Peter T. Sawicki

Smoking Is Associated With Progression of Diabetic Nephropathy

OBJECTIVE To investigate the association between cigarette smoking and the progression of diabetic nephropathy. RESEARCH DESIGN AND METHODS A prospective, follow-up study over one year was conducted in a sequential sample of 34 smokers, 35 nonsmokers, and 24 ex-smokers with type I diabetes, hypertension, and diabetic nephropathy. Progression of renal disease was defined according to the stage of nephropathy as an increase in proteinuria or serum creatinine or a decrease in the glomerular filtration rate. RESULTS Progression of nephropathy was less common in nonsmokers (11%) than in smokers (53%) and patients who had quit smoking (33%), P > 0.001. In a stepwise logistic regression analysis, cigarette pack years, 24-h sodium excretion, and GHb were independent predictive factors for the progression of diabetic nephropathy. Because blood pressure (BP) was well controlled in these patients and most values were within a normotensive range, neither standing, sitting, nor supine BP values were associated with progression of nephropathy. CONCLUSIONS Cigarette smoking represents an important factor associated with progression of nephropathy in treated hypertensive type I diabetic patients.

Cigarette-smoking as a risk factor for macroproteinuria and proliferative retinopathy in type 1 (insulin-dependent diabetes)

SummaryIn a case control study 192 cigarette-smoking patients with Type 1 (insulin-dependent) diabetes were compared with 192 non-cigarette-smoking patients pair-matched for sex (90 females), duration of diabetes (mean 14 years), and age (mean 32 years). Macroproteinuria was found in 19.3% of the smoking and in 8.3% of the non-smoking patients (p < 0.001). Proliferative retinopathy was present in 12.5% of the smoking and in 6.8% of the non-smoking patients (p < 0.025). The percentages of patients with normal proteinuria or without retinopathy were comparable between the two groups. In addition, glycosylated haemoglobin values and the prevalence of hypertension were similar between smoking and non-smoking patients. Thus, cigarette-smoking appears to be a risk factor for the progression of incipient to overt nephropathy and of background to proliferative retinopathy in Type 1 diabetes.

Prolonged QT interval as a predictor of mortality in diabetic nephropathy

SummaryPatients with diabetic nephropathy face an increased risk of dying due to cardiac causes. The aim of this follow-up trial was to describe the association between the length of the QT interval, as a marker of myocardial electrical stability, and the risk of death in insulin-dependent (IDDM) diabetic patients with overt diabetic nephropathy. A consecutive sample of 85 IDDM patients with overt diabetic nephropathy (i. e. persistent proteinuria ≥ 500 mg/24 h) were followed-up until death or for a period of 5–13 years. QT intervals were measured once at baseline in a 12-lead ECG and corrected for heart rate (QTc). During the follow-up period 33 patients (39%) died. In the Cox proportional hazards model independent predictors of death were age (p=0.0007), the length of the maximum QTc period (p=0.0049), presence of autonomic neuropathy (p=0.0068), diabetes duration (p=0.0163) and RR variation (p=0.0395). In conclusion, in nephropathic IDDM patients QT prolongation is associated with an increased mortality risk which is independent of the presence of autonomic neuropathy. Further studies are needed to determine whether this risk might be reduced by therapeutic interventions.

Influence of nebivolol and enalapril on metabolic parameters and arterial stiffness in hypertensive type 2 diabetic patients.

Objective To compare the effects of a cardioselective beta-blocker (nebivolol) with those of an angiotensin-converting enzyme inhibitor (enalapril) on parameters of insulin sensitivity, peripheral blood flow and arterial stiffness during one extended glucose clamp experiment. Design A randomized, double-blind crossover trial, consisting of two 12-week treatment phases separated by a 4-week wash-out phase. Methods Patients with type 2 diabetes and arterial hypertension were randomly assigned to one of two treatment sequences (nebivolol–enalapril, enalapril–nebivolol). Haemodynamic, metabolic and other laboratory measurements were carried out on the first and last day of each treatment period by means of a glucose clamp experiment that also involved the measurement of blood flow and arterial stiffness. Results Twelve patients were included in this study, of which two dropped out early. Efficacy parameters were therefore available for 10 patients. There was no significant difference in any of the primary efficacy parameters. Moreover, the effects on blood pressure did not significantly differ between both treatments. Six adverse events happened during treatment with nebivolol compared with two during treatment with enalapril, but only one was regarded as possibly related to the treatment. Conclusions This pilot study shows that the combined measurement of insulin sensitivity, blood flow and arterial stiffness is feasible. Nebivolol and enalapril did not show different effects with regard to these parameters in hypertensive diabetic patients. If these results are confirmed in larger clinical trials, this would argue against the reservations against beta-blockers as drugs of first choice in patients with diabetes because of potential metabolic side-effects.

