Type 2 Diabetes Mellitus, Chronic Kidney Disease
Conditions
Keywords
Glargine insulin, Chronic Kidney Disease, CGMS
Brief summary
Chronic kidney disease (CKD) is one of the most common microvascular complications of diabetes mellitus, and it is the leading cause of end stage renal disease on developed countries. The CKD diagnosis and its progression require re-evaluation of hypoglycemic therapy and constant dosing adjustments, in order to optimize glycemic control and minimize its side effects. Long acting insulin analogs and its pharmacokinetics have not been studied through different stages of kidney disease and there is no consensus defining the appropriate dosing adjustment based on the glomerular filtration rate (GFR). This research project will compare the glycemic response to intensive insulin treatment with NPH insulin and basal insulin analog (insulin glargine) in type 2 diabetes (DM 2) patients with CKD stages 3 and 4. Patients and methods - Inclusion Criteria: DM 2 patients with CKD secondary to diabetic nephropathy and GFR of 15-59 ml/min/1.73m². Exclusion Criteria: Patients with systemic neoplasia, HIV, CKD or nephropathy from other etiologies, severe psychiatric disorders and pregnant women. Study design: This study consists of a randomized, cross-over, open-label controlled clinical trial. Patients will be randomly divided into two groups: GROUP 1 - insulin analog glargine once a day and GROUP 2 - NPH human insulin, three applications per day, both group will be treated with insulin lispro at mealtime. The laboratory tests will be performed at baseline and 12, 24, 36 and 48 weeks after the study start. During routine medical appointments will be analyzed self- monitoring of capillary blood glucose (SMBG) and the hypoglycemia score. After 24 weeks the basal insulin will be changed, i.e. patients using NPH insulin will receive insulin glargine and patients on insulin glargine will be changed to NPH insulin. A CGMS will be carried out at 24 and 48 weeks. Methodology: The metabolic profile will be evaluated throughout SMBG; biochemical, hormonal and hematological measurements; hypoglycemia score and CGMS. Statistical analysis will be performed using comparative descriptive analyzes, such as chi-square distribution, t-test and non-parametric tests. Analyze of data CGMS will include the area under the curve and the related statistic. Finally, logistic regression models will be adopted to evaluate the effect of the treatment on the several variables in question.
Detailed description
This study consists of a randomized, cross-over, open-label controlled clinical trial. Randomized patients will be allocated alternately into two groups to receive the following therapies: GROUP 1 - insulin analog glargine once a day associated to insulin lispro at mealtime and GROUP 2 - NPH human insulin, three applications per day ( breakfast, lunch and bedtime) and insulin lispro at mealtime. Patients receiving insulin NPH plus insulin lispro will be oriented to mix both of them in the same syringe at breakfast and lunchtime. The laboratory tests will be performed at baseline and 12, 24, 36 and 48 weeks after the study start. During routine medical appointments the patient should bring the self- monitoring of capillary blood glucose (SMBG), eight points per day once a week, and hypoglycemia score. After 24 weeks of insulin therapy, a continuous glucose monitoring system (CGMS) will be implemented for three days, and after that, the basal insulin changed i.e. patients using NPH insulin will receive insulin glargine and patients on insulin glargine will be changed to NPH insulin, both groups will keep insulin lispro before meals. A new CGMS will be carried out 24 weeks after therapy has been changed. Methodology: The metabolic profile will be evaluated throughout SMBG; biochemical, hormonal and hematological measurements; hypoglycemia score and CGMS (Medtronic/Northridge, CA). All randomized patients who use at least one dose of any study treatment will be considered in the Intent-to-treat (ITT) population. The initial plan is to randomize 40 patients, assuming a drop-out rate of 15%, to obtain a sample size of at least 34 randomized patients. .Statistical analysis will be performed using comparative descriptive analyzes, such as chi-square distribution, t-test and non-parametric tests. Analyze of data CGMS will include the area under the curve and the related statistic. Finally, logistic regression models will be adopted to evaluate the effect of the treatment on the several variables in question.
