Managing DIabetes Remission After Combined Therapy in EarLy Stage of DiabetEs
NCT ID: NCT04271189
Last Updated: 2025-03-18
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
COMPLETED
Clinical Phase
PHASE3
Total Enrollment
108 participants
Study Classification
INTERVENTIONAL
Study Start Date
2020-09-01
Study Completion Date
2024-12-31
Brief Summary
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Epidemiologic, social and economic burdens of type 2 diabetes mellitus (T2DM) keep rising worldwide. Implementation of T2DM preventive trategies is lagging behind. Metabolic surgery, very low calorie diet can induce T2DM remission, but so far for few patients. The investigators will assess the efficacy to cause T2DM remission (primary end point) and direct costs to the National Health System of a 4-month polychemotherapy (metformin+pioglitazone+sitagliptin+empagliflozin) regimen vs standard care in patients with newly diagnosed T2DM by an open label, pragmatic RCT. Mechanisms of action will be investigated in a sub-cohort by a prolonged OGTT plus dual tracer technique and modeling of beta cell function.
If proved efficacious in this proof-of-concept study and inducer of durable remission in the future, T2DM polychemotherapy will turn out to be a convenient, relatively unexpensive strategy to restrain prevalence of T2DM and its complications and to alleviate its personal, social and economic burden.
If proved efficacious in this proof-of-concept study and inducer of durable remission in the future, T2DM polychemotherapy will turn out to be a convenient, relatively unexpensive strategy to restrain prevalence of T2DM and its complications and to alleviate its personal, social and economic burden.
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Detailed Description
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Hypothesis: at diagnosis of T2DM, a 4 month course of oral polychemotherapy (POLYCHEM), by engaging multiple glucose lowering mechanisms, results into euglycemia and, after suspension, in T2DM remission in a clinically significant higher number of patients when compared to standard diabetes care (SDC).
* Diabetes remission: simultaneous nondiabetic values of fasting glucose, 2-hour glucose (after OGTT) and HbA1c for at least 12 months with no pharmacologic/surgical treatment of diabetes.
* Complete remission: all values of fasting glucose, 2-hour glucose and HbA1c are within the limits of normal glucose regulation; otherwise, remission is partial.
* Hyperglycemia remission as in diabetes remission, but duration\<12 months.
Based on the "Consensus Report: Definition and Interpretation of Remission in Type 2 Diabetes" published on Diabetes Care 2021;44(10):2438-2444, remission should be defined as a return of HbA1c to \<6.5% (\<48 mmol/mol) that occurs spontaneously or following an intervention and that persists for at least 3 months in the absence of usual glucose-lowering pharmacotherapy.
A POLYCHEM (metformin, pioglitazone, sitagliptin and empagliflozin) will be used to improve:
1. Insulin sensitivity of endogenous glucose output (EGO) and peripheral (muscle) glucose uptake (PGU);
2. Beta cell function;
3. GLP-1 and GIP bioavailability. To these effects, the direct glycosuric action of EMPA is added; EMPA effects on alpha cell and liver (increased glucagon secretion and EGO), may be, at least in part, counterbalanced by SITA and MET/PIO, respectively. Increased heart failure events with PIO may be, at least in part, counteracted by EMPA.
In many patients POLYCHEM should result in stable euglycemia, with negligible risk of hypoglycemia, and the number of patients in T2DM remission should be much higher than with MET+SU. The underpinning is that euglycemia reverses the detrimental effects of glucose toxicity and glucose regulation can be maintained in the nondiabetic range.
If the invesigators hypothesis is proved, POLYCHEM would be a convenient, simple and relatively unexpensive strategy to induce remission in a great number of patients with newly diagnosed T2DM. Novel, more efficacious goals of therapy could be introduced. Duration of remission is expected to delay the processes which result into the T2DM related risk of tissue damage. At the patient acceptance level, the trade off between the full T2DM burden (diabetes, its care and the risk of its complications) and the risk of T2DM relapse should favor the latter. At the society level, achieving a durable remission in a substantial number of these patients should attenuate, or even annull, the rises in prevalence, burden and tolls of "active" T2DM.
