observe significant differences between the vildagliptin add-on group and the control group in hourly mean blood glucose concentrations or the incremental AUC >10 mmol/L (0.1 ± 0.2 vs. 0.4 ± 1.0 mmol/L day, P = 0.62) at the endpoint, or in the SDMG, the incremental AUC less than 3.9 mmol/L, and CV%. However, CGM data showed that the subjects in the vildagliptin add-on group had a lower MAGE (3.0 ± 1.1 vs. 4.2 ± 1.4 mmol/L, P = 0.01) than those in the control group at the endpoint.
Safety and Tolerance
Adverse effects in the two groups during the study
Upper respiratory tract infection
We conducted a 24-week, single-center, double-blind, placebo-controlled trial using CGM and found that the implementation of vildagliptin add-on insulin therapy led to a significant improvement in blood glycemic fluctuations in uncontrolled patients with T2D. We also observed that the patients treated with vildagliptin combination therapy exhibited a greater reduction in HbA1c than the patients in the placebo group at the endpoint, as well as a significant reduction in nocturnal GV.
In this trial, the HbA1c level was significantly decreased (by 0.9%) by the endpoint of vildagliptin combinational therapy, and the HbA1c level was 0.7% lower than that in the placebo group. These improvements are in good accord with those seen in Western populations treated with a combination of vildagliptin and insulin [39, 40]. Our results were somewhat different to those obtained in a previous study of a Japanese population , which indicated that the HbA1c level in patients receiving vildagliptin add-on therapy was 1.0% lower. Compared to Western patients, Asian patients were found to have a lower BMI [42, 43] and more visceral fat , and more Asian patients with diabetes had isolated postprandial hyperglycemia . Asian patients may show more favorable responses to vildagliptin than other ethnic groups , but a pooled analysis revealed that there was no difference in the response to vildagliptin between Caucasian and Asian patients , and our data support that finding.
Patients with T2D who were treated with the vidagliptin add-on plus metformin exhibited a significant improvement in glycemic fluctuations as assessed by CGM . The effects of vildagliptin on glycemic variation were also compared with those of sitagliptin, another DPP4I, as assessed by CGM. Based on the CGM data, patients with T2D who received vildagliptin therapy showed significant improvements in MAGE, MBG, and PPG, especially after breakfast and dinner, compared to patients with T2D who received sitagliptin . The improvements in MAGE were associated with improvements in oxidative stress and inflammation in the patients treated with vildagliptin [24, 25].
Reducing the HbA1c level in patients with diabetes decreases the risk of death, myocardial infarction, and microvascular complications . Moreover, studies have emphasized that GV is a potent risk factor for diabetic complications [49, 50, 51]. Therefore, treatment strategies that aim to reduce the HbA1c level as well as the GV appear to be more promising choices . Patients receiving vildagliptin as an add-on therapy may exhibit smoothed 24-h glycemic variations. As expected, in the current study, our CGM data showed that vildagliptin add-on insulin treatment provided significant improvements in the 24-h MBG and MAGE compared with a placebo treatment. We also analyzed the GV during the nocturnal period. Our data showed that the patients in the vildagliptin group had significantly reduced GV during the nocturnal period in terms of SDMG and MAGE compared with the patients in the placebo group. The reductions in HbA1c and GV during the daytime and the nocturnal period observed in this study indicate that vildagliptin in combination with insulin therapy could be a potent choice for reducing macrovascular complications in patients with T2D. Studies have shown that vildagliptin treatment yields a significantly greater reduction in the MAGE in patients with T2D compared to sitagliptin [25, 26] or saxagliptin  treatment. In this study, twice-daily administration of vildagliptin—especially administration before dinner—was observed to increase insulin secretion and inhibit glucagon release during the nocturnal period , which may explain, to some degree, why patients in the vildagliptin group achieved a significantly lower GV during the nocturnal period than those in the placebo group.
The efficacy (especially at preventing hypoglycemia) and safety of DPP4 inhibitors used in combination with insulin therapy in patients with T2DM—even in patients with cardiovascular disease—are well proven . In this study, the patients tolerated the vildagliptin therapy well and were weight neutral during the treatment period. We did not observe any serious adverse events (SAEs) during the vildagliptin combination therapy period. The application of vildagliptin add-on therapy to reduce the insulin dose required by the patient to achieve glycemic control remains controversial. In our study, the insulin dose at the endpoint of vildagliptin add-on therapy was significantly reduced compared with that for the placebo group. This result is in good agreement with a previous study which reported that vildagliptin as an add-on to insulin treatment lasting for two years was safe, showed glycemic efficacy, and led to a reduction in the insulin dose required . Moreover, in another study, the implementation of vildagliptin combination therapy resulted in a reduced bolus insulin dose . However, in our study we did not observe a significant difference in insulin dose between the groups, although the change in the insulin dose required by the patients receiving vildagliptin combination therapy from baseline to endpoint was lower than that for the patients in the control group.
In this study, we also observed a significant increase in insulin secretion levels based on the improved C-peptide concentrations seen in the vildagliptin add-on group compared with those in the control group after therapy. This may, to some degree, explan why the patients in the vildagliptin add-on group showed a greater improvement in blood glycemic variation than the subjects in the control group.
Our study does, however, have limitations. First, the study focused on a Chinese population, so the conclusions drawn from this study may not be valid for non-Chinese populations. Second, the sample size was relatively modest. Third, we did not observe the subjects for a long time period.
In conclusion, applying vildagliptin add-on insulin therapy led to a significant improvement in blood glycemic variation in uncontrolled patients with T2D. We also observed that, at the endpoint of the study, the patients treated with vildagliptin combination therapy had lower HbA1c levels and showed a significant reduction in nocturnal hypoglycemia compared to the patients in the placebo group.
This research was funded by the Science and Technology Support Program of Jiangsu Province (CN) (no. BL2014010) and by the China Postdoctoral Science Foundation (no. 2015M581829). All of the named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published. Jian-hua Ma and Lei Ye contributed to the conception and design of the study. Feng-fei Li, Yun Shen, Rui Sun, Dan-feng Zhang, Mao-yuan Chen, and Xiao-fang Zhai conducted the study and collected data. Xing Jin, Xiao-fang Zhai, Xiao-fei Su, and Jin-dan Wu contributed to the data analysis. Feng-fei Li wrote the manuscript and provided final approval of the published version. We also express our appreciation to Prof. Frank Elliott, who contributed to the final proof of the manuscript.
Feng-fei Li, Yun Shen, Rui Sun, Dan-feng Zhang, Xing Jin, Xiao-fang Zhai, Mao-yuan Chen, Xiao-fei Su, Jin-dan Wu, Lei Ye, and Jian-hua Ma declare that they have nothing to disclose.
Compliance with Ethics Guidelines
All procedures followed were in accordance with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all patients before they were included in the study.
The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
- 2.Tsukube S, Ikeda Y, Kadowaki T, Odawara M. Improved treatment satisfaction and self-reported health status after introduction of basal-supported oral therapy using insulin glargine in patients with type 2 diabetes: sub-analysis of ALOHA2 study. Diabetes Ther. 2015;6(2):153–71.CrossRefPubMedPubMedCentralGoogle Scholar
- 4.Odawara M, Kadowaki T, Naito Y. Effectiveness and safety of basal supported oral therapy with insulin glargine, in Japanese insulin-naive, type 2 diabetes patients, with or without microvascular complications: subanalysis of the observational, non-interventional, 24-week follow-up Add-on Lantus(R) to Oral Hypoglycemic Agents (ALOHA) study. J Diabetes Complic. 2015;29(1):127–33.CrossRefGoogle Scholar
- 6.The Diabetes Control and Complications Trial Research Group. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes. 1995;44(8):968–83.Google Scholar
- 7.Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405–12.CrossRefPubMedPubMedCentralGoogle Scholar
- 8.DECODE Study Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med. 2001;161(3):397–405.Google Scholar
- 12.Reichetzeder C, von Websky K, Tsuprykov O, Mohagheghi Samarin A, Falke LG, Dwi Putra SE, Hasan AA, Antonenko V, Curato C, Rippmann J, Klein T, Hocher B. Head-to-head comparison of structurally unrelated dipeptidyl peptidase 4 inhibitors in the setting of renal ischemia reperfusion injury. Br J Pharmacol. 2017;174(14):2273–86.CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Tsuprykov O, Ando R, Reichetzeder C, von Websky K, Antonenko V, Sharkovska Y, Chaykovska L, Rahnenfuhrer J, Hasan AA, Tammen H, Alter M, Klein T, Ueda S, Yamagishi SI, Okuda S, Hocher B. The dipeptidyl peptidase inhibitor linagliptin and the angiotensin II receptor blocker telmisartan show renal benefit by different pathways in rats with 5/6 nephrectomy. Kidney Int. 2016;89(5):1049–61.CrossRefPubMedGoogle Scholar
