Insulin degludec results in lower rates of nocturnal hypoglycaemia and fasting plasma glucose vs. insulin glargine: A meta-analysis of seven clinical trials.

BACKGROUND AND AIMS: Basal insulin analogues have a reduced risk of hypoglycaemia compared with NPH insulin, but hypoglycaemia still remains a major impediment to achieving recommended fasting plasma glucose (FPG) targets in patients with diabetes. Insulin degludec (IDeg) is a new basal insulin that forms soluble multihexamers after subcutaneous injection resulting in an ultra-long duration of action and stable glucose-lowering effect. The aim of this analysis was to compare the effect of IDeg on FPG and nocturnal confirmed hypoglycaemia as compared to insulin glargine (IGlar). METHODS AND RESULTS: Data were included from seven phase 3a, randomised, open-label, treat-to-target clinical trials in which once-daily IDeg was compared with once-daily IGlar. Two trials included a total of 957 patients with type 1 diabetes (T1D) and five trials included a total of 3360 patients with type 2 diabetes (T2D); all trials were 26 or 52 weeks in duration. Confirmed hypoglycaemia was defined as plasma glucose <3.1 mmol/L or severe episodes requiring assistance, and nocturnal hypoglycaemia occurred between 00:01 and 05:59. In all trials, the mean end-of-trial FPG was lower for IDeg than IGlar, reaching statistical significance in three trials. Similarly, IDeg was associated with a lower rate of nocturnal confirmed hypoglycaemia vs. IGlar, which was statistically significant in three trials, regardless of type of diabetes or background therapy. CONCLUSION: This analysis shows that the lower rate of nocturnal confirmed hypoglycaemia seen with IDeg relative to IGlar is accompanied by a reduced mean FPG, in particular in patients with T2D.

Efficacy and safety of insulin degludec given as part of basal-bolus treatment with mealtime insulin aspart in type 1 diabetes: a 26-week randomized, open-label, treat-to-target non-inferiority trial.

AIMS: The efficacy and safety of insulin degludec (IDeg) was compared with insulin detemir (IDet), both administered once daily (OD) as basal treatment in participants with type 1 diabetes mellitus (T1DM). The primary outcome was non-inferiority of IDeg to IDet in glycated haemoglobin (HbA1c) reduction after 26 weeks. METHODS: This multinational, 26-week, controlled, open-label, parallel-group trial randomized adults with T1DM to IDeg or IDet as OD basal insulin treatment combined with mealtime bolus insulin aspart (IAsp). Participants with T1DM treated with any basal-bolus insulin regimen for ≥ 12 months prior to the trial, a mean HbA1c ≤ 10.0% (85.8 mmol/mol) and body mass index (BMI) ≤ 35.0 kg/m(2) at screening participated in the trial (IDeg: N = 302; IDet: N = 153). RESULTS: After 26 weeks, HbA1c decreased 0.73% (8.0 mmol/mol) (IDeg) and 0.65% (7.1 mmol/mol) (IDet) [estimated treatment difference (ETD) IDeg-IDet: -0.09% (-0.23; 0.05)95% CI (-10.0 mmol/mol [-2.6; 0.6]95% CI ); confirming non-inferiority]. Mean fasting plasma glucose improved in both groups, and was lower with IDeg than IDet [ETD IDeg-IDet: -1.66 mmol/l (-2.37; -0.95)95% CI , p < 0.0001]. The rate of confirmed hypoglycaemia was similar with IDeg and IDet [45.83 vs. 45.69 episodes per patient-year of exposure (PYE); estimated rate ratio (RR) IDeg/IDet: 0.98 (0.80; 1.20)95% CI , p = 0.86]. The rate of nocturnal confirmed hypoglycaemia was lower with IDeg than IDet [4.14 vs. 5.93 episodes per PYE; RR IDeg/IDet: 0.66 (0.49; 0.88)95% CI , p = 0.0049]. Adverse event profiles were similar between groups. CONCLUSION: IDeg administered OD in basal-bolus therapy effectively improved long-term glycaemic control in participants with T1DM with a lower risk of nocturnal confirmed hypoglycaemia than IDet.

Safety and efficacy of inhaled insulin (AERx iDMS) compared with subcutaneous insulin therapy in patients with Type 1 diabetes: 1-year data from a randomized, parallel group trial.