Patients with newly diagnosed (i.e. less than 6 months) T2DM will be recruited in the Diabetes Outpatient Clinics and will provide informed written consent before participation. After a screening visit (V0), patients will be randomized 1:1, with center stratification through web-based data collection (eCRF), to receive POLYCHEM or SDC with standard lifestyle intervention in both.
In both arms, patients will undergo planned visits at week 0 (V1), week 16 (V2), and week 28 (V3), after at least 3 days of drug washout. Patients will perform weekly a 6-point home blood glucose profile. Between week 17 and week 28, if a patient in hyperglycemia remission relapses, V3 will be anticipated (V3B), after which the patient will be treated as in SDC and will be re-evaluated at week 28 .
Visit procedures:
* V0: assessment of patient eligibility , including medical history, physical examination, and lab exams, if needed.
* V0S: between V0 and V1; signature of informed written consent and randomization.
* V1, V2, V3 and V3B: assessment of anthropometry, ambulatory blood pressure and heart rate, WBC, fasting glucose, HbA1c, lipids, AST, ALT, creatinine, lipase, urine analysis, microalbuminuria, insulin, C-peptide, glucagon, GLP-1, GIP, quality of life (QoL), and, only in V1, blood for DNA collection (the last for post hoc studies).
POLYCHEM-ARM: After V1, patients will start POLYCHEM (MET titrated to 1000 mg b.i.d., PIO 15 mg b.i.d., SITA 100 mg q.d., EMPA 10 mg q.d.) for 16 weeks, at the end of which (V2) patients in hyperglycemia remission stop drug therapy, the others are transferred to SDC. Patients with MET intolerance will be treated with PIO+SITA+EMPA only.
SDC-ARM: After V1, patients will continue their SDC for 16 weeks, at the end of which (V2) patients in hyperglycemia remission stop drug therapy, the others continue SDC.
* Diabetes remission: simultaneous nondiabetic values of fasting glucose, 2-hour glucose (after OGTT) and HbA1c for at least 12 months with no pharmacologic/surgical treatment of diabetes.
* Complete remission: all values of fasting glucose, 2-hour glucose and HbA1c are within the limits of normal glucose regulation; otherwise, remission is partial.
* Hyperglycemia remission as in diabetes remission, but duration\<12 months.
Based on the "Consensus Report: Definition and Interpretation of Remission in Type 2 Diabetes" published on Diabetes Care 2021;44(10):2438-2444, remission should be defined as a return of HbA1c to \<6.5% (\<48 mmol/mol) that occurs spontaneously or following an intervention and that persists for at least 3 months in the absence of usual glucose-lowering pharmacotherapy.
A POLYCHEM (metformin, pioglitazone, sitagliptin and empagliflozin) will be used to improve:
1. Insulin sensitivity of endogenous glucose output (EGO) and peripheral (muscle) glucose uptake (PGU);
2. Beta cell function;
3. GLP-1 and GIP bioavailability. To these effects, the direct glycosuric action of EMPA is added; EMPA effects on alpha cell and liver (increased glucagon secretion and EGO), may be, at least in part, counterbalanced by SITA and MET/PIO, respectively. Increased heart failure events with PIO may be, at least in part, counteracted by EMPA.
In many patients POLYCHEM should result in stable euglycemia, with negligible risk of hypoglycemia, and the number of patients in T2DM remission should be much higher than with MET+SU. The underpinning is that euglycemia reverses the detrimental effects of glucose toxicity and glucose regulation can be maintained in the nondiabetic range.
If the invesigators hypothesis is proved, POLYCHEM would be a convenient, simple and relatively unexpensive strategy to induce remission in a great number of patients with newly diagnosed T2DM. Novel, more efficacious goals of therapy could be introduced. Duration of remission is expected to delay the processes which result into the T2DM related risk of tissue damage. At the patient acceptance level, the trade off between the full T2DM burden (diabetes, its care and the risk of its complications) and the risk of T2DM relapse should favor the latter. At the society level, achieving a durable remission in a substantial number of these patients should attenuate, or even annull, the rises in prevalence, burden and tolls of "active" T2DM.
