Effects of Nateglinide on Postprandial Glucose Excursion by Restoring Early Phase Insulin Secretion

• Nateglinide (Drug): Nateglinide tablets, oral administration, three times daily, 120 mg orally 10 minutes immediately before 3 meals three times daily.
• Acarbose (Drug): Acarbose tablets, oral administration, three times daily, dosage of 50 mg orally chewing with the first bite of a meal three times daily.

Primary outcomes

• Change in Area Under Curve of 0-4 Hours Postprandial Glucose (AUCpp0-4hours) in Standardized Meal Test Using Continuous Glucose Monitoring System (CGMS) [3 weeks (end of study) minus baseline]: The postprandial glucose area under the curve (AUC)was calculated using values from the 3 time points. Participants were fasting (no calorie intake for at least 8 hours prior to the meal test) and completed the standardized meal test between 7 and 10 AM. 0-4 hours AUC were calculated using trapezoid methods.

Secondary outcomes

• Change in Incremental Glucose Peak (IGP) From Baseline [baseline, 3 weeks (end of study)]: Incremental glucose peak (IGP) was the maximal incremental increase in blood glucose obtained at any point after meal
• Change in Mean Blood Glucose (MBG) [baseline and at 3 weeks (end of study)]: The 24 hour mean blood glucose (MBG) level was calculated as the mean of all the consecutive readings on baseline and end of study(3 weeks later) separately.
• Change in Standard Deviation (SD) From Baseline of Mean Blood Glucose (MBG) Over 24 Hours. [baseline, 3 weeks (end of study)]: Change in standard deviation (SD) from baseline of mean blood glucose (MBG) describes the range of blood glucose fluctuation over 24 hours.
• Change in Mean of Daily Difference of Paired Blood Glucose Value (MODD) [baseline, 3 weeks (end of study)]: The mean of the daily differences (MODD), calculated as the average absolute difference of paired glucose values during two successive 24 hour periods, was used to assess day-to-day glycaemic variability.
• Changes in 24 Hour Glucose Area Under Curve (AUCpp) [baseline, end of study (3 weeks)]: Blood samples were collected for measurement of plasma glucose at 30, 60, 90, and 120 minutes following the start of a standardized meal test at Baseline and Week 4. The postprandial glucose area under the curve was calculated using values from the 4 time points. Participants were fasting (no calorie intake for at least 8 hours prior to the meal test) and completed the standardized meal test between 7 and 10 AM.
• Change in Glycated Serum Albumin (GSA) Levels From Baseline After Treatment [baseline, 3 weeks (end of study)]: GSA levels were to be determined by CGMS at 7:00\~10:00 am in the 4-hour standardized meal test before treatment after overnight fasting for efficacy assessments
• Change in Insulin Levels (μU/ml) During Standardized Meal Test at Endpoint From Baseline [baseline, 3 weeks (end of study)]: This outcome measure calculated the change in insulin levels between groups over time at 0, 30 then 120 minutes
• Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) [baseline, 3 weeks (end of study)]: change in LDL-C at 0, 30 and 120 minutes
• Change of Total Cholesterol in Blood Lipids Levels During Standardized Meal Test at Endpoint From Baseline at Each Time Point [baseline, 3 weeks (end of study)]: time to change in Total Cholesterol blood lipids level at 0, 30, 120 minutes
• Change in Triglyceride (TG)Levels in Blood Lipid Levels During Standardized Meal Test at Endpoint [baseline, 3 weeks (end of study)]: TG change in blood lipids level from baseline to endpoint
• Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) at the End of the Study [baseline, 3 weeks (end of study)]: Blood samples were collected for measurement of HDL-C prior to (fasting) and 120 minutes following the start of a standardized meal test at Baseline and Week 3. Participants were fasting (no calorie intake for at least 8 hours prior to the meal test) and completed the standardized meal test between 7 and 10 AM. HDL-C was assessed at each study site using the same method and same reference value.
• Change in Mean Amplitude of Glycaemic Excursion (MAGE) [baseline, 3 weeks (end of study)]: mean amplitude of glycaemic excursion (MAGE) is an average of the amplitudes of all glycemic excursions greater than a prespecified threshold size
• The Percent of 24 Hour Hypoglycemic Measurements [baseline, 3 weeks (end of study)]: Measures/compares changes in percentage of hypoglycemia(<3.9mmol/l or <70 mg/dl) in glucose measurements in 24hours by continuous glucose monitoring system (CGMS) at endpoint from baseline between groups. Reported values are percent change of the base absolute values \[100% * ((X-Y)/Y)\]
• Change in Percent of 24 Hour Hyperglycemic Measurements [baseline, 3 weeks (end of study)]: Measures/compares changes in percentage of hyperglycemia (>7.8mmol/l or 140 mg/dl) in glucose measurements in 24 hours by continuous glucose monitoring system (CGMS) at endpoint from baseline between groups. Reported values are percent change of the base absolute values \[100% * ((X-Y)/Y)\]

Sex: All, ages: 18 Years to 75 Years

Inclusion criteria

1. Patients must give written informed consent before any assessment is performed.
2. Male, non-fertile female or female of childbearing potential using a medically approved birth control method based on local regulations.
3. Drug naïve type 2 diabetes patients, defined as who neither take consecutive anti-hyperglycemic drug treatment more than 3 months anytime, nor any anti-hyperglycemic drug treatment in 4 weeks prior to visit 1.
4. Age in the range of 18-75 years inclusive.
5. HbA1c in the range of > 6.5 to ≤9.0% at Visit 1.