AIMS: Assessment of the long-term safety and efficacy of liquid inhaled insulin via AERx insulin Diabetes Management System (iDMS) in a basal/bolus treatment regimen of adults with Type 1 diabetes. METHODS: Patients were randomized 2 : 1 to prandial inhaled (n = 205) or subcutaneous (s.c.) (n = 99) insulin, plus one/two daily injections of neutral protamine Hagedorn (NPH) insulin for 12 months. The primary endpoints were pulmonary function tests (PFT) and baseline changes in chest X-rays at 12 months. Safety and efficacy assessments were measured at regular intervals. RESULTS: PFTs after 12 months were comparable between the groups, except for reduced per cent of predicted carbon monoxide lung diffusing capacity with inhaled insulin (difference: -2.03%, P = 0.04) occurring after the first 3 months and then stabilizing. There were no apparent treatment differences in chest X-rays. Overall risk of hypoglycaemia [risk ratio (RR) 1.02, P = 0.83] and adverse events were comparable between groups. Risk of nocturnal hypoglycaemia was higher in the inhaled group (RR 1.58, P = 0.001). Cough [10% (inhaled); 3% (s.c.)] tended to be mild in nature. Inhaled insulin was non-inferior to s.c. insulin for change in glycated haemoglobin (HbA(1c)) after 12 months [difference 0.18% (CI 95%-0.04; 0.39)]. At trial end, mean laboratory measured fasting plasma glucose was lower in the inhaled group (inhaled 9.2 mmol/l; s.c. 11.7 mmol/l; difference: -2.53 mmol/l, P < 0.001). CONCLUSIONS: The safety and efficacy results in this trial were similar to those reported with other inhaled insulins; however, inhaled insulin using AERx iDMS requires further optimization to reduce nocturnal hypoglycaemia before it has comparable safety and efficacy to s.c. insulin aspart.

Effect of the antilipolytic nicotinic acid analogue acipimox on whole-body and skeletal muscle glucose metabolism in patients with non-insulin-dependent diabetes mellitus.

Increased nonesterified fatty acid (NEFA) levels may be important in causing insulin resistance in skeletal muscles in patients with non-insulin-dependent diabetes mellitus (NIDDM). The acute effect of the antilipolytic nicotinic acid analogue Acipimox (2 X 250 mg) on basal and insulin-stimulated (3 h, 40 mU/m2 per min) glucose metabolism was therefore studied in 12 patients with NIDDM. Whole-body glucose metabolism was assessed using [3-3H]glucose and indirect calorimetry. Biopsies were taken from the vastus lateralis muscle during basal and insulin-stimulated steady-state periods. Acipimox reduced NEFA in the basal state and during insulin stimulation. Lipid oxidation was inhibited by Acipimox in all patients in the basal state (20 +/- 2 vs. 33 +/- 3 mg/m2 per min, P less than 0.01) and during insulin infusion (8 +/- 2 vs. 17 +/- 2 mg/m2 per min, P less than 0.01). Acipimox increased the insulin-stimulated glucose disposal rate (369 +/- 49 vs. 262 +/- 31 mg/m2 per min, P less than 0.01), whereas the glucose disposal rate was unaffected by Acipimox in the basal state. Acipimox increased glucose oxidation in the basal state (76 +/- 4 vs. 50 +/- 4 mg/m2 per min, P less than 0.01). During insulin infusion Acipimox increased both glucose oxidation (121 +/- 7 vs. 95 +/- 4 mg/m2 per min, P less than 0.01) and nonoxidative glucose disposal (248 +/- 47 vs. 167 +/- 29 mg/m2 per min, P less than 0.01). Acipimox enhanced basal and insulin-stimulated muscle fractional glycogen synthase activities (32 +/- 2 vs. 25 +/- 3%, P less than 0.05, and 50 +/- 5 vs. 41 +/- 4%, P less than 0.05). Activities of muscle pyruvate dehydrogenase and phosphofructokinase were unaffected by Acipimox. In conclusion, Acipimox acutely improved insulin action in patients with NIDDM by increasing both glucose oxidation and nonoxidative glucose disposal. This supports the hypothesis that elevated NEFA concentrations may be important for the insulin resistance in NIDDM. The mechanism responsible for the increased insulin-stimulated nonoxidative glucose disposal may be a stimulatory effect of Acipimox on glycogen synthase activity in skeletal muscles.

