Essential Hypertension Complicated by Type 2 Diabetes Mellitus
Conditions
Brief summary
Multicenter, randomized, open-label, parallel-group exploratory study to explore the effects of azilsartan (Azirva), compared with telmisartan, on insulin resistance in participants with essential hypertension complicated by type 2 diabetes mellitus
Detailed description
The primary objective of the present study is to explore the effects of azilsartan 20 mg, compared with telmisartan 40 mg, once daily orally for 12 weeks on insulin resistance in participants with essential hypertension complicated by type 2 diabetes mellitus.
Interventions
DRUGAzilsartan
Azilsartan tablets
DRUGTelmisartan
Telmisartan tablets
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. The participant was given the diagnosis of grade I or II essential hypertension and was judged by the principal investigator or investigator that they can be appropriately treated with azilsartan 20 mg and telmisartan 40 mg. 2. Sitting systolic blood pressure of ≥ 130 mmHg and \< 180 mmHg or sitting diastolic blood pressure of ≥ 80 mmHg and \< 110 mmHg at the start of the treatment period (Week 0) Sitting blood pressure will be measured until 2 consecutive stable measurements are obtained (i.e., the difference between 2 measurements: diastolic blood pressure of \<5 mmHg and systolic blood pressure of \< 10 mmHg) after resting in a sitting position for at least 5 minutes. The average value of the last 2 measurements will be recorded (the first the decimal place is rounded off). 3. Type 2 diabetes mellitus 4. HbA1c (NGSP (National Glycohemoglobin Standardization Program) value) of \< 8.4% during 3 months before informed consent, with a ≤ 0.3% change in HbA1c (peak minus nadir) during 3 months before informed consent 5. No change in diet/exercise therapy during the 3 months before the informed consent in a participant who has been on diet/exercise therapy and instructed to improve life style (e.g., diet and exercise) 6. Age ≥ 20 years at the time of consent 7. Outpatients 8. Capable of providing written consent before participation in this study.
Exclusion criteria
1. Grade III essential hypertension (i.e., sitting systolic blood pressure 180 mmHg or sitting diastolic blood pressure ≥ 110 mmHg), secondary hypertension, or malignant hypertension. 2. Grade II essential hypertension (i.e., sitting systolic blood pressure ≥ 160 mmHg or sitting diastolic blood pressure ≥ 100 mmHg) for which antihypertensive drug(s) are used 3. Use of oral antihypertensive medication within 2 weeks before the start of the treatment period Participants who are on any antihypertensive agent at the time of informed consent can be enrolled in the study only after 2-week washout following informed consent. 4. Use of RAS inhibitors or thiazolidines within 3 months before the start of the treatment period 5. Type 1 diabetes mellitus 6. Fasting blood glucose of \< 180 mg/dL and HOMA-R of ≤ 1.6 at the start of the treatment period (Week 0) 7. Receiving or requiring any of the following at the time of informed consent: * Insulin, glucagon-like peptide-1 (GLP-1) receptor agonists, or other parenteral hypoglycemic agents * Combination therapy with 3 or more oral hypoglycemic agents 8. Change of antidiabetic medication (including dosage change) within 3 months before the start of the treatment period 9. Having diagnosed/treated any of the following cardiovascular diseases within 3 months before the start of the treatment period: * Cardiac disease/condition: myocardial infarction, coronary revascularization procedure * Cerebrovascular disease: cerebral infarction, cerebral haemorrhage, transient ischaemic attack * Advanced hypertensive retinopathy (retinal bleeding or oozing, papilloedema) 10. Having diagnosed/treated for any of the following cardiovascular diseases more than 3 months before the start of the treatment period, and is now still in unstable condition. * Cardiac disease/condition: myocardial infarction, coronary revascularization procedure * Cerebrovascular disease: cerebral infarction, cerebral haemorrhage, transient ischaemic attack 11. Past or current history of any of the following cardiovascular diseases. * Cardiac valve stenosis * Angina pectoris requiring medication * Congestive cardiac failure requiring medication * Arrhythmia requiring medication (e.g., paroxysmal atrial fibrillation, severe bradycardia, torsade de pointes, and ventricular fibrillation) * Arteriosclerosis obliterans with intermittent claudication or other symptoms 12. Have severe ketosis, diabetic coma or precoma, severe infection, or serious trauma 13. Clinically evident renal disorder (e.g., eGFR \<30 mL/min/1.73 m2) 14. Markedly low bile secretion or severe hepatic disorder 15. History of hypersensitivity or allergy to azilsartan or telmisartan or to both. 16. Presence of hyperkalemia (potassium level ≥ 5.5 mEq/L on laboratory testing) 17. Currently participating in any other clinical study. 18. Pregnant women, women with possible pregnancy, or breast-feeding women. 19. Other participants who are inappropriate for participation in this study in the opinion of the principal investigator or investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Insulin Resistance Index (HOMA-R) From Baseline at the End of the Treatment Period (Week 12) | Baseline and Week 12 | Change from the start of the treatment period (baseline) at the end of the treatment period (Week 12) was reported. Insulin Resistance Index (HOMA-R) measures insulin resistance, calculated by fasting insulin (μU/mL) multiplied by fasting glucose (mg/dL), and divided by a constant (405). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Insulin From Baseline at the End of the Treatment Period (Week 12) | Baseline and Week 12 | Change from baseline in fasting insulin values collected at week 12 or final visit relative to baseline was reported. |
