Effects of Short-term Intensive Insulin Therapy on Long-term Complications in Type 2 Diabetes

Study Overview
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Brief Summary
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Short-term intensive insulin therapy (SIIT) is able to reverse β cell dysfunction and induce glycemic remission in patients with newly diagnosed type 2 diabetes. On the other hand, intensive control of glucose and lifestyle modification are two key elements in preventing chronic complications, especially microvascular neuropathy. However, no study reported the long-term effect of SIIT on the chronic complications. In this multi-center, case-control study, effects of SIIT on the proportion of long-term chronic complications as well as potential biomarkers were investigated. In total, 777 patients with type 2 diabetes, including 259 patients who participated SIIT when diabetes was newly diagnosed and 518 patients who received routine diabetic therapy will be enrolled in 12 centers in China. After baseline assessments, all patients will undergo complications assessment, including records of cardiovascular diseases (CVD), carotid ultrasonography, electrocardiogram, echocardiography, fundus photography, urinary albumin excretion, Toronto Clinical Neuropathy Scale and Composite Autonomic Symptom Score. Primary endpoint is the difference in the proportions of macrovascular and microvascular complications between groups. Secondary endpoints include the difference of glucose control, insulin resistance, complexity of anti-diabetic therapy and self-management skills and quality of life between two groups. What's more, new biomarkers, which may indicate the occurrence of chronic complications of diabetes, such as circulating endothelial progenitor, β cell dysfunction, and T cells.

Official Title
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Effects of Short-term Intensive Insulin Therapy on Long-term Complications in Patients With Type 2 Diabetes

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Other: Complications assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed as type 2 diabetes for at least 5 years; When diagnosed as diabetes for the first time, aged between 25 and 65 years, body mass index (BMI) 22-35 kg/m2, fasting plasma glucose (FPG) between 7.0 mmol/l (126 mg/dl) and 16.7 mmol/l (300 mg/dl); Short-term intensive insulin therapy group: Patients received short-term intensive insulin therapy for 14 days when newly diagnosed as type 2 diabetes and induce glycemic remission. Routine diabetic therapy group: Patients received routine diabetic therapy as guideline indicated and never induce glycemic remission. Exclusion Criteria: Type 1 diabetes or special type of diabetes; Acute complications of diabetes (including DKA, HHS and lactic acidosis) when diagnosed as diabetes; Serious microvascular complications: proliferative stage of retinopathy; urine AER >300 mg/g or urine protein positive, quantification >0.5 g/d; uncontrolled painful diabetic neuropathy and significant diabetic autonomic neuropathy when diagnosed as diabetes; Severe macrovascular complications: acute cerebrovascular accident, acute coronary syndrome, vascular intervention for peripheral arterial disease or amputation requiring hospitalization within 12 months prior to enrollment when diagnosed as diabetes; Blood creatinine clearance less than 50 ml/min, alanine aminotransferase ≥2.5×upper limit of normal, total bilirubin ≥1.5×upper limit of normal; Hemoglobin <100 g/L or need regular blood transfusion; Use of drugs that may influence blood glucose within 12 weeks; Systemic infection or serious concomitant disease; patients with malignancy or chronic diarrhea; Uncontrolled endocrine gland dysfunction; Patients with mental or communication disorders; Chronic cardiac insufficiency, heart function class III and above; Pregnant women, lactating women and women of child bearing age who are not willing to take contraception during the study; Subjects who don't cooperate, cannot be followed up or have difficulty in completing the study considered by the investigator.

Ages Eligible for Study
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Minimum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Short-term intensive insulin therapy<br>Patients who used to participated in short-term intensive insulin therapy for 14 days when diabetes was newly diagnosed | Other: Complications assessment<br>* Records of cardiovascular diseases (CVD), carotid ultrasonography, electrocardiogram, echocardiography, fundus photography, urinary albumin excretion, Toronto Clinical Neuropathy Scale and Composite Autonomic Symptom Score.<br>|
| Routine diabetic therapy<br>Received routine diabetic therapy | Other: Complications assessment<br>* Records of cardiovascular diseases (CVD), carotid ultrasonography, electrocardiogram, echocardiography, fundus photography, urinary albumin excretion, Toronto Clinical Neuropathy Scale and Composite Autonomic Symptom Score.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in the proportions of chronic complications | Difference in the proportions of macrovascular and microvascular complications between groups | 5 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference of glycosylated hemoglobin A1C | Difference of glycosylated hemoglobin A1C between groups | 5 year | 
| Difference of fast blood glucose | Difference of fast blood glucose between groups | 5 year | 
| Difference of C-peptides | Difference of fast C-peptides between groups. | 5 year | 
| Difference of insulin resistance | Difference of HOMA2-IR between groups. HOMA2-IR is calculated by fast blood glucose and C-peptide according to formula proposed by DR Matthew (the software can be accessed at http://www.ocdem.ox.ac.uk). | 5 year | 
| Difference of insulin usage | Compare the proportion of insulin usage (including rapidly acting insulin, regular insulin, long-acting insulin and premixed insulin) between groups | 5 year | 
| Difference of oral anti-diabetic drugs usage | Compare the proportion of oral anti-diabetic drugs usage (including biguanides, sulfonylureas, Glinides, glucosidase inhibitors, thiazolidinediones, DPP 4 inhibitors, SGLT-2 inhibitor and their combination) between groups | 5 year | 
| Difference of attitudes toward diabetes | Compare the score of Diabetes Care Profile questionnaire between groups. Patients were questioned about five aspects, including positive attitude, negative attitude, ability to care for their diabetes, belief in importance of care, and self-care adherence. Each statement included a 5-point ranking scale, ranging from strongly disagree (never) to strongly agree (always), with 3 points as neutral. Items under the subscales of positive attitude, care ability, importance of care, and self-care adherence scoring ≥4 points and items of negative attitude scoring≤2 points were designated as good performance, whereas the opposites were poor. | 5 year | 
| Difference of quality of life | Compare the score of Diabetes quality of life (DQOL) between groups. The DQOL contains a total of 46 items, and all the items are categorized into one of the following four domains: life satisfaction (15 items), diabetes impact (20 items), social/vocational related worries (7 items), and diabetes related worries (4 items). The DQOL adopts a 5-point Likert scale for its response options. The scores range from 1, labeled as very satisfied, to 5, labeled as very dissatisfied, for items in the life satisfaction domain; from 1, labeled as never impacted, to 5, labeled as always impacted, for items in the diabetes impact domain; and from 1, labeled as never worried, to 5, labeled as always worried, for the social/vocational related and diabetes related worries domains. Higher score indicating better outcome. | 5 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes mellitus, Continuous subcutaneous insulin infusion, chronic complications