Impact of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy.

Diabetic nephropathy is characterized by hypertension and a relentless decline in kidney function. Angiotensin-converting enzyme inhibitors have been claimed to preserve kidney function better than an equal blood pressure (BP) reduction with conventional antihypertensive treatment (renoprotection). We compared the effect on kidney function of lisinopril (10-20 mg/day) and atenolol (50-100 mg/day) in hypertensive NIDDM patients (mean age 60 +/- 8 years) with diabetic nephropathy. Forty-three (21 lisinopril and 22 atenolol) patients were enrolled in a 1-year randomized double-blind parallel study. Eight patients dropped out, and the results for the remaining 35 patients (16 lisinopril and 19 atenolol) are presented. Diuretics were required in 10 of 16 lisinopril patients and 12 of 19 atenolol patients. The following variables were measured: 24-hour ambulatory BP (Takeda TM2420), albuminuria (enzyme-linked immunosorbent assay), fractional albumin clearance, and glomerular filtration rate (GFR) ([51Cr]EDTA technique). The average reduction in mean arterial BP during the 12 months was identical in the two groups 12 +/- 2 vs. 11 +/- 1 mmHg in the lisinopril and atenolol group, respectively. Albuminuria was on average reduced 45% in the lisinopril group vs. 12% in the atenolol group (P < 0.01), and fractional albumin clearance was on average reduced 49% in the lisinopril group vs. 1% in the atenolol group (P < 0.05). GFR declined identically in the two groups 11.7 +/- 2.3 vs. 11.6 +/- 2.3 ml.min-1.year-1 in the lisinopril and atenolol groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Albuminuria and poor glycemic control predict mortality in NIDDM.

The impact of microalbuminuria and macroalbuminuria on mortality was evaluated prospectively in 328 Caucasian patients with non-insulin-dependent diabetes mellitus (NIDDM) followed for 5 years. One hundred ninety-one (109 men and 82 women) patients with normoalbuminuria (albumin excretion rate [AER] < 30 mg/24 h), 86 (50 men and 36 women) patients with microalbuminuria (AER 30-299 mg/24 h), and 51 (43 men and 8 women) patients with macroalbuminuria (AER > or = 300 mg/24 h) < 66 years old at entry were followed from 1987 until death or until 1 January 1993. Mean age at entry was 54 (SD 9) years. In January 1993, 8% of patients with normoalbuminuria, 20% of patients with microalbuminuria, and 35% of patients with macroalbuminuria had died (predominantly from cardiovascular disease) (P < 0.01 [normoalbuminuria versus micro- and macroalbuminuria] and P < 0.05 [microalbuminuria versus macroalbuminuria]). Cox multiple regression analysis revealed significant predictors of all-cause mortality to be preexisting coronary heart disease (relative risk [95% confidence interval]), 2.9 (1.6-5.1); log10AER (factor 10), 1.9 (1.4-2.6); HbA1c level (%), 1.2 (1.0-1.4); and age (years), 1.08 (1.03-1.13). Significant predictors of cardiovascular mortality included preexisting coronary heart disease, 6.1 (2.8-13.5); macroalbuminuria, 2.5 (1.1-5.8); HbA1c level (%), 1.3 (1.1-1.6); and systolic blood pressure (10 mmHg), 1.2 (1.0-1.4). Univariate Cox survival analysis in the normoalbuminuric group revealed that AER above the median of 8 mg/24 h was associated with an increased all-cause mortality risk of 2.7 (0.93-7.69) (P = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term effect of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy.