Exclusion criteria

1. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (>5 mIU/mL).
2. With known hypersensitivity to Nateglinide, Acarbose or any of the excipients.
3. A history of,

   1. type 1 diabetes, diabetes that is a result of pancreatic injury, or secondary forms of diabetes, e.g., Cushing's syndrome and acromegaly.
   2. acute metabolic diabetic complications such as ketoacidosis or hyperosmolar state (coma) within the past 6 months.
   3. Torsades de pointes, sustained and clinically relevant ventricular tachycardia or ventricular fibrillation.
   4. percutaneous coronary intervention within the past 3 months.
   5. any of the following within the past 6 months: myocardial infarction (MI), coronary artery bypass surgery, unstable angina, or stroke.
4. Evidence of significant diabetic complications, e.g., symptomatic autonomic neuropathy or gastroparesis.
5. Acute infections which may affect blood glucose control within 4 weeks prior to visit 1.
6. Congestive heart failure requiring pharmacologic treatment. mg/dL (123μmol/L)

Participant flow

Outcome results

• Change in Area Under Curve of 0-4 Hours Postprandial Glucose (AUCpp0-4hours) in Standardized Meal Test Using Continuous Glucose Monitoring System (CGMS) (Primary), Least squares mean, millimoles hours per litre (mmol*hr/L): Nateglinide -9.20 (-11.780 to -6.621); Acarbose -9.92 (-12.407 to -7.438)
• Change in Incremental Glucose Peak (IGP) From Baseline (Secondary), Mean, millimoles per litre (mmol/L): Nateglinide -2.72 +/- 2.86; Acarbose -1.89 +/- 2.76
• Change in Mean Blood Glucose (MBG) (Secondary), Mean, millimoles per litre (mmol/l): Nateglinide -1.16 +/- 1.24; Acarbose -0.78 +/- 1.29
• Change in Standard Deviation (SD) From Baseline of Mean Blood Glucose (MBG) Over 24 Hours. (Secondary), Mean, mmol/l: Nateglinide -0.48 +/- 0.63; Acarbose -0.63 +/- 0.59
• Change in Mean of Daily Difference of Paired Blood Glucose Value (MODD) (Secondary), Mean, millimoles per litre (mmol/l): Nateglinide -0.06 +/- 0.95; Acarbose -0.21 +/- 0.86
• Changes in 24 Hour Glucose Area Under Curve (AUCpp) (Secondary), Mean, mmol*min/L: Nateglinide -1.16 +/- 1.24; Acarbose -0.78 +/- 1.29
• Change in Glycated Serum Albumin (GSA) Levels From Baseline After Treatment (Secondary), Mean, percent: Nateglinide -2.22 +/- 1.90; Acarbose -1.74 +/- 1.50
• Change in Insulin Levels (μU/ml) During Standardized Meal Test at Endpoint From Baseline (Secondary), Mean, (μU/ml): Nateglinide 0.32 +/- 5.88; Acarbose -0.21 +/- 3.16
• Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) (Secondary), Mean, millimoles per litre (mmol/l): Nateglinide -0.04 +/- 0.65; Acarbose 0.064 +/- 0.44
• Change of Total Cholesterol in Blood Lipids Levels During Standardized Meal Test at Endpoint From Baseline at Each Time Point (Secondary), Mean, millimoles per litre (mmol/l): Nateglinide -0.03 +/- 0.67; Acarbose -0.09 +/- 0.55
• Change in Triglyceride (TG)Levels in Blood Lipid Levels During Standardized Meal Test at Endpoint (Secondary), Mean, millimoles per litre (mmol/l): Nateglinide -0.19 +/- 0.63; Acarbose -0.48 +/- 1.16
• Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) at the End of the Study (Secondary), Mean, millimoles per litre (mmol/l): Nateglinide 0.20 +/- 0.10; Acarbose -0.02 +/- 0.31
• Change in Mean Amplitude of Glycaemic Excursion (MAGE) (Secondary), Mean, mmol/l: Nateglinide 5.27 +/- 2.09; Acarbose 5.03 +/- 1.82
• The Percent of 24 Hour Hypoglycemic Measurements (Secondary), Mean, percent of measurements: Nateglinide 0.82 +/- 2.22; Acarbose -0.57 +/- 1.77
• Change in Percent of 24 Hour Hyperglycemic Measurements (Secondary), Mean, percent of measurements: Nateglinide -50.83 +/- 64.62; Acarbose -33.82 +/- 75.39

Adverse events

Time frame: 3 weeks

Other adverse events by term

• Gao HW, Xie C, Wang HN, Lin YJ, Hong TP. Beneficial metabolic effects of nateglinide versus acarbose in patients with newly-diagnosed type 2 diabetes. Acta Pharmacol Sin. 2007 Apr;28(4):534-9. doi: 10.1111/j.1745-7254.2007.00534.x. PMID 17376293
• Results publication: Zhou J, Deng Z, Lu J, Li H, Zhang X, Peng Y, Mo Y, Bao Y, Jia W. Differential therapeutic effects of nateglinide and acarbose on fasting and postprandial lipid profiles: a randomized trial. Diabetes Technol Ther. 2015 Apr;17(4):229-34. doi: 10.1089/dia.2014.0299. PMID 25781235
• Results publication: Zhou J, Li H, Zhang X, Peng Y, Mo Y, Bao Y, Jia W. Nateglinide and acarbose are comparably effective reducers of postprandial glycemic excursions in chinese antihyperglycemic agent-naive subjects with type 2 diabetes. Diabetes Technol Ther. 2013 Jun;15(6):481-8. doi: 10.1089/dia.2013.0046. Epub 2013 Apr 30. PMID 23631607

• Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals