Diabetes Mellitus, Type II, Hypertension
Conditions
Keywords
Bisoprolol, Hypertension, Diabetes mellitus, Type II, Blood pressure, Glycemic level
Brief summary
This is a 24-week, prospective, multicenter, open-label, single-arm study to assess the effect of bisoprolol on glycemic level in Type 2 diabetes mellitus (T2DM) controlled subjects with hypertension. The hypothesis of study is that there is no change in glycemic level and lipid metabolism as determined by glycosylated hemoglobin (HbA1c) using bisoprolol in T2DM subjects with suboptimal blood pressure (BP) control.
Detailed description
Diabetes mellitus and hypertension are two of the most common chronic conditions, and each predisposes to accelerated atherosclerosis, cardiovascular disease, and death. There has been a concern that beta-blocker might have adverse effects in subjects with diabetes on glucose metabolism, but some data shows that highly beta-1 selective agents such as bisoprolol are essentially free of metabolic disturbances involving blood sugar, insulin sensitivity and lipids. This is a prospective, multicenter, single-arm, open-label study to assess the glycemic effect of bisoprolol in T2DM subjects with suboptimal BP control. After pre-screening period, each enrolled subject with T2DM and suboptimal BP control will undergo laboratory test for efficacy and safety measurement. After that, subject will continue his/her usual dosage of antihypertensive medication and bisoprolol will be added. Subjects will be instructed to continue their diet and level of physical activity and to attempt to maintain current body weight until completion of the study. Bisoprolol will be titrated upward until a dosage that lowers BP to less than 130/80 millimeter of mercury (mmHg) during the first 2 months of treatment. The maximum dosage of bisoprolol will be 10 mg once daily. Following 6 month of added bisoprolol therapy, all efficacy and safety measurements will be repeated. The duration of study will be up to 24 weeks for each subject. Objectives Primary objective: * To assess the effect of bisoprolol on glycemic control measured by change from baseline in HbA1c in T2DM subjects with suboptimal BP control Secondary objectives: * To evaluate the effects of bisoprolol, as add-on therapy, on BP in T2DM subjects with suboptimal BP control * To evaluate the effects of bisoprolol, as add-on therapy, on insulin sensitivity as determined by Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) * To evaluate the effects of bisoprolol, as add-on therapy, on lipid metabolism as determined by lipid profile in T2DM subjects with suboptimal BP control * To evaluate the safety and tolerability of bisoprolol in T2DM subjects with suboptimal BP control * To assess the effects of bisoprolol combination therapy on insulin and c-peptide in T2DM subjects with suboptimal BP control compared to baseline * To assess the effects of bisoprolol combination therapy on microalbumin and albumin/creatinine ratio in T2DM subjects with suboptimal BP control compared to baseline
Interventions
DRUGBisoprolol
Bisoprolol tablet will be administered orally at dose of 5 milligram (mg) once daily for 24 weeks. If the blood pressure is not less than 130/80 millimeter of mercury (mmHg) during the first 8 weeks of treatment (up-titration), then the dose will be adjusted to 10 mg daily. In cases of hypotensive effect, symptomatic bradycardia or arrhythmia, the daily dose will be reduced to 2.5 mg.
Sponsors
Merck Ltd.