The aim of our study was to evaluate whether inhibition of ACE (lisinopril 10-20 mg/day) can reduce the rate of decline in kidney function more than reducing blood pressure with conventional antihypertensive treatment (atenolol 50-100 mg/day), usually in combination with a diuretic. We performed a prospective, randomized, parallel study for 42 months, double blind for the first 12 months and single blind thereafter. Forty-three (21 lisinopril and 22 atenolol) hypertensive NIDDM patients with diabetic nephropathy were enrolled. Data from 36 patients (17 lisinopril and 19 atenolol, 60 +/- 7 years of age, 27 men) who completed at least 12 months of the study period are presented. At baseline, the two groups were comparable: glomerular filtration rate (51Cr-EDTA plasma clearance) was 75 +/- 6 and 74 +/- 8 ml x min(-1) x 1.73 m(-2), mean 24-h ambulatory blood pressure (A&D TM2420) was 110 +/- 3 and 114 +/- 2 mmHg, and 24-h urinary albumin excretion rate was 961 (range 331-5,727) and 1,578 (476-5,806) mg/24 h in the lisinopril and atenolol groups, respectively. The mean follow-up time was similar, 37 and 35 months in the lisinopril and atenolol groups, respectively. Mean ambulatory blood pressure was equally reduced in the two groups, 12 +/- 2 and 10 +/- 2 mmHg in the lisinopril and atenolol groups, respectively. Glomerular filtration rate declined in a biphasic manner with a faster initial (0 to 6 months) change of 1.25 +/- 0.49 and 0.81 +/- 0.29 ml x min(-1) x month(-1) followed by a slower sustained decline (6 to 42 months) of 0.59 +/- 0.10 and 0.54 +/- 0.13 ml x min(-1) x month(-1) in the lisinopril and atenolol groups, respectively. No significant differences were observed in either initial or sustained decline in glomerular filtration rate between the two groups. Urinary albumin excretion was reduced (% reduction of baseline) more in the lisinopril than in the atenolol group, at 55 (95% CI 29-72) and 15% (-13 to 34), respectively (P = 0.01). In conclusion, the relentless decline in kidney function characteristically found in hypertensive NIDDM patients with diabetic nephropathy can be reduced equally effectively by two antihypertensive treatments, the beta-blocker atenolol and the ACE inhibitor lisinopril.

On the mechanisms of blunted nocturnal decline in arterial blood pressure in NIDDM patients with diabetic nephropathy.

Nondiabetic hypertensive patients lacking the normal nocturnal decline in arterial blood pressure have enhanced cardiovascular complications. Since cardiovascular morbidity and mortality are increased in non-insulin-dependent diabetes mellitus (NIDDM), we performed a prospective cross-sectional case-controlled study comparing the diurnal variation in arterial blood pressure, prevalence of dippers, cardiac autonomic nervous function (beat-to-beat variation during deep breathing), and extracellular fluid volume (51Cr-labeled EDTA) in 55 NIDDM patients with diabetic nephropathy (group 1), 55 NIDDM patients with normoalbuminuria (group 2), and 22 nondiabetic control subjects (group 3). All antihypertensive treatments were withdrawn at least 2 weeks before the study. The nocturnal blood pressure reduction (daytime-to-nighttime)/daytime (mean +/- SE) was impaired in group 1 (6.6 +/- 1.5%) and group 2 (11.1 +/- 1.4%) as compared with group 3 (17.6 +/- 1.7%), and it was impaired in group 1 as compared with group 2 (P < 0.05 for each comparison). The prevalence of dippers (95% confidence interval) was lower in group 1 (42% [29-56]) as compared with group 2 (58% [44-71]; P = 0.08) and group 3 (86% [65-97]; P < 0.001) and in group 2 as compared with group 3 (P < 0.01). Abolished beat-to-beat variation was more prevalent in group 1 (63% [50-76]) as compared with group 2 (15% [7-27]) and with group 3 (5% [0-23]) (P < 0.001). Nocturnal blood pressure reduction was associated with beat-to-beat variation during deep breathing (r = 0.22, P < 0.01). Extracellular fluid volume (mean +/- SE) was higher in group 1 (15.9 +/- 0.5 l/m2) as compared with group 3 (14.1 +/- 0.8 l/m2) (P < 0.05) with group 2 between the two (15.1 +/- 0.4 l/m2).(ABSTRACT TRUNCATED AT 250 WORDS)

Course of glomerular filtration rate in albuminuric type 2 diabetic patients with or without diabetic glomerulopathy.

