A. Schmitz, M. Mau Pedersen, and CE. Mogensen
The effect of a blood pressure reduction by 10 mg extended release felodipine once daily on urinary albumin excretion (UAE) as well as the possible diabetogenic effect of felodipine was studied. A 2 X 12 week placebo-controlled double-blind crossover study was performed in 12 hypertensive n o n insulin-dependent diabetic (NIDDM) patients with out nephropathy on concomitant treatment with βblocker and/or a diuretic agent. Metabolic control as estimated by fasting plasma glucose, hemoglobin A and fasting plasma C-peptide was unaltered after felodipine. Blood pressure was significantly reduced by felodipine: systolic 166 ± 26 mm Hg (placebo) ν 153 ± 26 mm Hg (felodipine) (P < .05) and diastolic 95 ± 7 mm Hg ν 90 ± 8 mm Hg (P < .05). Heart rate was unchanged. There was no corre lc
H
ypertension is known to be very common in diabetic patients. In insulin-dependent dia betes (IDDM) the hypertension is most often a consequence of the development of dia betic nephropathy. In non-insulin-dependent dia betes (NIDDM) hypertension and diabetes are fre quently coexisting, the hypertension may be present years before the manifestation of diabetes. Even so dia1
2
3
lation between blood pressure and UAE, but the rel ative change in UAE expressed as UAE placebo/ UAE felodipine was significantly correlated to the fall in systolic blood pressure (r = 0.64, Ρ = .03) and mean blood pressure (r = 0.66, Ρ = .02). Since mi croalbuminuria predicts proteinuria and reduced survival, early antihypertensive treatment may be beneficial in NIDDM as it is in IDDM. Long-term consequences on kidney function and mortality re mains, however, to be elucidated. Am J Hypertens 1990;3:611-617
KEY WORDS: Felodipine, non-insulin-dependent diabetes, hypertension, metabolic control, urinary albumin excretion.
betic nephropathy with hypertension is present in this group of patients also. Hypertension per se seems to accelerate microvascular damage and a major cause of death in diabetes is cardiovascular disease. Microal buminuria, ie, an increased urinary albumin excretion (UAE) below the dipstick-positive or proteinuric range (20 to 200 //g/min), predicts the development of clini cal nephropathy in IDDM ' and the development of proteinuria as well as increased mortality in NIDDM. Antihypertensive treatment in IDDM re duces microalbuminuria in incipient and the rate of decline in glomerular filtration rate (GFR) in overt ne phropathy, thus postponing end-stage renal failure. In NIDDM also an association between blood pressure and UAE has been found. ' ' Antihypertensive treatment in diabetes requires spe4,5
6-8
9
10 11
12
71213
14
From the Second University Clinic of Internal Medicine Kommunehospitalet, Aarhus, Denmark. This study was supported by AB Hassle, Sweden. Address correspondence and reprint requests to A. Schmitz, MD, Second University Clinic of Internal Medicine Kommunehospitalet, DK-8000 Aarhus C, Denmark.
15
7 16 17
Downloaded from http://ajh.oxfordjournals.org/ at University of Otago on November 29, 2016
Effects of Felodipine on Urinary Albumin Excretion and Metabolic Control in Hypertensive Non - Insulin-Dependent Diaoetics
cial concerns regarding renal, metabolic and other side effects. Felodipine, a dihydropyridine derivative, is a new an tihypertensive calcium antagonist. Several studies have been performed on the influence of various calcium an tagonists on insulin secretion and glucose metabolism in normal and diabetic subjects. Impaired, unchanged or even improved glu cose tolerance have been reported. In essential hyper tension two studies have shown unchanged glucose tol erance after felodipine. ' Apart from a very small (n = 5) group of diabetics of either type included in one study no investigations on the influence of felodipine on glycemic control in diabetes have been published. Consequently the aims of the present study were two fold: to study the influence of blood pressure reduction on urinary albumin excretion in hypertensive NIDDM patients without clinical nephropathy and to study whether felodipine had an impact on metabolic control.
ment with the diuretic or the ^-blocker and diuretic as well as the antidiabetic treatment were kept unchanged during the entire study period. After the run-in period and after 6 and 12 weeks of either treatment the following parameters were ob tained: blood pressure and heart rate after 5 min rest in the sitting position and after standing 1 min. Weight, fasting plasma glucose measured by standard enzymatic technique, hemoglobin A (HbA ) measured by cation exchange chromatography and fasting plasma C-peptide by a radioimmunoassay kit (Incstar Corp., Still water, Minnesota). Urinary albumin excretion rate (UAE) was obtained from two consecutive timed over night collections. The albumin concentration was deter mined by radioimmunoassay. After the run-in period and after 12 weeks of either treatment a blood screening was carried out: hemoglobin, protein, Na, K, creatinine and uric acid. Any adverse experiences were also recorded.