Merck KGaA, Darmstadt, Germany
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Age of 20 years or older and less than 80 years * Subjects with T2DM * Subjects who have failed to achieve an appropriate BP level as a result of treatment with any antihypertensive drug other than beta blockers - that is, with BP inadequately controlled to greater than or equal to (\>=) 130/80 mmHg. However, those who have used a beta blocker before 12 weeks can be enrolled * Subjects who underwent stable anti-diabetic regimen during the 12 weeks prior to screening * Signed written informed consent
Exclusion criteria
* Ongoing insulin therapy * Change in two HbA1c levels measured at an interval of 4 weeks or longer for the previous 6 months is at least 1% (the last HbA1c is measured within 4 weeks) * Secondary hypertension * Subjects with renal impairment (creatinine greater than 150 micromol per liter or 1.7 milligram per deciliter) * Cardiovascular disease (uncontrolled or symptomatic arrhythmia, unstable angina, sick sinus syndrome, second or third degree atrioventricular (AV) block, bradycardia \[less than 50 beats per minute\], congestive heart failure, myocardial infarction, cerebral infraction attached within 12 weeks) * Subjects requiring BP control by at least 3 different antihypertensive drugs, or with either systolic blood pressure (SBP) \>=180 mmHg or diastolic blood pressure (DBP) \>=110 mmHg at baseline * Subjects with type 1 diabetes mellitus (T1DM) * Uncontrolled diabetes with HbA1c \>9% * BMI \>40 kilogram per square meter (kg/m\^2) * Pulmonary disease (chronic obstructive pulmonary disease \[COPD\], bronchial asthma) * Other patients considered by the investigator to be not eligible for participation in this study for a legal or mental reason * Contraindications for beta-blocker * Pregnant or lactating women * Use of an investigational drug within 30 days of entry to the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Month 6 | Baseline, Month 6 | HbA1c represents the percentage of glycosylated hemoglobin. The change in HbA1c at Month 6 was calculated as HbA1c at Month 6 minus HbA1c at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Blood Pressure (BP) at Month 6 | Baseline, Month 6 | The change in SBP, DBP, and mean BP at Month 6 were calculated as SBP, DBP, and mean BP at Month 6 minus SBP, DBP, and mean BP at baseline, respectively. Mean BP was calculated using the formula: (DBP plus \[{SBP minus DBP} divided by 3\]). |
| Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) at Months 3 and 6 | Baseline, Months 3 and 6 | HOMA-IR is as an indicator of insulin resistance in participants with Type 2 diabetes mellitus and comorbid hypertension. HOMA-IR was derived from fasting plasma glucose (FPG) and fasting insulin (FI) using the formula: (FI \[micro international units per milliliter {mcIU/mL}\] \* FPG \[millimole per liter {mmol/L}\]) divided by 22.5. The change in HOMA-IR at Months 3 and 6 was calculated as HOMA-IR at Months 3 and 6 minus HOMA-IR at baseline. |
| Change From Baseline in Insulin Level at Months 3 and 6 | Baseline, Months 3 and 6 | The change in insulin level at Months 3 and 6 was calculated as insulin level at Months 3 and 6 minus insulin level at baseline. |
| Change From Baseline in C-Peptide Level at Months 3 and 6 | Baseline, Months 3 and 6 | The change in C-peptide level at Months 3 and 6 was calculated as C-peptide level at Months 3 and 6 minus C-peptide level at baseline. |
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Month 3 | Baseline, Month 3 | HbA1c represents the percentage of glycosylated hemoglobin. The change in HbA1c at Month 3 was calculated as HbA1c at Month 3 minus HbA1c at baseline. |
| Change From Baseline in Albumin/Creatinine Ratio at Month 6 | Baseline, Month 6 | The change in albumin/creatinine ratio at Month 6 was calculated as albumin/creatinine ratio at Month 6 minus albumin/creatinine ratio at baseline. |
| Change From Baseline in Microalbumin Level at Month 6 | Baseline, Month 6 | The change in microalbumin level at Month 6 was calculated as microalbumin level at Month 6 minus microalbumin level at baseline. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline up to Month 6 | An Adverse Event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A Serious Adverse Event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. |
| Change From Baseline in Total Cholesterol, Low Density Lipoprotein (LDL) Cholesterol, High Density Lipoprotein (HDL) Cholesterol and Triglyceride Level at Month 6 | Baseline, Month 6 | The change in total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, and triglyceride levels at Month 6 was calculated as total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels at Month 6 minus total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels at baseline, respectively. |
Countries
South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bisoprolol Bisoprolol tablet was administered orally at dose of 5 mg once daily for 24 weeks. If the blood pressure was not less than 130/80 mmHg during the first 8 weeks of treatment (up-titration), then the dose was adjusted to 10 mg daily. In cases of hypotensive effect, symptomatic bradycardia or arrhythmia, the daily dose was reduced to 2.5 mg. | 202 |
| Total | 202 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Additional Antihypertensive Required | 4 |
| Overall Study | Adverse Event | 6 |
| Overall Study | Dropout due to Insulin Administration | 1 |
| Overall Study | Drug/Dose Adjustment Required | 1 |
| Overall Study | Failure to Control Blood Pressure | 1 |
| Overall Study | Inclusion/Exclusion Criteria Violation | 9 |
| Overall Study | Investigator's Request | 1 |
| Overall Study | Protocol Violation | 2 |
| Overall Study | Volunteer Failed to Make the Next Visit | 2 |
| Overall Study | Withdrawal by Subject | 17 |
Baseline characteristics
| Characteristic | Bisoprolol |
|---|---|
| Age, Continuous | 59.1 years STANDARD_DEVIATION 8.8 |
| Sex: Female, Male Female | 92 Participants |
| Sex: Female, Male Male | 110 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 61 / 200 |
| serious Total, serious adverse events | 7 / 200 |
Outcome results
Primary
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Month 6
HbA1c represents the percentage of glycosylated hemoglobin. The change in HbA1c at Month 6 was calculated as HbA1c at Month 6 minus HbA1c at baseline.
Time frame: Baseline, Month 6
Population: Full analysis set (FAS) included all participants who received at least one dose of investigational product and for whom the primary efficacy endpoint (HbA1c) was measured.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bisoprolol | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Month 6 | Baseline | 6.79 Percent HbA1c | Standard Deviation 0.66 |
| Bisoprolol | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Month 6 | Change at Month 6 | 0.26 Percent HbA1c | Standard Deviation 0.64 |
Secondary
Change From Baseline in Albumin/Creatinine Ratio at Month 6
The change in albumin/creatinine ratio at Month 6 was calculated as albumin/creatinine ratio at Month 6 minus albumin/creatinine ratio at baseline.
Time frame: Baseline, Month 6
Population: FAS included all participants who took the investigational product at least once and for whom the primary efficacy endpoint (HbA1c) was measured. Here, N (number of participants analyzed) signifies those participants who were evaluable for this outcome measure and n signifies those participants who were evaluable for the specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bisoprolol | Change From Baseline in Albumin/Creatinine Ratio at Month 6 | Baseline (n = 89) | 127.7 ratio | Standard Deviation 630.9 |
| Bisoprolol | Change From Baseline in Albumin/Creatinine Ratio at Month 6 | Change at Month 6 (n = 85) | 34.3 ratio | Standard Deviation 186.6 |
Secondary
Change From Baseline in C-Peptide Level at Months 3 and 6
The change in C-peptide level at Months 3 and 6 was calculated as C-peptide level at Months 3 and 6 minus C-peptide level at baseline.
Time frame: Baseline, Months 3 and 6
Population: FAS included all participants who took the investigational product at least once and for whom the primary efficacy endpoint (HbA1c) was measured.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bisoprolol | Change From Baseline in C-Peptide Level at Months 3 and 6 | Baseline | 2.3 nanogram per milliliter (ng/mL) | Standard Deviation 0.9 |
| Bisoprolol | Change From Baseline in C-Peptide Level at Months 3 and 6 | Change at Month 3 | 0.1 nanogram per milliliter (ng/mL) | Standard Deviation 0.8 |
| Bisoprolol | Change From Baseline in C-Peptide Level at Months 3 and 6 | Change at Month 6 | 0.2 nanogram per milliliter (ng/mL) | Standard Deviation 1 |
Secondary
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Month 3
HbA1c represents the percentage of glycosylated hemoglobin. The change in HbA1c at Month 3 was calculated as HbA1c at Month 3 minus HbA1c at baseline.