Interventions
DRUGNPH insulin
The same total daily NPH insulin dose was maintained for those randomized to INPH. All of them had pre-prandial Regular insulin (Humulin R™, Lilly, Brazil) switched to Lispro insulin (Humalog™, Lilly, Brazil), at the same dose as in use previously. . After 24 weeks, basal insulins were switched; in other words, individuals on NPH in the first period switched to glargine insulin, and the doses of pre-meal insulin were sustained.
DRUGGlargine insulin
The initial insulin dose for those randomized to IGlar was 80% of the total daily NPH dose that was being discontinued. All of them had pre-prandial Regular insulin switched to Lispro insulin (Humalog™, Lilly, Brazil), at the same dose as in use previously. After 24 weeks, basal insulins were switched; in other words, individuals on IGlar in the first period switched to INPH, and the doses of pre-meal insulin were sustained
Sponsors
University of Sao Paulo General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Patients with type 2 diabetes mellitus and chronic kidney disease secondary to diabetic nephropathy in stages 3 and 4 (moderate and severe nephropathy, corresponding to glomerular filtration rate of 15-59 ml/min/1.73m²) will be included in the study.
Exclusion criteria
* Patients with systemic neoplasias, * HIV, chronic kidney disease or nephropathy from other etiologies, * severe psychiatric disorders * pregnant women.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in A1c Levels | baseline and 24 weeks | A1c using high performance liquid chromatography measured in percentage |
| Number of Hypoglycemic Events | between 1rst and 24 weeks of each treatment arm | Hypoglycemia was defined by capillary glycemia\< 70 mg/dL (3.9 mmol/L), even if it was not accompanied by typical symptoms. Otherwise, hypoglycemia was classified as severe with SMBG below 50 mg/dL (2.8 mmol/L) or when it resulted in stupor, seizure, or unconsciousness that precluded self-treatment, thus requiring the assistance of another individual. Nocturnal events were defined as SMBG \< 70mg/dL occurring after midnight and before wake-up in the morning (before 7:00am)12. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Body Mass Index (BMI) | baseline and 24 weeks | The BMI is defined as the body mass divided by the square of the body height, and is universally expressed in units of kg/m2, resulting from mass in kilograms and height in metres. |
| Glycemic Variability | 24 week | In order to observe variability in interstitial glucose levels related to the therapy in use, participants wore a blinded CGM for 3 days. Changes in glycemic patterns were expressed by the average daily time spent in hypoglycemia (≤70 mg/dL or \<3.9 mmol/L), hyperglycemia (\>180 mg/dL or \>10 mmol/L) and euglycemia (70-180 mg/dL or 3.9-10 mmol/L). |
| Estimated Glomerular Filtration Rate (eGFR) Calculated by CKD-EPI | baseline and 24 weeks | Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is one of the most widely used IDMS traceable equations for estimating GFR in patients age 18 and over. CKD-EPI equation includes variables for age, gender, and race, which may allow providers to observe that CKD is present despite a serum creatinine concentration that appears to fall within or just above the normal reference interval. CKD-EPI equation expressed as a single equation: GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 \[if female\] × 1.159 \[if black\] where: Scr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males,min indicates the minimum of Scr /κ or 1, and max indicates the maximum of Scr /κ or 1. |
| Serum Creatinine | baseline and 24 weeks | Creatinine is measured in milligrams per deciliter of blood (mg/dL |
| Total Daily Insulin Dose | baseline and 24 weeks | Daily total insulin dose at baseline compared to dose at week 24. |
Countries
Brazil