PATIENTS AND METHODS
Compliance, Calculations and Statistical Analysis Nine of the 12 patients completed the study fully. Two patients were withdrawn after 6 weeks of the second treatment period (felodipine) due to ankle edema. One patient died from cardiac arrest during the last treatment period (felodipine). For the parameters obtained at 6 and 12 weeks of either treatment period the mean was calculated. For the three withdrawn patients only values at 6 weeks were used. During calculations UAE was log transformed and is therefore given as geometric mean X/-r- tolerance factor. Period effect and carryover effect were evaluated for blood pressure and fasting plasma glucose with a Ρ = . 1 0 . Differences between the pla cebo period and the felodipine period was judged by Student's t test for paired observations (two-tailed). Correlations was calculated as Pearson's correlation co efficients (r). A Ρ < .05 was considered statistically sig nificant.
18,19
20-25
26
27 28
27
lc
29
30
Methods A double-blind placebo-controlled crossover study was performed. After a run-in period of 4 weeks during which placebo was given the patients were ran domly allocated to 12 weeks treatment with placebo followed by 12 weeks treatment with 10 mg extended release felodipine once daily or vice versa. The treat
31
RESULTS The treatment sequences were felodipine—^placebo 5 patients and placebo—^felodipine 7 patients. No period effect or carry over effect was found. Systemic Hemodynamics Blood pressure, systolic as well as diastolic, was significantly reduced (P < 0.05,
TABLE 1. CLINICAL DATA
Diabetes Sex Age duration Ν M/F (years) (years) 12
4/8
60 ± 8
6 ±5
BMI (kg/m ) 2
Fasting plasma glucose (mmol/L)
HbA (%)
lc
Blood pressure systolic/ diastolic (mm Hg)
31.9 ± 5.5 10.1 ± 2.8 7.5 ± 1.4 174 ± 1 9 / 99 ± 4
Duration of hypertension (years) 6 ±5
AntiAntiWHO stage diabetic hyperhyperSerum treattensive tension) creatinine ment treatment 1/2/3 (μπιοΙ/L) D/T/I D/B + D 9/2/1
Mean ± SD. BMI: body mass index. D/T/I: diet/tablets/insulin. D: diuretics alone. Β + D: β-blockers and diuretics. WHO stages: see World Health Organization: Arterial Hypertension, Technical Report Series No. 628 (1978).
85 ± 19
2/10/0
7/5
Downloaded from http://ajh.oxfordjournals.org/ at University of Otago on November 29, 2016
Patients Twelve non-insulin-dependent diabetics currently treated for hypertension with a ^-blocker and/or a diuretic agent participated. The diabetes was treated with diet and/or oral agents only. Patients with the following conditions were excluded: myocardial in farction or stroke less than three months prior to the start of the study, severely impaired liver function, chronic pancreatitis, proteinuria and a supine diastolic blood pressure > 120 mm Hg or < 9 5 mm Hg at ran domization. One patient had former cardiac failure, one a previous myocardial infarction and one had sequelae from an apoplectic insult. No other clinically significant diseases including secondary causes of hypertension were present. The clinical data of the patients appear in Table 1. The patients gave their informed consent to the study which was performed according to the Declara tion of Helsinki and with the approval of the local Ethi cal Committee.
