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Effects of SGLT2 Inhibitors on Islet Cell Function and Insulin Sensitivity in Patients of Type 2 Diabetes Mellitus

Primary Purpose

Type 2 Diabetes Mellitus

Status

Unknown status

Phase

Phase 4

Locations

China

Study Type

Interventional

Intervention

Dapagliflozin

Empagliflozin

Canagliflozin

About this trial

This is an interventional treatment trial for Type 2 Diabetes Mellitus focused on measuring Sodium and Glucose Synergistic Transporter 2 Inhibitor, Beta Cell Function, Alpha Cell Function, Insulin Sensitivity

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

(1)According to the diagnostic criteria of World Health Organization (WHO) in 1999, type 2 diabetes mellitus was diagnosed clinically. The age ranged from 18 to 70 years (including 18 and 70 years). There was no limit to the duration of diabetes mellitus and gender.
(2)Basic antidiabetic therapy is not limited.
(3)HbA1c ≥ 7%.
(4)eGFR ≥60 ml/min；without contraindications to SGLT2 Inhibitors.
(5)Sign written consent form voluntarily.

Exclusion Criteria:

(1)Other types of diabetes mellitus.
(2)Unstable control of blood glucose(fasting blood glucose > 11.1 mmol/L).
(3)Acute complications of diabetes mellitus within 6 months.
(4)History of myocardial infarction or stroke within 6 months, or existing severe cardiovascular disease and risk.
(5)Abnormal liver function [i.e. serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is 1.5 times higher than the upper limit of normal value].
(6)Severe hypertension that defined as systolic blood pressure ≥160 mmHg, diastolic blood pressure ≥90 mmHg with drug therapy, or hypotension (resting seat blood pressure < 90/50 mmHg).
(7)psychosis, alcohol dependence or history of drug abuse, lactation women, participation in other studies three months before the trial, allergic constitution or allergic to a variety of drug and those researchers think inappropriate to the research.

Sites / Locations

Peking Union Medical College HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

No Intervention

Arm Label

Dapagliflozin Group

Empagliflozin Group

Canagliflozin Group

Normal Glucose Tolerance Group

Arm Description

10mg/d for one week

100mg/d for one week

Outcomes

Primary Outcome Measures

Change from baseline to post-treatment in insulin sensitivity.

Insulin sensitivity is calculated by the following formula according to blood glucose and insulin levels in OGTT (Oral Glucose Tolerance Test). 1.1 OGTT Matsuda and De Fronzo Insulin Sensitivity Index（ISOGTT）：10000/square root(Gluc0×Ins0×mean Gluc×mean Ins)。Mean gluc and mean Ins are average values calculated by each value in 0, 60, 120 and 180 minutes of OGTT. 1.2 QUICKI（quantitative insulin sensitivity check index）model：1/(log[Ins0]+ log[Gluc0]) 1.3 HOMA-IR：(Gluc0×Ins0)/22.5

Change from baseline to post-treatment in islet beta cell secretory function.

Islet beta cell secretory function is calculated by area under the curve of blood glucose、 insulin、C-peptide in OGTT and following formula above. 2.1 Stumvoll first phase insulin secretion：1,194+4.724×Ins0-117.0 ×Gluc60 + 1.414×Ins60 2.2 Stumvoll second phase insulin secretion：295+0.349×Ins60-25.72×Gluc60+1.107×Ins0 2.3 HOMA-β：(20×Ins0)/(Gluc0-3.5)

Change from baseline to post-treatment in islet alpha cell secretory function.

Islet Alpha Cell secretory function is calculated by area under the curve of blood glucose、glucagon level in OGTT.

Secondary Outcome Measures

Change from baseline to post-treatment in weight.

Change from baseline to post-treatment in fasting blood glucose and non-fasting blood glucose.

Change from baseline to post-treatment in fasting insulin level.

Change from baseline to post-treatment in blood lipid including cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol.

Change from baseline to post-treatment in urine volume and urine glucose level.

Change from baseline to post-treatment in urinary output of uric acid, sodium, calcium, and phosphorus.