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Glargine Insulin, Then NPH Insulin The initial insulin dose for those randomized to IGlar was 80% of the total daily NPH dose that was being discontinued. All of them had pre-prandial Regular insulin switched to Lispro insulin (Humalog™, Lilly, Brazil), at the same dose as in use previously. After 24 weeks, basal insulins were switched; in other words, individuals on IGlar in the first period switched to INPH, and the doses of pre-meal insulin were sustained | 16 |
| NPH Insulin, Then Glargine Insulin The same total daily NPH insulin dose was maintained for those randomized to INPH. All of them had pre-prandial Regular insulin (Humulin R™, Lilly, Brazil) switched to Lispro insulin (Humalog™, Lilly, Brazil), at the same dose as in use previously. . After 24 weeks, basal insulins were switched; in other words, individuals on NPH in the first period switched to glargine insulin, and the doses of pre-meal insulin were sustained. | 18 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (24 Weeks) | Adverse Event | 0 | 2 |
| First Intervention (24 Weeks) | Death | 0 | 1 |
| First Intervention (24 Weeks) | Lost to Follow-up | 2 | 0 |
Baseline characteristics
| Characteristic | NPH Insulin, Then Glargine Insulin | Total | Glargine Insulin, Then NPH Insulin |
|---|---|---|---|
| Age, Continuous | 60.1 years STANDARD_DEVIATION 8.7 | 61.4 years STANDARD_DEVIATION 7.9 | 62.8 years STANDARD_DEVIATION 7 |
| BMI | 30.4 kg/m² STANDARD_DEVIATION 4.3 | 29.6 kg/m² STANDARD_DEVIATION 4.6 | 28.6 kg/m² STANDARD_DEVIATION 4.8 |
| Body weight | 82.6 kg STANDARD_DEVIATION 17.4 | 79.2 kg STANDARD_DEVIATION 15.3 | 75.4 kg STANDARD_DEVIATION 11.9 |
| Diastolic Blood Pressure | 75 mmHg STANDARD_DEVIATION 13 | 76 mmHg STANDARD_DEVIATION 12 | 79 mmHg STANDARD_DEVIATION 12 |
| Duration of Diabetes | 19.2 years STANDARD_DEVIATION 7 | 19.1 years STANDARD_DEVIATION 9.4 | 19.0 years STANDARD_DEVIATION 11.7 |
| Region of Enrollment Brazil | 18 participants | 34 participants | 16 participants |
| Sex: Female, Male Female | 7 Participants | 11 Participants | 4 Participants |
| Sex: Female, Male Male | 11 Participants | 23 Participants | 12 Participants |
| Systolic Blood Pressure | 136 mmHg STANDARD_DEVIATION 18 | 141 mmHg STANDARD_DEVIATION 20 | 147 mmHg STANDARD_DEVIATION 22 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 34 | 0 / 34 |
| serious Total, serious adverse events | 0 / 34 | 2 / 34 |
Outcome results
Primary
Difference in A1c Levels
A1c using high performance liquid chromatography measured in percentage
Time frame: baseline and 24 weeks
Population: Primary endpoint A1c was assessed using an analysis of covariance (ANOVA) model.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glargine Insulin Period | Difference in A1c Levels | Baseline | 8.86 percentage | Standard Deviation 1.4 |
| Glargine Insulin Period | Difference in A1c Levels | 24 weeks treatement | 7.95 percentage | Standard Deviation 1.1 |
| NPH Insulin Period | Difference in A1c Levels | Baseline | 8.21 percentage | Standard Deviation 1.3 |
| NPH Insulin Period | Difference in A1c Levels | 24 weeks treatement | 8.44 percentage | Standard Deviation 1.3 |
Comparison: A sample size of 34 participants (16 randomized to sequence IGlar/INPH and 18 randomized to sequence INPH/IGlar) provided 90% power to detect a mean difference of 0.7% in the primary endpoint (A1c), considering a 15% dropout rate and assuming an SD of 0.85%, and a type I error of 5%. Test for data normality (Kolmogorov-Smirnov statistics) was performed at baseline for each sequence of the therapy.p-value: 0.00045ANOVA
Primary
Number of Hypoglycemic Events
Hypoglycemia was defined by capillary glycemia\< 70 mg/dL (3.9 mmol/L), even if it was not accompanied by typical symptoms. Otherwise, hypoglycemia was classified as severe with SMBG below 50 mg/dL (2.8 mmol/L) or when it resulted in stupor, seizure, or unconsciousness that precluded self-treatment, thus requiring the assistance of another individual. Nocturnal events were defined as SMBG \< 70mg/dL occurring after midnight and before wake-up in the morning (before 7:00am)12.