lc
Blood pressure (mm Hg) 25o]
mean blood pressure (r = 0.66, Ρ = .02) (Figure 2), but not to the fall in diastolic pressure. However, there was no overall difference in urinary albumin excretion be tween the two treatment periods and there was no correlation between blood pressure per se and UAE in either group. There was a borderline significant positive correlation (r = 0.54, Ρ = .07) between H b A and UAE during placebo treatment; but no correlations between changes in glycemic control and UAE were seen. lc
lc
Blood Screening There were no significant changes in Na, K, protein and hemoglobin concentrations. Serum uric acid was slightly increased (0.33 ± 0.07 mmol/L ν 0.36 ± 0.08 mmol/L, Ρ < .05), during felodipine. Adverse Experiences The adverse experiences re ported during run-in, placebo and felodipine respec tively (numbers given consecutively for each period) were: flushing: 1 , 1 , 1 ; palpitations: 1, 0 , 0 ; ankle edema: 0 , 1 , 5; dizziness: 1 , 1 , 0, and sexual dysfunction: 0, 0 , 1 . DISCUSSION Felodipine reduces blood pressure by a selective inhibi tion of the contractile activity of the smooth muscle in the arterial resistance vessels, without significantly af fecting cardiac cells. It has no direct effect on smooth muscle in venous capacitance vessels. The reduction in blood pressure leads initially to a reflex rise in heart rate; the baroreceptors reset, however, within one week of treatment. In accordance with these actions the addi tion of felodipine gave rise to a significant reduction in blood pressure, no orthostatic hypotension and an un changed heart rate in this group of hypertensive NIDDM patients. Five of the patients were on concomi tant treatment with a ^-blocker which might also con tribute to the lack of rise in heart rate. The glucose induced insulin secretion from the yS-cell is dependent on calcium influx. ' Calcium antagonists may therefore inhibit the insulin secretion and give rise to a reduced glucose tolerance. An inhibition of insulin secretion has been demonstrated in vitro. Studies on glucose tolerance in normal and diabetic subjects are contradictive. Nifedipine has been reported to impair insulin secretion and reduce glucose tolerance. Other studies with nifedipine showed no diabetogenic ef fects in accordance with studies on verapamil, dil tiazem, nitrendepine and bepridil. Even improve ment of glucose tolerance has been reported during verapamil therapy. In one study with nitrendipine large variations in insulin secretion after a standard meal 32
33
34
FIGURE 1. Systolic * * and diastolic · · blood pres sure during placebo and 10 mg extended release felodipine in twelve non-insulin-dependent patients. The reduction in both parameters were significant, Ρ < .05. Figure 1 and Table 2), though two patients had diastolic pressures above 95 mm Hg during active treatment. Heart rate was unchanged. There was no differences in the orthostatic changes of blood pressure and heart rate between the two periods (Table 2). Kidney Function Serum creatinine was unaltered (Table 2). The relative change in UAE expressed as UAE placebo/UAE felodipine was significantly correlated to the fall in systolic blood pressure (r = 0.64, Ρ = .03) and
35 36
37
18
19
20,21
22
23
24
26
25
38
Downloaded from http://ajh.oxfordjournals.org/ at University of Otago on November 29, 2016
Metabolic Control There were no significant differ ences in metabolic control and insulin secretion as esti mated by fasting plasma glucose (10.2 ± 2.5 mmol/L ν 10.6 ± 2.1 mmol/L (mean ± SD, placebo ν felodipine), H b A (7.7 ± 1.7% ν 7.8 ± 1.6%) and fasting plasma C-peptide (4.2 ± 1 . 7 n g / m L ν 4.2 ± 1 . 6 ng/mL).