| Change in Glycosylated Hemoglobin (HbA1c) From Baseline at the End of the Treatment Period (Week 12) | Baseline and Week 12 | Change from baseline in the values of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 12 or final visit relative to baseline was reported. |
| Change in Fasting Blood Glucose From Baseline at the End of the Treatment Period (Week 12) | Baseline and Week 12 | Change from baseline in fasting blood glucose values collected at week 12 or final visit relative to baseline was reported. |
| Change in 1,5-anhydroglucitol (1,5-AG) From Baseline at the End of the Treatment Period (Week 12) | Baseline and Week 12 | Change from baseline in 1,5-G concentration collected at week 12 or final visit relative to baseline was reported. |
| Number of Participants With Treatment-Emergent Adverse Events | Up to Week 12 | — |
| Change in Homeostasis Model Assessment of Beta Cell Function (HOMA-β) From Baseline at the End of the Treatment Period (Week 12) | Baseline and Week 12 | Change from baseline in HOMA-β collected at week 12 or final visit relative to baseline was reported. Homeostasis model assessment of beta cell function measures as following; HOMA-β = fasting insulin (μU/mL) ×360/{fasting glucose (mg/dL) - 63}. |
Countries
Japan
Participant flow
Recruitment details
Participants took part in the study at 27 investigative sites in Japan, from 04 June 2014 to 25 April 2016.
Pre-assignment details
Participants with diagnosis of type 2 diabetes mellitus were enrolled in 2 treatment group: Azilsartan 20 mg, and Telmisartan 40 mg for 12 weeks as treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Telmisartan 40 mg Participants received telmisartan 40 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod. | 16 |
| Azilsartan 20 mg Participants received azilsartan 20 mg, once daily in the morning before or after breakfast for 12 weeks as treatment priod. | 17 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Pretreatment Event/Adverse Event | 0 | 1 |
| Overall Study | Voluntary Withdrawal | 0 | 1 |
Baseline characteristics
| Characteristic | Telmisartan 40 mg | Azilsartan 20 mg | Total |
|---|---|---|---|
| Age, Continuous | 65.3 Years STANDARD_DEVIATION 9.1 | 63.2 Years STANDARD_DEVIATION 12.76 | 64.2 Years STANDARD_DEVIATION 11.02 |
| Alcohol Classification No | 10 participants | 12 participants | 22 participants |
| Alcohol Classification Yes | 6 participants | 5 participants | 11 participants |
| Blood Pressure Diastolic Mean | 89.3 mmHg STANDARD_DEVIATION 10.61 | 88.8 mmHg STANDARD_DEVIATION 7.19 | 89.0 mmHg STANDARD_DEVIATION 8.87 |
| Blood Pressure Systolic Mean | 145.6 mmHg STANDARD_DEVIATION 9.91 | 143.3 mmHg STANDARD_DEVIATION 9.28 | 144.4 mmHg STANDARD_DEVIATION 9.51 |
| BMI | 27.18 kg/m^2 STANDARD_DEVIATION 3.72 | 27.19 kg/m^2 STANDARD_DEVIATION 4.642 | 27.19 kg/m^2 STANDARD_DEVIATION 4.154 |
| Duration of Diabetes Mellitus | 4.53 Years STANDARD_DEVIATION 4.279 | 4.89 Years STANDARD_DEVIATION 5.039 | 4.72 Years STANDARD_DEVIATION 4.617 |
| Duration of Hypertention | 4.71 Years STANDARD_DEVIATION 4.391 | 3.54 Years STANDARD_DEVIATION 4.392 | 4.11 Years STANDARD_DEVIATION 4.363 |
| Glycosylated Hemoglobin (HbA1c) | 6.63 percent STANDARD_DEVIATION 0.411 | 6.81 percent STANDARD_DEVIATION 0.488 | 6.72 percent STANDARD_DEVIATION 0.454 |
| Insulin Resistance Index (HOMA-R) | 3.31 HOMA-R Score STANDARD_DEVIATION 1.366 | 4.24 HOMA-R Score STANDARD_DEVIATION 1.843 | 3.79 HOMA-R Score STANDARD_DEVIATION 1.671 |
| Sex: Female, Male Female | 9 Participants | 10 Participants | 19 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 14 Participants |
| Smoking Classification Current smoker | 2 participants | 3 participants | 5 participants |
| Smoking Classification Ex-smoker | 6 participants | 6 participants | 12 participants |
| Smoking Classification Never smoked | 8 participants | 8 participants | 16 participants |
| Taking Biguanides Had taken | 3 participants | 4 participants | 7 participants |
| Taking Biguanides Not had taken | 13 participants | 13 participants | 26 participants |
| Weight | 70.95 kg STANDARD_DEVIATION 16.689 | 70.41 kg STANDARD_DEVIATION 14.878 | 70.67 kg STANDARD_DEVIATION 15.534 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 16 | 6 / 17 |
| serious Total, serious adverse events | 0 / 16 | 0 / 17 |
Outcome results
Primary
Change in Insulin Resistance Index (HOMA-R) From Baseline at the End of the Treatment Period (Week 12)
Change from the start of the treatment period (baseline) at the end of the treatment period (Week 12) was reported. Insulin Resistance Index (HOMA-R) measures insulin resistance, calculated by fasting insulin (μU/mL) multiplied by fasting glucose (mg/dL), and divided by a constant (405).