Full Information

NCT ID

NCT04014192

First Posted

July 7, 2019

Last Updated

September 20, 2019

Sponsor

Peking Union Medical College Hospital

1. Study Identification

Unique Protocol Identification Number

NCT04014192

Brief Title

Effects of SGLT2 Inhibitors on Islet Cell Function and Insulin Sensitivity in Patients of Type 2 Diabetes Mellitus

Official Title

Effects of SGLT2 Inhibitors on Islet Cell Function and Insulin Sensitivity in Patients of Type 2 Diabetes Mellitus

Study Type

Interventional

2. Study Status

Record Verification Date

August 2019

Overall Recruitment Status

Unknown status

Study Start Date

September 1, 2019 (Actual)

Primary Completion Date

July 31, 2020 (Anticipated)

Study Completion Date

July 31, 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Peking Union Medical College Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

The main pathogenesis of type 2 diabetes mellitus is insulin resistance and insufficient secretion of insulin by pancreatic beta cells. SGLT2 (sodium-glucose synergistic transporter 2) inhibitor is a kind of newly developed hypoglycemic medicine, which increases urinary glucose excretion and lowers blood glucose in an insulin-independent manner. The mechanisms of its effects on insulin resistance, insulin secretion by pancreatic beta cells and glucagon secretion by pancreatic alpha cells, are not well studied in domestic and foreign, and there is no unified conclusion. A few studies concerning SGLT2 inhibitors have observed that insulin resistance and islet beta cell secretion function can be improved by the improvement of glucotoxicity and lipotoxicity, but its effect on pancreatic alpha cell function to increase glucagon level, thereby increasing liver glucose output, may be one of the mechanisms of its side effects. In this study, patients with type 2 diabetes mellitus were treated with three domestic listed SGLT2 inhibitors (dapagliflozin, empagliflozin and canagliflozin) for one week, which were expected to improve the glucotoxicity, but excluding the effects on lipotoxicity and body weight, to observe the changes of islet beta cell and alpha cell function and insulin sensitivity. Three different SGLT2 inhibitors were used in order to make clear whether this effect is the unique effect of different structure of drugs or the similar effect of this kind of drugs.

Detailed Description

In this study, type 2 diabetes patients were treated with three kinds of SGLT2 inhibitors (dapagliflozin, empagliflozin and canagliflozin) for one week. With routine dose applied, (dapagliflozin 10mg/d, empagliflozin 10mg/d, canagliflozin 100mg/d), blood glucose level could be improved with small expected effect on body weight and no effect in lipid metabolism after the treatment period of one week. Normal glucose tolerance subjects (diagnosed of OGTT) were included as the control group.According to previous studies in three major SGLT2 inhibitors currently on the market, an increase in urinary glucose excretion and a decrease in blood glucose within three days after application in mice and human could be observed. Therefore, the short-term treatment cycle in this study is intended to be set at one week, and can be extended to two weeks if there is no significant decrease in blood glucose. The insulin sensitivity, islet beta cell secretion function and islet alpha cell function of diabetic patients were measured at baseline (before taking SGLT2 inhibitors) and one week after taking SGLT2 inhibitors, of normal glucose tolerance subjects were measured only at baseline. The effect of SGLT2 inhibitors on islet cell function and insulin sensitivity would be evaluated in order to study the extrarenal action mechanism of SGLT2 inhibitors.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Type 2 Diabetes Mellitus

Keywords

Sodium and Glucose Synergistic Transporter 2 Inhibitor, Beta Cell Function, Alpha Cell Function, Insulin Sensitivity

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Dapagliflozin Group

Arm Type

Experimental

Arm Description

10mg/d for one week

Arm Title

Empagliflozin Group

Arm Type

Experimental

Arm Description

10mg/d for one week

Arm Title

Canagliflozin Group

Arm Type

Experimental

Arm Description

100mg/d for one week

Arm Title

Normal Glucose Tolerance Group

Arm Type

No Intervention

Intervention Type

Drug

Intervention Name(s)

Dapagliflozin

Intervention Description

Treated with dapagliflozin 10mg/d for one week.

Intervention Type

Drug

Intervention Name(s)

Empagliflozin

Intervention Description

Treated with empagliflozin 10mg/d for one week.

Intervention Type

Drug

Intervention Name(s)

Canagliflozin

Intervention Description

Treated with canagliflozin 100mg/d for one week.

Primary Outcome Measure Information:

Title

Change from baseline to post-treatment in insulin sensitivity.

Description

Time Frame