- 17.Tura A, Farngren J, Schweizer A, Foley JE, Pacini G, Ahren B. Four-point preprandial self-monitoring of blood glucose for the assessment of glycemic control and variability in patients with type 2 diabetes treated with insulin and vildagliptin. Int J Endocrinol. 2015;2015:484231.CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Boland E, Monsod T, Delucia M, Brandt CA, Fernando S, Tamborlane WV. Limitations of conventional methods of self-monitoring of blood glucose: lessons learned from 3 days of continuous glucose sensing in pediatric patients with type 1 diabetes. Diabetes Care. 2001;24(11):1858–62.CrossRefPubMedGoogle Scholar
- 22.Weng J, Li Y, Xu W, Shi L, Zhang Q, Zhu D, Hu Y, Zhou Z, Yan X, Tian H, Ran X, Luo Z, Xian J, Yan L, Li F, Zeng L, Chen Y, Yang L, Yan S, Liu J, Li M, Fu Z, Cheng H. Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet. 2008;371(9626):1753–60.CrossRefPubMedGoogle Scholar
- 32.Rodbard D. Increased glycemic variability at the onset and during progression of type 2 diabetes—commentary. Diabetes Technol Ther. 2013;15(6):445–7.Google Scholar
- 34.Li FF, Liu BL, Zhu HH, Li T, Zhang WL, Su XF, Wu JD, Wang XQ, Xu N, Yu WN, Yuan Q, Qi GC, Ye L, Lee KO, Ma JH. Continuous glucose monitoring in newly diagnosed type 2 diabetes patients reveals a potential risk of hypoglycemia in older men. J Diabetes Res. 2017;2017:2740372.PubMedPubMedCentralGoogle Scholar
- 35.Ning G, Wang W, Li L, Ma J, Lv X, Yang M, Woloschak M, Lukashevich V, Kothny W. Vildagliptin as add-on therapy to insulin improves glycemic control without increasing risk of hypoglycemia in Asian, predominantly Chinese, patients with type 2 diabetes mellitus. J Diabetes. 2016;8(3):345–53.CrossRefPubMedGoogle Scholar
- 41.Saito D, Kanazawa A, Shigihara N, Sato F, Uchida T, Sato J, Goto H, Miyatsuka T, Ikeda F, Ogihara T, Ohmura C, Watada H. Efficacy and safety of vildagliptin as an add-on therapy in inadequately controlled type 2 diabetes patients treated with basal insulin. J Clin Med Res. 2017;9(3):193–9.CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Ntuk UE, Gill JM, Mackay DF, Sattar N, Pell JP. Ethnic-specific obesity cutoffs for diabetes risk: cross-sectional study of 490,288 UK Biobank participants. Diabetes Care. 2014;37(9):2500–7.Google Scholar
- 45.Qiao Q, Hu G, Tuomilehto J, Nakagami T, Balkau B, Borch-Johnsen K, Ramachandran A, Mohan V, Iyer SR, Tominaga M, Kiyohara Y, Kato I, Okubo K, Nagai M, Shibazaki S, Yang Z, Tong Z, Fan Q, Wang B, Chew SK, Tan BY, Heng D, Emmanuel S, Tajima N, Iwamoto Y, Snehalatha C, Vijay V, Kapur A, Dong Y, Nan H, Gao W, Shi H, Fu F. Age- and sex-specific prevalence of diabetes and impaired glucose regulation in 11 Asian cohorts. Diabetes Care. 2003;26(6):1770–80.CrossRefPubMedGoogle Scholar
- 48.He YL, Foteinos G, Neelakantham S, Mattapalli D, Kulmatycki K, Forst T, Taylor A. Differential effects of vildagliptin and glimepiride on glucose fluctuations in patients with type 2 diabetes mellitus assessed using continuous glucose monitoring. Diabetes Obes Metab. 2013;15(12):1111–9.CrossRefPubMedGoogle Scholar
- 53.Xiaoyan C, Jing W, Xiaochun H, Yuyu T, Shunyou D, Yingyu F. Effects of vildagliptin versus saxagliptin on daily acute glucose fluctuations in Chinese patients with T2DM inadequately controlled with a combination of metformin and sulfonylurea. Curr Med Res Opin. 2016;32(6):1131–6.CrossRefPubMedGoogle Scholar
- 54.Balas B, Baig MR, Watson C, Dunning BE, Ligueros-Saylan M, Wang Y, He YL, Darland C, Holst JJ, Deacon CF, Cusi K, Mari A, Foley JE, DeFronzo RA. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007;92(4):1249–55.CrossRefPubMedGoogle Scholar
- 55.von Websky K, Reichetzeder C, Hocher B. Linagliptin as add-on therapy to insulin for patients with type 2 diabetes. Vasc Health Risk Manag. 2013;9:681–94.Google Scholar