Time frame: Baseline, Month 3
Population: FAS included all participants who received at least one dose of investigational product and for whom the primary efficacy endpoint (HbA1c) was measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bisoprolol | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Month 3 | 0.15 Percent HbA1c | Standard Deviation 0.51 |
Secondary
Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) at Months 3 and 6
HOMA-IR is as an indicator of insulin resistance in participants with Type 2 diabetes mellitus and comorbid hypertension. HOMA-IR was derived from fasting plasma glucose (FPG) and fasting insulin (FI) using the formula: (FI \[micro international units per milliliter {mcIU/mL}\] \* FPG \[millimole per liter {mmol/L}\]) divided by 22.5. The change in HOMA-IR at Months 3 and 6 was calculated as HOMA-IR at Months 3 and 6 minus HOMA-IR at baseline.
Time frame: Baseline, Months 3 and 6
Population: FAS included all participants who received at least one dose of investigational product and for whom the primary efficacy endpoint (HbA1c) was measured.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bisoprolol | Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) at Months 3 and 6 | Baseline | 2.3 mcIU/mL * mmol/L | Standard Deviation 1.8 |
| Bisoprolol | Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) at Months 3 and 6 | Change at Month 3 | 0.1 mcIU/mL * mmol/L | Standard Deviation 1.8 |
| Bisoprolol | Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) at Months 3 and 6 | Change at Month 6 | 0.4 mcIU/mL * mmol/L | Standard Deviation 2.5 |
Secondary
Change From Baseline in Insulin Level at Months 3 and 6
The change in insulin level at Months 3 and 6 was calculated as insulin level at Months 3 and 6 minus insulin level at baseline.
Time frame: Baseline, Months 3 and 6
Population: FAS included all participants who took the investigational product at least once and for whom the primary efficacy endpoint (HbA1c) was measured.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bisoprolol | Change From Baseline in Insulin Level at Months 3 and 6 | Baseline | 7.5 mcIU/mL | Standard Deviation 4.8 |
| Bisoprolol | Change From Baseline in Insulin Level at Months 3 and 6 | Change at Month 3 | 0.2 mcIU/mL | Standard Deviation 4.5 |
| Bisoprolol | Change From Baseline in Insulin Level at Months 3 and 6 | Change at Month 6 | 0.6 mcIU/mL | Standard Deviation 6 |
Secondary
Change From Baseline in Microalbumin Level at Month 6
The change in microalbumin level at Month 6 was calculated as microalbumin level at Month 6 minus microalbumin level at baseline.
Time frame: Baseline, Month 6
Population: FAS included all participants who took the investigational product at least once and for whom the primary efficacy endpoint (HbA1c) was measured. Here, N (number of participants analyzed) signifies those participants who were evaluable for this outcome measure and n signifies those participants who were evaluable for the specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bisoprolol | Change From Baseline in Microalbumin Level at Month 6 | Baseline (n = 167) | 56.6 mg/dL | Standard Deviation 261.6 |
| Bisoprolol | Change From Baseline in Microalbumin Level at Month 6 | Change at Month 6 (n = 161) | -3.1 mg/dL | Standard Deviation 204.4 |
Secondary
Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Blood Pressure (BP) at Month 6
The change in SBP, DBP, and mean BP at Month 6 were calculated as SBP, DBP, and mean BP at Month 6 minus SBP, DBP, and mean BP at baseline, respectively. Mean BP was calculated using the formula: (DBP plus \[{SBP minus DBP} divided by 3\]).
Time frame: Baseline, Month 6
Population: FAS included all participants who received at least one dose of investigational product and for whom the primary efficacy endpoint (HbA1c) was measured.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bisoprolol | Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Blood Pressure (BP) at Month 6 | SBP: Baseline | 147.8 mmHg | Standard Deviation 11.5 |
| Bisoprolol | Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Blood Pressure (BP) at Month 6 | Mean BP: Baseline | 108.6 mmHg | Standard Deviation 6.9 |
| Bisoprolol | Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Blood Pressure (BP) at Month 6 | SBP: Change at Month 6 | -13.4 mmHg | Standard Deviation 15.4 |
| Bisoprolol | Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Blood Pressure (BP) at Month 6 | DBP: Baseline | 89.0 mmHg | Standard Deviation 7.3 |
| Bisoprolol | Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Blood Pressure (BP) at Month 6 | DBP: Change at Month 6 | -9.1 mmHg | Standard Deviation 9 |
| Bisoprolol | Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Blood Pressure (BP) at Month 6 | Mean BP: Change at Month 6 | -10.5 mmHg | Standard Deviation 10.2 |
Secondary
Change From Baseline in Total Cholesterol, Low Density Lipoprotein (LDL) Cholesterol, High Density Lipoprotein (HDL) Cholesterol and Triglyceride Level at Month 6
The change in total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, and triglyceride levels at Month 6 was calculated as total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels at Month 6 minus total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels at baseline, respectively.