Time frame: between 1rst and 24 weeks of each treatment arm
Population: Endpoint hypoglycemia was assessed using an analysis of covariance (ANOVA) model
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glargine Insulin Period | Number of Hypoglycemic Events | total hypoglycemic events | 4.87 events per patients during 24 weeks | Standard Deviation 5.39 |
| Glargine Insulin Period | Number of Hypoglycemic Events | nocturnal hypoglycemias | 0.52 events per patients during 24 weeks | Standard Deviation 1.03 |
| NPH Insulin Period | Number of Hypoglycemic Events | total hypoglycemic events | 6.34 events per patients during 24 weeks | Standard Deviation 9.37 |
| NPH Insulin Period | Number of Hypoglycemic Events | nocturnal hypoglycemias | 1.52 events per patients during 24 weeks | Standard Deviation 2.54 |
Comparison: A sample size of 34 participants (16randomized to sequence IGlar/INPH and 18 randomized to sequence INPH/IGlar) provided 90% power and assuming an SD of 0.85%, and a type I error of 5%.p-value: 0.047ANOVA
Comparison: Analysis of covariance (ANOVA) model - total hypoglycemic events per patient during 24 weeksp-value: 0.35ANOVA
Other Pre-specified
Body Mass Index (BMI)
The BMI is defined as the body mass divided by the square of the body height, and is universally expressed in units of kg/m2, resulting from mass in kilograms and height in metres.
Time frame: baseline and 24 weeks
Population: BMI endpoint was assessed using an analysis of covariance (ANOVA) model.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glargine Insulin Period | Body Mass Index (BMI) | Baseline | 29.7 Kg/m² | Standard Deviation 4.7 |
| Glargine Insulin Period | Body Mass Index (BMI) | 24 weeks treatement | 30.0 Kg/m² | Standard Deviation 4.3 |
| NPH Insulin Period | Body Mass Index (BMI) | Baseline | 30.0 Kg/m² | Standard Deviation 4.3 |
| NPH Insulin Period | Body Mass Index (BMI) | 24 weeks treatement | 30.4 Kg/m² | Standard Deviation 4.7 |
Comparison: A sample size of 34 participants (16 randomized to sequence IGlar/INPH and 18r andomized to sequence INPH/IGlar) provided 90% power and assuming an SD of 0.85%, and a type I error of 5%.p-value: 0.999ANOVA
Other Pre-specified
Estimated Glomerular Filtration Rate (eGFR) Calculated by CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is one of the most widely used IDMS traceable equations for estimating GFR in patients age 18 and over. CKD-EPI equation includes variables for age, gender, and race, which may allow providers to observe that CKD is present despite a serum creatinine concentration that appears to fall within or just above the normal reference interval. CKD-EPI equation expressed as a single equation: GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 \[if female\] × 1.159 \[if black\] where: Scr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males,min indicates the minimum of Scr /κ or 1, and max indicates the maximum of Scr /κ or 1.
Time frame: baseline and 24 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glargine Insulin Period | Estimated Glomerular Filtration Rate (eGFR) Calculated by CKD-EPI | Baseline | 28.0 ml/min/1.7m² | Standard Deviation 9.6 |
| Glargine Insulin Period | Estimated Glomerular Filtration Rate (eGFR) Calculated by CKD-EPI | 24 weeks treatement | 26.9 ml/min/1.7m² | Standard Deviation 10 |
| NPH Insulin Period | Estimated Glomerular Filtration Rate (eGFR) Calculated by CKD-EPI | Baseline | 27.4 ml/min/1.7m² | Standard Deviation 9.1 |
| NPH Insulin Period | Estimated Glomerular Filtration Rate (eGFR) Calculated by CKD-EPI | 24 weeks treatement | 25.9 ml/min/1.7m² | Standard Deviation 9.7 |
Comparison: A sample size of 34 participants (16randomized to sequence IGlar/INPH and 18 randomized to sequence INPH/IGlar) provided 90% power and assuming an SD of 0.85%, and a type I error of 5%.p-value: 0.994ANOVA
Other Pre-specified
Glycemic Variability
In order to observe variability in interstitial glucose levels related to the therapy in use, participants wore a blinded CGM for 3 days. Changes in glycemic patterns were expressed by the average daily time spent in hypoglycemia (≤70 mg/dL or \<3.9 mmol/L), hyperglycemia (\>180 mg/dL or \>10 mmol/L) and euglycemia (70-180 mg/dL or 3.9-10 mmol/L).