TABLE 2. HEMODYNAMICS AND KIDNEY FUNCTION DURING PLACEBO AND 10 MG EXTENDED RELEASE FELODIPINE IN 12 NIDDM PATIENTS Placebo Felodipine Ρ Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mean blood pressure (mm Hg) Heart rate (beats/min) Orthostatic changes Fall in systolic blood pressure (mm Hg)
Increase in heart rate (beats/min) Serum creatinine (μιηοΙ/L) Urinary albumin excretion* (//g/min) Mean ± SD. * geometric mean X / h - tolerance
153 ± 2 6 (125-220) 90 ± 8 (78-110) 111 ± 13 (93-147) 72 ± 10 (56-92)
6 ± 10 (-10-22) 1 ±4 (-5-7) 6±4 (0-12) 86 ± 19 (64-117) 6.0 X / - 2.0 (2.2-18.0)
4±5 (-5-11) -2 ±5 (-12-5) 7±4 (0-14) 87 ± 19 (59-116) 5.9 X/-S- 1.7 (2.8-15)
The effect of a blood pressure reduction by 10 mg extended release felodipine once daily on urinary albumin excretion (UAE) as well as the possible diabetogenic effect of felodipine was studied. A 2 X 12 week placebo-controlled double-blind crossover study was performed in 12 hypertensive n o n insulin-dependent diabetic (NIDDM) patients with out nephropathy on concomitant treatment with βblocker and/or a diuretic agent. Metabolic control as estimated by fasting plasma glucose, hemoglobin A and fasting plasma C-peptide was unaltered after felodipine. Blood pressure was significantly reduced by felodipine: systolic 166 ± 26 mm Hg (placebo) ν 153 ± 26 mm Hg (felodipine) (P < .05) and diastolic 95 ± 7 mm Hg ν 90 ± 8 mm Hg (P < .05). Heart rate was unchanged. There was no corre lc
H
ypertension is known to be very common in diabetic patients. In insulin-dependent dia betes (IDDM) the hypertension is most often a consequence of the development of dia betic nephropathy. In non-insulin-dependent dia betes (NIDDM) hypertension and diabetes are fre quently coexisting, the hypertension may be present years before the manifestation of diabetes. Even so dia1
2
3
lation between blood pressure and UAE, but the rel ative change in UAE expressed as UAE placebo/ UAE felodipine was significantly correlated to the fall in systolic blood pressure (r = 0.64, Ρ = .03) and mean blood pressure (r = 0.66, Ρ = .02). Since mi croalbuminuria predicts proteinuria and reduced survival, early antihypertensive treatment may be beneficial in NIDDM as it is in IDDM. Long-term consequences on kidney function and mortality re mains, however, to be elucidated. Am J Hypertens 1990;3:611-617
KEY WORDS: Felodipine, non-insulin-dependent diabetes, hypertension, metabolic control, urinary albumin excretion.
betic nephropathy with hypertension is present in this group of patients also. Hypertension per se seems to accelerate microvascular damage and a major cause of death in diabetes is cardiovascular disease. Microal buminuria, ie, an increased urinary albumin excretion (UAE) below the dipstick-positive or proteinuric range (20 to 200 //g/min), predicts the development of clini cal nephropathy in IDDM ' and the development of proteinuria as well as increased mortality in NIDDM. Antihypertensive treatment in IDDM re duces microalbuminuria in incipient and the rate of decline in glomerular filtration rate (GFR) in overt ne phropathy, thus postponing end-stage renal failure. In NIDDM also an association between blood pressure and UAE has been found. ' ' Antihypertensive treatment in diabetes requires spe4,5
6-8
9
10 11
12
71213
14
From the Second University Clinic of Internal Medicine Kommunehospitalet, Aarhus, Denmark. This study was supported by AB Hassle, Sweden. Address correspondence and reprint requests to A. Schmitz, MD, Second University Clinic of Internal Medicine Kommunehospitalet, DK-8000 Aarhus C, Denmark.
15
7 16 17
Downloaded from http://ajh.oxfordjournals.org/ at University of Otago on November 29, 2016
Effects of Felodipine on Urinary Albumin Excretion and Metabolic Control in Hypertensive Non - Insulin-Dependent Diaoetics
cial concerns regarding renal, metabolic and other side effects. Felodipine, a dihydropyridine derivative, is a new an tihypertensive calcium antagonist. Several studies have been performed on the influence of various calcium an tagonists on insulin secretion and glucose metabolism in normal and diabetic subjects. Impaired, unchanged or even improved glu cose tolerance have been reported. In essential hyper tension two studies have shown unchanged glucose tol erance after felodipine. ' Apart from a very small (n = 5) group of diabetics of either type included in one study no investigations on the influence of felodipine on glycemic control in diabetes have been published. Consequently the aims of the present study were two fold: to study the influence of blood pressure reduction on urinary albumin excretion in hypertensive NIDDM patients without clinical nephropathy and to study whether felodipine had an impact on metabolic control.
ment with the diuretic or the ^-blocker and diuretic as well as the antidiabetic treatment were kept unchanged during the entire study period. After the run-in period and after 6 and 12 weeks of either treatment the following parameters were ob tained: blood pressure and heart rate after 5 min rest in the sitting position and after standing 1 min. Weight, fasting plasma glucose measured by standard enzymatic technique, hemoglobin A (HbA ) measured by cation exchange chromatography and fasting plasma C-peptide by a radioimmunoassay kit (Incstar Corp., Still water, Minnesota). Urinary albumin excretion rate (UAE) was obtained from two consecutive timed over night collections. The albumin concentration was deter mined by radioimmunoassay. After the run-in period and after 12 weeks of either treatment a blood screening was carried out: hemoglobin, protein, Na, K, creatinine and uric acid. Any adverse experiences were also recorded.
PATIENTS AND METHODS
Compliance, Calculations and Statistical Analysis Nine of the 12 patients completed the study fully. Two patients were withdrawn after 6 weeks of the second treatment period (felodipine) due to ankle edema. One patient died from cardiac arrest during the last treatment period (felodipine). For the parameters obtained at 6 and 12 weeks of either treatment period the mean was calculated. For the three withdrawn patients only values at 6 weeks were used. During calculations UAE was log transformed and is therefore given as geometric mean X/-r- tolerance factor. Period effect and carryover effect were evaluated for blood pressure and fasting plasma glucose with a Ρ = . 1 0 . Differences between the pla cebo period and the felodipine period was judged by Student's t test for paired observations (two-tailed). Correlations was calculated as Pearson's correlation co efficients (r). A Ρ < .05 was considered statistically sig nificant.
18,19
20-25
26
27 28
27
lc
29
30
Methods A double-blind placebo-controlled crossover study was performed. After a run-in period of 4 weeks during which placebo was given the patients were ran domly allocated to 12 weeks treatment with placebo followed by 12 weeks treatment with 10 mg extended release felodipine once daily or vice versa. The treat
31
RESULTS The treatment sequences were felodipine—^placebo 5 patients and placebo—^felodipine 7 patients. No period effect or carry over effect was found. Systemic Hemodynamics Blood pressure, systolic as well as diastolic, was significantly reduced (P < 0.05,
TABLE 1. CLINICAL DATA
Diabetes Sex Age duration Ν M/F (years) (years) 12
4/8
60 ± 8
6 ±5
BMI (kg/m ) 2
Fasting plasma glucose (mmol/L)
HbA (%)
lc
Blood pressure systolic/ diastolic (mm Hg)
31.9 ± 5.5 10.1 ± 2.8 7.5 ± 1.4 174 ± 1 9 / 99 ± 4
Duration of hypertension (years) 6 ±5
AntiAntiWHO stage diabetic hyperhyperSerum treattensive tension) creatinine ment treatment 1/2/3 (μπιοΙ/L) D/T/I D/B + D 9/2/1
Mean ± SD. BMI: body mass index. D/T/I: diet/tablets/insulin. D: diuretics alone. Β + D: β-blockers and diuretics. WHO stages: see World Health Organization: Arterial Hypertension, Technical Report Series No. 628 (1978).
85 ± 19
2/10/0
7/5
Downloaded from http://ajh.oxfordjournals.org/ at University of Otago on November 29, 2016
Patients Twelve non-insulin-dependent diabetics currently treated for hypertension with a ^-blocker and/or a diuretic agent participated. The diabetes was treated with diet and/or oral agents only. Patients with the following conditions were excluded: myocardial in farction or stroke less than three months prior to the start of the study, severely impaired liver function, chronic pancreatitis, proteinuria and a supine diastolic blood pressure > 120 mm Hg or < 9 5 mm Hg at ran domization. One patient had former cardiac failure, one a previous myocardial infarction and one had sequelae from an apoplectic insult. No other clinically significant diseases including secondary causes of hypertension were present. The clinical data of the patients appear in Table 1. The patients gave their informed consent to the study which was performed according to the Declara tion of Helsinki and with the approval of the local Ethi cal Committee.