Hyperinsulinaemia is not linked with blood pressure elevation in patients with insulinoma.

SummaryWe have investigated the hypothesis that insulin is a causal and independent risk factor for blood pressure elevation in humans by comparing pre- and post-operative blood pressure values of 34 consecutive patients with histologically-confirmed diagnosis of insulinoma and 34 age- and sex-matched control patients. In patients with insulinoma hypoglycaemic symptoms were present for 18 (9–36) months. (Values are given as median and 95% confidence interval or mean and SD). After removal of insulinoma fasting plasma insulin levels decreased from 22 (16–28) mU/l to 11 (6–20) mU/l (p<0.003) and minimal fasting plasma glucose concentrations increased from 2.5 (2.0–3.0) to 4.4 (4.2–5.7) mmol/l (p<0.002) while blood pressure values remained unchanged. Body mass index before operation was comparable between the groups: 25.5 (5.4) kg/m2 in insulinoma patients and 24.8 (4.7) kg/m2 in control subjects. Pre-operative and post-operative blood pressure values did not differ between the groups, being (systolic/diastolic) 133 (18)/82 (9) mm Hg in insulinoma patients and 128 (15)/78 (10) mm Hg in control subjects before and 129 (19)/80 (10) mm Hg and 125 (11)/76 (7) after surgery. Chronic hyperinsulinaemia in patients with insulinoma is not associated with a detectable elevation of blood pressure values. Correction of hyperinsulinaemia after surgery for insulinoma does not result in blood pressure changes. These results argue against the hypothesis that insulin is an independent causal factor in the development of essential hypertension in humans.

Value of blood pressure self-monitoring as a predictor of progression of diabetic nephropathy

OBJECTIVE To determine the impact of self-monitoring of blood pressure values (BP(S)) as compared with office blood pressure measurements (BP(O)) on the progression of diabetic nephropathy. DESIGN Long-term, follow-up cohort study. SUBJECTS AND METHODS Hypertensive, type 1 diabetic patients with overt diabetic nephropathy were investigated. Patients initially participated in a hypertension treatment and teaching programme including extensive advice on blood pressure self-monitoring. Self-monitoring and office blood pressure values were continuously assessed during the entire follow-up period. Progression of diabetic nephropathy over the study period was individually assessed as the mean decline of glomerular filtration rate (GFR) per patient per year. Baseline and follow-up parameters were included in stepwise multiple regression analyses with the decline of GFR per year as the dependent variable. RESULTS Seventy-seven type 1 diabetic patients (37 women, 40 men) were followed for a mean period of 6.2 +/- 2.8 years (mean +/- SD; range 2-12) resulting in a total of 481 patient-years. During the follow-up period, mean BP(O) decreased from 166/95 at baseline to 154/89 mmHg during follow-up, and mean BP(S) fell from 159/93 to 138/83 mmHg. The mean decline of GFR was 4.1 +/- 5.6 ml/min per year. Loss of kidney function was significantly correlated with proteinuria, blood pressure and glycosylated haemoglobin values. In the multiple regression analyses, BP(S) predicted the loss of renal function better than BP(O) (R2 = 0.52 versus 0.42). The simple correlation between BP(S) and GFR decline was higher compared to BP(O) and GFR (r = -0.42; P < 0.0001 versus -0.33; P < 0.004). CONCLUSION Blood pressure self-monitoring values are a better predictor of progression of diabetic nephropathy when compared with office blood pressure measurements.

Insulin Resistance and the Effect of Insulin on Blood Pressure in Essential Hypertension

The aim of this study was to investigate the effect of 2 weeks of insulin administration on blood pressure and to simultaneously measure insulin sensitivity and insulin-induced vasodilatation in obese hypertensive patients. In a prospective, randomized, double-blind, crossover study (study 1), 23 obese, untreated, nondiabetic, hypertensive patients received either neutral protamine Hagedorn (NPH) insulin (0.3 U/kg body wt per day) or placebo subcutaneously for 2 weeks (washout period, 2 weeks). Office and 24-hour blood pressure values were measured at the beginning and end of each treatment period. In an open-label study (study 2), 8 obese hypertensive patients and 10 healthy control subjects underwent a 3-step hyperinsulinemic, euglycemic glucose clamp (step 1, 0.5; step 2, 2.5; step 3, 5.0 mU x kg(-1) x min(-1) [120 minutes each]). Leg blood flow (LBF) was measured by venous occlusion plethysmography. Insulin administration decreased mean+/-SD office blood pressure from 131+/-13 to 128+/-12 mm Hg (placebo, 132+/-13 and 132+/-13 mm Hg; P<0.05 between final examinations) and mean+/-SD 24-hour blood pressure by -3.3+/-6.9 mm Hg (placebo, +0.7+/-4.6 mm Hg; P<0.05). Insulin infusion increased LBF significantly in the healthy controls but not in obese insulin-resistant hypertensive subjects. Obese hypertensive patients are resistant to the effects of insulin with regard to both glucose uptake and vasodilatation. Administration of insulin exerts a small blood pressure-lowering effect in these patients. These data strongly argue against the postulated pressor action of insulin in essential hypertension.