Patients with newly diagnosed (i.e. less than 6 months) T2DM will be recruited in the Diabetes Outpatient Clinics and will provide informed written consent before participation. After a screening visit (V0), patients will be randomized 1:1, with center stratification through web-based data collection (eCRF), to receive POLYCHEM or SDC with standard lifestyle intervention in both.
In both arms, patients will undergo planned visits at week 0 (V1), week 16 (V2), and week 28 (V3), after at least 3 days of drug washout. Patients will perform weekly a 6-point home blood glucose profile. Between week 17 and week 28, if a patient in hyperglycemia remission relapses, V3 will be anticipated (V3B), after which the patient will be treated as in SDC and will be re-evaluated at week 28 .
Visit procedures:
* V0: assessment of patient eligibility , including medical history, physical examination, and lab exams, if needed.
* V0S: between V0 and V1; signature of informed written consent and randomization.
* V1, V2, V3 and V3B: assessment of anthropometry, ambulatory blood pressure and heart rate, WBC, fasting glucose, HbA1c, lipids, AST, ALT, creatinine, lipase, urine analysis, microalbuminuria, insulin, C-peptide, glucagon, GLP-1, GIP, quality of life (QoL), and, only in V1, blood for DNA collection (the last for post hoc studies).
POLYCHEM-ARM: After V1, patients will start POLYCHEM (MET titrated to 1000 mg b.i.d., PIO 15 mg b.i.d., SITA 100 mg q.d., EMPA 10 mg q.d.) for 16 weeks, at the end of which (V2) patients in hyperglycemia remission stop drug therapy, the others are transferred to SDC. Patients with MET intolerance will be treated with PIO+SITA+EMPA only.
SDC-ARM: After V1, patients will continue their SDC for 16 weeks, at the end of which (V2) patients in hyperglycemia remission stop drug therapy, the others continue SDC.
Conditions
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Newly Diagnosed Type 2 Diabetes
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
Multicenter, open label pragmatic phase IIb/III RCT with a duration of 3 years
Primary Study Purpose
TREATMENT
Blinding Strategy
NONE
Study Groups
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POLYCHEM
Metformin (extended release), Pioglitazone, Sitagliptin and Empaglifozin.
Group Type
EXPERIMENTAL
Metformin-Sitagliptin-Empaglifozin-Pioglitazone
Intervention Type
DRUG
1000 mg metformin (extended release) b.i.d., pioglitazone 15 mg b.i.d., sitagliptin 100 mg q.d., empaglifozin 10 mg q.d..
STANDARD CARE
Standard of care according to the local health service.
Group Type
ACTIVE_COMPARATOR
Standard of care
Intervention Type
DRUG
Usual medical care to treat diabetes.
Interventions
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Metformin-Sitagliptin-Empaglifozin-Pioglitazone
1000 mg metformin (extended release) b.i.d., pioglitazone 15 mg b.i.d., sitagliptin 100 mg q.d., empaglifozin 10 mg q.d..
Intervention Type
DRUG
Standard of care
Usual medical care to treat diabetes.
Intervention Type
DRUG
Other Intervention Names
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POLYCHEM
SDC
Eligibility Criteria
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Inclusion Criteria
* Age 35-75 years;
* HbA1c \<= 10.0% (86 mmol/mol);
* T2DM diagnosis (\< 6 months)
* BMI\>=23 and \<=40 kg/m2
* Fasting C-peptide \> 0.3 nmol/l;
* GAD-antibody negative.
* HbA1c \<= 10.0% (86 mmol/mol);
* T2DM diagnosis (\< 6 months)
* BMI\>=23 and \<=40 kg/m2
* Fasting C-peptide \> 0.3 nmol/l;
* GAD-antibody negative.
Exclusion Criteria
* Diagnosis of type 1 diabetes;
* History of cancer in the previous 5 years;
* Multiple daily insulin treatment;
* Acute cardiovascular event within the previous 6 months;
* Chronic heart failure;
* eGFR \< 45 ml.min-1.1.73 m2 according to the MDRD formula;
* Women of child bearing potential with no use of acceptable contraception;
* Presence of diabetic retinopathy;
* Contraindications to the use of any drug of POLYCHEM.
* History of cancer in the previous 5 years;
* Multiple daily insulin treatment;
* Acute cardiovascular event within the previous 6 months;
* Chronic heart failure;
* eGFR \< 45 ml.min-1.1.73 m2 according to the MDRD formula;
* Women of child bearing potential with no use of acceptable contraception;
* Presence of diabetic retinopathy;
* Contraindications to the use of any drug of POLYCHEM.
Minimum Eligible Age
35 Years
Maximum Eligible Age
75 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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Azienda Ospedaliero-Universitaria di Parma
OTHER
Sponsor Role
lead
Responsible Party
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Riccardo Bonadonna
Director of Endocrinology Unit
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
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Riccardo Bonadonna, MD
Role: PRINCIPAL_INVESTIGATOR
Azienda Ospedaliero-Universitaria di Parma
Locations
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Azienda Ospedaliero Universitaria di Parma
Parma, Parma, Italy
Site Status
Countries
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Italy
References
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Other Identifiers
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2018-833-12
Identifier Type: -
Identifier Source: org_study_id
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NCT03700801
COMPLETED
PHASE4
A Study of the Safety and Efficacy of Sitagliptin Addition During Metformin Up-titration (MK-0431-848)
NCT02791490
COMPLETED
PHASE3
Efficay and Safety of Empagliflozin Versus Sitagliptin for the In-patient Management of Hyperglycemia
NCT06187285
COMPLETED
NA
Evaluating the Glycemic Control wIth Vildagliptin and Metformin Combination Therapy.
NCT03577184
WITHDRAWN
A Study in China Evaluating the Safety and Efficacy of Adding Sitagliptin to Stable Therapy With Insulin With or Without Metformin in Participants With Type 2 Diabetes Mellitus (T2DM) (MK-0431-254)
NCT01590797
COMPLETED
PHASE3
Safety and Efficacy of Saxagliptin in Triple Therapy to Treat Subjects With Type 2 Diabetes
NCT01619059
COMPLETED
PHASE3
Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of MBX-2982 Administered Daily for 4 Weeks as Monotherapy in Patients With Type 2 Diabetes
NCT01035879
COMPLETED
PHASE2
Monotherapy Study in Patients With Type 2 Diabetes Mellitus (0431-021)
NCT00087516
COMPLETED
PHASE3
Out-Patient Study in Patients With Type 2 Diabetes Mellitus Who Are Taking no Diabetes Medication or Metformin Only
NCT00518115
COMPLETED
PHASE2
A Study of the Effects of Sitagliptin (MK0431) and Metformin on Incretin Hormone Concentrations (0431-050)(COMPLETED)
NCT00975052
COMPLETED
PHASE1
30-Week Extension to an Initial Combination Study (24 Weeks in Duration) of Sitagliptin With Pioglitazone (0431-064)
NCT01028391
COMPLETED
PHASE3
Sitagliptin for Hyperglycemia in Patients With T2DM Undergoing Cardiac Surgery
NCT02556918
COMPLETED
PHASE4
Efficacy and Safety of Albiglutide in Treatment of Type 2 Diabetes
NCT00838903
COMPLETED
PHASE3
MK0431A Comparative Study in Patients With Type 2 Diabetes (0431A-079)(COMPLETED)
NCT00482729
COMPLETED
PHASE3
Comparative Effectiveness of Two Initial Combination Therapies in Patients With Recent Onset Diabetes
NCT06246799
RECRUITING
PHASE3
Glimepiride, Empagliflozin, and Sitagliptin With Metformin for Type 2 Diabetes
NCT06759922
COMPLETED
PHASE4
A Study of an Investigational Drug Sitagliptin for Type 2 Diabetes Mellitus (0431-044)
NCT00127192
COMPLETED
PHASE2
Efficacy and Safety of Evogliptin When Added to Ongoing Metformin and Dapagliflozin Combination Therapy in Patients With Type 2 Diabetes Who Have Inadequate Glycemic Control
NCT04170998
COMPLETED
PHASE3
Effects of Different Early Intensive Therapies on Long-term β-cell Function
NCT01471808
COMPLETED
PHASE4