Time frame: 24 week
Population: Patients were excluded from the analysis because of unfamiliarity with mechanical procedures related to the CGM use, visual impairment or technical problems with the sensor measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glargine Insulin Period | Glycemic Variability | hypoglycemia | 3 percentage of time | Standard Deviation 6 |
| Glargine Insulin Period | Glycemic Variability | hyperglycemia | 30 percentage of time | Standard Deviation 19 |
| Glargine Insulin Period | Glycemic Variability | normoglycemia | 67 percentage of time | Standard Deviation 19 |
| NPH Insulin Period | Glycemic Variability | normoglycemia | 59 percentage of time | Standard Deviation 19 |
| NPH Insulin Period | Glycemic Variability | hypoglycemia | 3 percentage of time | Standard Deviation 5 |
| NPH Insulin Period | Glycemic Variability | hyperglycemia | 38 percentage of time | Standard Deviation 19 |
Comparison: A sample size of 34 participants (16 randomized to sequence IGlar/INPH and 18 randomized to sequence INPH/IGlar) provided 90% power and assuming an SD of 0.85%, and a type I error of 5%.p-value: <0.05t-test, 1 sided
Other Pre-specified
Serum Creatinine
Creatinine is measured in milligrams per deciliter of blood (mg/dL
Time frame: baseline and 24 weeks
Population: Creatinine endpoint was assessed using an analysis of covariance (ANOVA) model.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glargine Insulin Period | Serum Creatinine | Baseline | 2.4 mg/dL | Standard Deviation 0.7 |
| Glargine Insulin Period | Serum Creatinine | 24 weeks treatement | 2.6 mg/dL | Standard Deviation 0.8 |
| NPH Insulin Period | Serum Creatinine | Baseline | 2.5 mg/dL | Standard Deviation 1 |
| NPH Insulin Period | Serum Creatinine | 24 weeks treatement | 2.6 mg/dL | Standard Deviation 1 |
Comparison: A sample size of 34 participants (16randomized to sequence IGlar/INPH and 18 randomized to sequence INPH/IGlar) provided 90% power and assuming an SD of 0.85%, and a type I error of 5%.p-value: 0.999ANOVA
Other Pre-specified
Total Daily Insulin Dose
Daily total insulin dose at baseline compared to dose at week 24.
Time frame: baseline and 24 weeks
Population: Randomization was stratified by the A1c value at baseline: \<9.0% or ≥9.0%, in a 1:1 ratio, and the individuals who met all inclusion-criteria were allocated alternately to either an IGlar/INPH or an INPH/IGlar treatment sequence.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glargine Insulin Period | Total Daily Insulin Dose | Baseline | 0.61 units/Kg/day | Standard Deviation 0.21 |
| Glargine Insulin Period | Total Daily Insulin Dose | 24 weeks treatment | 0.64 units/Kg/day | Standard Deviation 0.26 |
| NPH Insulin Period | Total Daily Insulin Dose | Baseline | 0.63 units/Kg/day | Standard Deviation 0.21 |
| NPH Insulin Period | Total Daily Insulin Dose | 24 weeks treatment | 0.64 units/Kg/day | Standard Deviation 0.25 |
Comparison: A sample size of 34 participants (16randomized to sequence IGlar/INPH and 18 randomized to sequence INPH/IGlar) provided 90% power and assuming an SD of 0.85%, and a type I error of 5%.p-value: 0.668ANOVA