Intensified antihypertensive therapy is associated with improved survival in type 1 diabetic patients with nephropathy

Objective: To determine the prognosis of treated hypertensive type 1 (insulin-dependent) diabetic patients with overt nephropathy. Design: A controlled, prospective, parallel, 5-year follow-up trial. Setting: The tertiary care centre of the Heinrich Heine University Hospital in Dusseldorf, Germany. Patients and interventions: A sequential sample of 91 hypertensive patients with overt diabetic nephropathy participated in a diabetes treatment programme. Thereafter 45 patients received intensified antihypertensive therapy including blood pressure self-monitoring and self-adjustment of antihypertensive drug treatment with the goal of permanent normalization of blood pressure values below 140/90 mmHg. The remaining 46 patients were administered routine antihypertensive therapy and formed the control group. At baseline both groups were comparable in age, sex, metabolic control and renal function. The groups differed at baseline in their duration of diabetes and blood pressure values, which were higher in the intensified antihypertensive therapy group. Outcome measures: Total mortality and the need for renal replacement therapy. Main results: Blood pressure control was significantly improved in patients who were subjected to intensified antihypertensive therapy, whereas it deteriorated in the group of patients who received routine antihypertensive therapy. At follow-up, primary end points of the study occurred in five (11 %) patients of the intensified therapy group and in 19 (41%) patients of the routine therapy group. According to life table analysis, intensified antihypertensive therapy was associated with less frequent primary end points (P= 0.0058) and longer survival (P=0.01). The differences between the groups remained significant after adjustment for covariates in the proportional hazards model. Conclusion: Participation in a treatment programme aimed at intensification of antihypertensive therapy is associated with a reduction of mortality in hypertensive type 1 diabetic patients with overt nephropathy.

Severe hypoglycemia in type I diabetic patients with impaired kidney function

Objective To assess the frequency and possible risk indicators of severe hypoglycemia in insulin-dependent (type I) diabetic patients with impaired kidney function. Research Design and Methods Retrospective follow-up examination of case subjects and control subjects with mean follow-up periods of 2.9 and 1.3 yr, respectively. The setting was the diabetes center at the Düsseldorf University hospital. Subjects were consecutive type I diabetic patients. Case subjects consisted of 44 patients with initial serum creatinine levels of ≥133 μM and pathological proteinuria. Control subjects consisted of 46 patients with normal serum creatinine levels matched for age, duration of diabetes, and hypertension; 57% of case subjects and 67% of control subjects were being treated with p-blockers. Incidence of severe hypoglycemia (cases/patient-yr) was assessed through an interviewer-administered questionnaire. Results At comparable levels of HbA1c (7.9 ±1.8 vs. 7.6 ± 1.1%), case subjects had a fivefold higher incidence of severe hypoglycemic episodes (1.28 vs. 0.25 cases/patient-yr, P <0.02) than control subjects. Within the group with impaired kidney function, patients with severe hypoglycemic episodes had lower HbA1c levels (7.4 ± 1.6 vs. 8.7 ± 2.0%, P <0.03) and a lower body mass index (22.0 ± 3.4 vs. 24.4 ± 3.8 kg/m2 P <han those without severe hypoglycemic episodes, whereas serum creatinine levels, body weight-related insulin dosage (U kg−1 day−1), prevalence of blindness, autonomic neuropathy, and treatment with β-blockers were comparable. Conclusions Type I diabetic patients with impaired kidney function are at an excessively high risk of severe hypoglycemia. In addition to low HbA1c levels, a low body mass index appears to be a risk indicator for this adverse effect of insulin therapy.

A time-limited, problem-orientated psychotherapeutic intervention in Type 1 diabetic patients with complications: a randomized controlled trial

Aims To examine the effects of a time‐limited, problem‐orientated psychotherapeutic intervention on self‐defined psychological problems and metabolic control in Type 1 diabetic patients with microvascular complications.