lc
Blood pressure (mm Hg) 25o]
mean blood pressure (r = 0.66, Ρ = .02) (Figure 2), but not to the fall in diastolic pressure. However, there was no overall difference in urinary albumin excretion be tween the two treatment periods and there was no correlation between blood pressure per se and UAE in either group. There was a borderline significant positive correlation (r = 0.54, Ρ = .07) between H b A and UAE during placebo treatment; but no correlations between changes in glycemic control and UAE were seen. lc
lc
Blood Screening There were no significant changes in Na, K, protein and hemoglobin concentrations. Serum uric acid was slightly increased (0.33 ± 0.07 mmol/L ν 0.36 ± 0.08 mmol/L, Ρ < .05), during felodipine. Adverse Experiences The adverse experiences re ported during run-in, placebo and felodipine respec tively (numbers given consecutively for each period) were: flushing: 1 , 1 , 1 ; palpitations: 1, 0 , 0 ; ankle edema: 0 , 1 , 5; dizziness: 1 , 1 , 0, and sexual dysfunction: 0, 0 , 1 . DISCUSSION Felodipine reduces blood pressure by a selective inhibi tion of the contractile activity of the smooth muscle in the arterial resistance vessels, without significantly af fecting cardiac cells. It has no direct effect on smooth muscle in venous capacitance vessels. The reduction in blood pressure leads initially to a reflex rise in heart rate; the baroreceptors reset, however, within one week of treatment. In accordance with these actions the addi tion of felodipine gave rise to a significant reduction in blood pressure, no orthostatic hypotension and an un changed heart rate in this group of hypertensive NIDDM patients. Five of the patients were on concomi tant treatment with a ^-blocker which might also con tribute to the lack of rise in heart rate. The glucose induced insulin secretion from the yS-cell is dependent on calcium influx. ' Calcium antagonists may therefore inhibit the insulin secretion and give rise to a reduced glucose tolerance. An inhibition of insulin secretion has been demonstrated in vitro. Studies on glucose tolerance in normal and diabetic subjects are contradictive. Nifedipine has been reported to impair insulin secretion and reduce glucose tolerance. Other studies with nifedipine showed no diabetogenic ef fects in accordance with studies on verapamil, dil tiazem, nitrendepine and bepridil. Even improve ment of glucose tolerance has been reported during verapamil therapy. In one study with nitrendipine large variations in insulin secretion after a standard meal 32
33
34
FIGURE 1. Systolic * * and diastolic · · blood pres sure during placebo and 10 mg extended release felodipine in twelve non-insulin-dependent patients. The reduction in both parameters were significant, Ρ < .05. Figure 1 and Table 2), though two patients had diastolic pressures above 95 mm Hg during active treatment. Heart rate was unchanged. There was no differences in the orthostatic changes of blood pressure and heart rate between the two periods (Table 2). Kidney Function Serum creatinine was unaltered (Table 2). The relative change in UAE expressed as UAE placebo/UAE felodipine was significantly correlated to the fall in systolic blood pressure (r = 0.64, Ρ = .03) and
35 36
37
18
19
20,21
22
23
24
26
25
38
Downloaded from http://ajh.oxfordjournals.org/ at University of Otago on November 29, 2016
Metabolic Control There were no significant differ ences in metabolic control and insulin secretion as esti mated by fasting plasma glucose (10.2 ± 2.5 mmol/L ν 10.6 ± 2.1 mmol/L (mean ± SD, placebo ν felodipine), H b A (7.7 ± 1.7% ν 7.8 ± 1.6%) and fasting plasma C-peptide (4.2 ± 1 . 7 n g / m L ν 4.2 ± 1 . 6 ng/mL).
TABLE 2. HEMODYNAMICS AND KIDNEY FUNCTION DURING PLACEBO AND 10 MG EXTENDED RELEASE FELODIPINE IN 12 NIDDM PATIENTS Placebo Felodipine Ρ Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mean blood pressure (mm Hg) Heart rate (beats/min) Orthostatic changes Fall in systolic blood pressure (mm Hg)
Increase in heart rate (beats/min) Serum creatinine (μιηοΙ/L) Urinary albumin excretion* (//g/min) Mean ± SD. * geometric mean X / h - tolerance
153 ± 2 6 (125-220) 90 ± 8 (78-110) 111 ± 13 (93-147) 72 ± 10 (56-92)
6 ± 10 (-10-22) 1 ±4 (-5-7) 6±4 (0-12) 86 ± 19 (64-117) 6.0 X / - 2.0 (2.2-18.0)
4±5 (-5-11) -2 ±5 (-12-5) 7±4 (0-14) 87 ± 19 (59-116) 5.9 X/-S- 1.7 (2.8-15)