Time frame: Baseline and Week 12
Population: The full analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Telmisartan 40 mg | Change in Insulin Resistance Index (HOMA-R) From Baseline at the End of the Treatment Period (Week 12) | -0.23 HOMA-R Score | Standard Deviation 0.928 |
| Azilsartan 20 mg | Change in Insulin Resistance Index (HOMA-R) From Baseline at the End of the Treatment Period (Week 12) | 0.22 HOMA-R Score | Standard Deviation 2.449 |
Comparison: Telmisartan 40 mg, Azilsartan 20 mg95% CI: [-0.89, 1.78]
Secondary
Change in 1,5-anhydroglucitol (1,5-AG) From Baseline at the End of the Treatment Period (Week 12)
Change from baseline in 1,5-G concentration collected at week 12 or final visit relative to baseline was reported.
Time frame: Baseline and Week 12
Population: The full analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Telmisartan 40 mg | Change in 1,5-anhydroglucitol (1,5-AG) From Baseline at the End of the Treatment Period (Week 12) | 0.24 μg/mL | Standard Deviation 2.143 |
| Azilsartan 20 mg | Change in 1,5-anhydroglucitol (1,5-AG) From Baseline at the End of the Treatment Period (Week 12) | -0.66 μg/mL | Standard Deviation 2.454 |
Secondary
Change in Fasting Blood Glucose From Baseline at the End of the Treatment Period (Week 12)
Change from baseline in fasting blood glucose values collected at week 12 or final visit relative to baseline was reported.
Time frame: Baseline and Week 12
Population: The full analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Telmisartan 40 mg | Change in Fasting Blood Glucose From Baseline at the End of the Treatment Period (Week 12) | -1.06 mg/dL | Standard Deviation 14.991 |
| Azilsartan 20 mg | Change in Fasting Blood Glucose From Baseline at the End of the Treatment Period (Week 12) | 2.00 mg/dL | Standard Deviation 18.308 |
Secondary
Change in Fasting Insulin From Baseline at the End of the Treatment Period (Week 12)
Change from baseline in fasting insulin values collected at week 12 or final visit relative to baseline was reported.
Time frame: Baseline and Week 12
Population: The full analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Telmisartan 40 mg | Change in Fasting Insulin From Baseline at the End of the Treatment Period (Week 12) | -0.818 µU/mL | Standard Deviation 2.7623 |
| Azilsartan 20 mg | Change in Fasting Insulin From Baseline at the End of the Treatment Period (Week 12) | 0.475 µU/mL | Standard Deviation 6.3847 |
Secondary
Change in Glycosylated Hemoglobin (HbA1c) From Baseline at the End of the Treatment Period (Week 12)
Change from baseline in the values of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 12 or final visit relative to baseline was reported.
Time frame: Baseline and Week 12
Population: The full analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Telmisartan 40 mg | Change in Glycosylated Hemoglobin (HbA1c) From Baseline at the End of the Treatment Period (Week 12) | 0.10 percent | Standard Deviation 0.29 |
| Azilsartan 20 mg | Change in Glycosylated Hemoglobin (HbA1c) From Baseline at the End of the Treatment Period (Week 12) | 0.09 percent | Standard Deviation 0.382 |
Secondary
Change in Homeostasis Model Assessment of Beta Cell Function (HOMA-β) From Baseline at the End of the Treatment Period (Week 12)
Change from baseline in HOMA-β collected at week 12 or final visit relative to baseline was reported. Homeostasis model assessment of beta cell function measures as following; HOMA-β = fasting insulin (μU/mL) ×360/{fasting glucose (mg/dL) - 63}.
Time frame: Baseline and Week 12
Population: The full analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Telmisartan 40 mg | Change in Homeostasis Model Assessment of Beta Cell Function (HOMA-β) From Baseline at the End of the Treatment Period (Week 12) | -3.88 percent | Standard Deviation 20.151 |
| Azilsartan 20 mg | Change in Homeostasis Model Assessment of Beta Cell Function (HOMA-β) From Baseline at the End of the Treatment Period (Week 12) | -0.44 percent | Standard Deviation 30.985 |
Secondary
Number of Participants With Treatment-Emergent Adverse Events
Time frame: Up to Week 12
Population: The safety analysis set was defined as the participants who received at least 1 dose of the study drug for the treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Telmisartan 40 mg | Number of Participants With Treatment-Emergent Adverse Events | 8 participants |
| Azilsartan 20 mg | Number of Participants With Treatment-Emergent Adverse Events | 6 participants |