Time frame: Baseline, Month 6
Population: FAS included all participants who took the investigational product at least once and for whom the primary efficacy endpoint (HbA1c) was measured. Here, N (number of participants analyzed) signifies those participants who were evaluable for this outcome measure and n signifies those participants who were evaluable for the specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bisoprolol | Change From Baseline in Total Cholesterol, Low Density Lipoprotein (LDL) Cholesterol, High Density Lipoprotein (HDL) Cholesterol and Triglyceride Level at Month 6 | Total Cholesterol: Baseline (n = 174) | 168.6 milligram per deciliter (mg/dL) | Standard Deviation 32.3 |
| Bisoprolol | Change From Baseline in Total Cholesterol, Low Density Lipoprotein (LDL) Cholesterol, High Density Lipoprotein (HDL) Cholesterol and Triglyceride Level at Month 6 | Total Cholesterol: Change at Month 6 (n = 173) | -0.8 milligram per deciliter (mg/dL) | Standard Deviation 26.3 |
| Bisoprolol | Change From Baseline in Total Cholesterol, Low Density Lipoprotein (LDL) Cholesterol, High Density Lipoprotein (HDL) Cholesterol and Triglyceride Level at Month 6 | LDL: Baseline (n = 174) | 93.3 milligram per deciliter (mg/dL) | Standard Deviation 26.3 |
| Bisoprolol | Change From Baseline in Total Cholesterol, Low Density Lipoprotein (LDL) Cholesterol, High Density Lipoprotein (HDL) Cholesterol and Triglyceride Level at Month 6 | LDL: Change at Month 6 (n = 173) | -1.6 milligram per deciliter (mg/dL) | Standard Deviation 22.5 |
| Bisoprolol | Change From Baseline in Total Cholesterol, Low Density Lipoprotein (LDL) Cholesterol, High Density Lipoprotein (HDL) Cholesterol and Triglyceride Level at Month 6 | HDL: Baseline (n = 174) | 49.2 milligram per deciliter (mg/dL) | Standard Deviation 11.7 |
| Bisoprolol | Change From Baseline in Total Cholesterol, Low Density Lipoprotein (LDL) Cholesterol, High Density Lipoprotein (HDL) Cholesterol and Triglyceride Level at Month 6 | HDL: Change at Month 6 (n = 173) | -3.4 milligram per deciliter (mg/dL) | Standard Deviation 8 |
| Bisoprolol | Change From Baseline in Total Cholesterol, Low Density Lipoprotein (LDL) Cholesterol, High Density Lipoprotein (HDL) Cholesterol and Triglyceride Level at Month 6 | Triglyceride: Baseline (n = 174) | 155.0 milligram per deciliter (mg/dL) | Standard Deviation 96.3 |
| Bisoprolol | Change From Baseline in Total Cholesterol, Low Density Lipoprotein (LDL) Cholesterol, High Density Lipoprotein (HDL) Cholesterol and Triglyceride Level at Month 6 | Triglyceride: Change at Month 6 (n = 173) | 13.5 milligram per deciliter (mg/dL) | Standard Deviation 87.6 |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An Adverse Event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A Serious Adverse Event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.
Time frame: Baseline up to Month 6
Population: Safety population included all participants who received at least one dose of investigational product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bisoprolol | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 68 participants |
| Bisoprolol | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 7 participants |