Effects of Dapagliflozin+Saxagliptin in Addition to Metformin v/s Saxagliptin or Dapagliflozin in Patients With DM2.

A Randomized Study of the Effects of Dapagliflozin+Saxagliptin in Addition to Metformin Versus Single Addition Saxagliptin or Dapagliflozin on Glucose Metabolism in Patients With DM2 Poorly Controlled With Metformin

A phase IV, randomized, double-blind, single center pilot study in subjects with type 2 diabetes poorly controlled with metformin therapy will be randomized to receive, on top of metformin: saxagliptin (5 mg/day) and dapagliflozin (10 mg/day) (Group 1);saxagliptin (5 mg/day) and placebo (Group 2); dapagliflozin (10 mg/day) and placebo (Group 3) for 4 weeks.

Study Overview

• Status: Completed
• Conditions: Type2 Diabetes Mellitus
• Intervention / Treatment: Drug: Dapagliflozin 10mg; Drug: Saxagliptin 5mg; Drug: Saxagliptin 5mg + Dapagliflozin 10 mg

Detailed Description

Dapagliflozin (Forxiga) currently is approved for the treatment of T2DM (6). Dapagliflozin inhibits SGLT2, promote the excretion of 80-90 grams of glucose per day in the urine, and lower the plasma glucose concentration. This class of drugs has been shown to effectively reduce the HbA1c at all stages of T2DM and can be used in combination of all other anti-diabetic agents including insulin.

Saxagliptin is a highly potent DPP4 inhibitor.In patients with type 2 diabetes, administration of saxagliptin led to inhibition of DPP4 enzyme activity for a 24-hour period.After an oral glucose load,this DPP4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), decreased glucagon concentrations and increased glucose-dependent beta-cell responsiveness, which resulted in higher insulin and C-peptide concentrations.The rise in insulin from pancreatic beta-cells and the decrease in glucagon from pancreatic alpha-cells were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.Saxagliptin improves glycaemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Pisa, Italy, 56124
    • Department of Endocrinology and Metabolism, University of Pisa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males and females
2. Age = 35-70 years
3. BMI ≤ 40 Kg/m 2 and stable weight (± 3 lbs) over the preceding three months
4. Type 2 diabetes (HbA1c > 7 % and < 10 %)
5. Metformin on stable dose (at least 1500 mg/day) for at least 12 weeks before screening and at study initiation.
6. Subjects who are women of childbearing potential must agree to utilize a highly effective contraceptive measure throughout the course of the study.. 7.7. Subjects are capable of giving informed consent

Exclusion Criteria:

1. Drugs known to affect glucose metabolism (other than metformin) for more than14 days during the 12 weeks before screening
2. Known Dapagliflozin and Saxagliptin Excipient Hypersensitivity
3. Type 1 Diabetes or History of Ketoacidosis
4. history of cancer of any type;
5. cerebrovascular or symptomatic peripheral vascular disease;
6. heart disease class III or IV NYHA;
7. Estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73m 2 or serum creatinine > 1.5mg/dL in men or >1.4mg/dL in women
8. Liver function enzymes higher more than two times the upper limit
9. Ongoing urinary tract infection
10. drug or alcohol abuse;
11. life expectancy <3 yrs
12. blood pressure >160/100 mmHg
13. Donation of blood to a blood bank, blood transfusion, or participation in a clinical study requiring withdrawal of > 400 mL of blood during the 8 weeks prior to the enrollment visit and at least 8 weeks thereafter
14. Women of child bearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study (estrogen and/or progesterone treatment)
15. Women who are pregnant or breastfeeding
16. Patient with a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance which, in the opinion of the investigator or coordinator, might pose an unacceptable risk to the patient or interfere with trial procedures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dapagliflozin 10mg; Dapagliflozin inhibits SGLT2 promoting the excretion of glucose in the urine,and lowers the plasma glucose concentration. This class of drugs has been shown to effectively reduce the HbA1c at all stages of T2DM and can be used in combination of all other anti-diabetic agents including insulin.	Drug: Dapagliflozin 10mg; Dapagliflozin inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2) which are responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter mechanism causes blood glucose to be eliminated through the urine.[; Other Names: forxiga
Active Comparator: Saxagliptin 5mg; Saxagliptin is a DPP4 inhibitor.In patients with type 2 diabetes,administration of saxagliptin led to inhibition of DPP4 enzyme activity.After an oral glucose load,this DPP4 inhibition resulted in a increase in circulating levels of active incretin hormones include GLP-1 and GIP, decreased glucagon concentrations and increased glucose-dependent beta-cell responsiveness,which resulted in higher insulin and C-peptide concentrations.The rise in insulin from pancreatic beta-cells and the decrease in glucagon from pancreatic alpha-cells were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.Saxagliptin improves glycaemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes.	Drug: Dapagliflozin 10mg; Dapagliflozin inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2) which are responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter mechanism causes blood glucose to be eliminated through the urine.[; Other Names: forxiga; Drug: Saxagliptin 5mg; Inhibits DPP-4 and slows inactivation of incretin hormones, thereby increasing blood concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus; Other Names: Onglyza
Active Comparator: Saxagliptin 5 mg + dapagliflozin 10 mg; Please see Arm 1 and 2	Drug: Saxagliptin 5mg + Dapagliflozin 10 mg; Please see Intervention 1 and 2; Other Names: No other intervention name specified

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucose Metabolism	To determine the effect of the combination of dapagliflozin (a SGLT2-inhibitor) and saxagliptin (a DPP-4 inhibitor) on pancreatic hormones secretion and endogenous glucose production in Type 2 diabetic subjects through comparison of the effects of co-administration of Saxagliptin and Dapagliflozin vs. Saxagliptin or Dapagliflozin alone.	from first day

Collaborators and Investigators

• Sponsor: University of Pisa
• Investigators: Principal Investigator: Stefano Del prato, University of Pisa

Study record dates

Study Major Dates

• Study Start (Actual): July 24, 2018
• Primary Completion (Actual): August 31, 2022
• Study Completion (Actual): August 31, 2022

Study Registration Dates

• First Submitted: July 25, 2018
• First Submitted That Met QC Criteria: October 19, 2018
• First Posted (Actual): October 22, 2018

Study Record Updates

• Last Update Posted (Actual): November 8, 2022
• Last Update Submitted That Met QC Criteria: November 7, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Sodium-Glucose Transporter 2 Inhibitors; Dipeptidyl-Peptidase IV Inhibitors; Dapagliflozin; Saxagliptin
• Other Study ID Numbers: Saxa-Dapa 1

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No