OBJECTIVE: To evaluate and compare the clinical course and prognosis in type 2 diabetic patients with persistent albuminuria, with biopsy-proven diabetic glomerulosclerosis (DG), or with nondiabetic glomerulopathies (NDG). RESEARCH DESIGN AND METHODS: A kidney biopsy was performed in 34 consecutive type 2 diabetic patients with persistent albuminuria (> or = 300 mg/24 h). Glomerular filtration rate (GFR) (51Cr-EDTA) was determined at least once a year, and albuminuria, arterial blood pressure, and HbA1c were determined every 3-6 months. RESULTS: The biopsy revealed DG in 26 patients (25 men/1 woman) (DG group), age 52 +/- 2 (mean +/- SEM) years, and NDG in 8 patients (7 men/1 woman) (NDG group), age 54 +/- 3 years. The patients were followed for a median of 7.7 years (range 1.0-14.2). In the DG group, GFR decreased from 82 (24-146) to 38 (2-116) ml.min-1.1.73 m-2 (P < 0.001), with a median rate of decline in GFR of 5.6 (0.3-21.6) ml.min-1.year-1, and in the NDG group, GFR decreased from 107 (89-135) to 90 (17-119) ml.min-1.1.73 m-2 (P < 0.05), with a median rate of decline in GFR of 1.3 (0.3-7.6) ml.min-1.year-1 (P < 0.05 between groups). In the DG group, albuminuria increased from 1.4 (0.3-7.2) to 2.6 (0.1-21.6) g/24 h (P < 0.05) and in the NDG group, decreased from 2.2 (0.8-8.7) to 0.8 (0.2-2.5) g/24 h (P = 0.05). Mean arterial blood pressure (MABP) decreased from 118 +/- 3 to 104 +/- 3 mmHg (P < 0.05) in the DG group, whereas it remained unchanged in the NDG group (106 +/- 3 vs. 105 +/- 3 mmHg). In the DG group, the rate of decline in GFR correlated with systolic blood pressure (r = 0.62, P < 0.001), MABP (r = 0.52, P < 0.01), albuminuria (r = 0.55, P < 0.005), and GFR at entry (r = -0.45, P < 0.05). CONCLUSIONS: Our study demonstrated a more rapid decline in GFR and a progressive rise in albuminuria in type 2 diabetic patients with DG compared with type 2 diabetic patients with NDG.

Prevalence of arterial hypertension in diabetic patients before and after the JNC-V.

OBJECTIVE: To compare the prevalence of arterial hypertension in patients with insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) according to blood pressure (BP) criteria from the World Health Organization (WHO) and The Fifth Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC-V). RESEARCH DESIGN AND METHODS: Two cohorts of Caucasian patients attending the outpatient clinic at Hvidöre Hospital were identified: 1) 957 patients with IDDM; 53% men, 40 (18-75) years of age (mean [range]); and 2) 549 patients with NIDDM; 53% men, 60 (20-76) years of age. BP was measured at least yearly, while patients rested in a sitting position, with a standard clinical sphygmomanometer. Patients were classified as hyper- or normotensive based on average BP during a 3-year follow-up period. Patients receiving antihypertensive treatment were classified as hypertensives. RESULTS: In IDDM patients, the prevalence of arterial hypertension rose from 15 to 42% in the normoalbuminuric group, from 26 to 52% in the microalbuminuric group, and from 61 to 79% in the macroalbuminuric group when WHO and JNC-V criteria were compared. The corresponding rises in NIDDM patients were from 51 to 71% (normo-), from 73 to 90% (micro-), and from 82 to 93% (macroalbuminuria). Of the untreated hypertensive patients, 78% of IDDM patients and 50% of NIDDM patients had stage 1 (140-159/90-99 mmHg) hypertension; 20% of IDDM patients and 37% of NIDDM patients had stage 2 (160-179/100-109 mmHg) hypertension. Two out of three untreated hypertensive patients had isolated systolic hypertension. CONCLUSIONS: The new JNC-V criteria approved by the American Diabetes Association leads to a considerable increase in the prevalence of arterial hypertension in a population of IDDM and NIDDM patients. Isolated systolic hypertension contributes importantly.

Raised serum sialic acid concentration in NIDDM patients with and without diabetic nephropathy.

OBJECTIVE: Raised serum sialic acid concentration is a strong predictor of cardiovascular mortality in the general white population. A progressive increase in cardiovascular morbidity and mortality takes place in relation to increasing albuminuria in NIDDM patients. Therefore, we investigated the potential association between serum sialic acid and micro- and macroangiopathy in NIDDM patients. RESEARCH DESIGN AND METHODS: We studied a prevalence cohort of all white NIDDM patients < 76 years of age attending a diabetic clinic during 1 year. Of the patients, 319 had normoalbuminuria, 148 had microalbuminuria, and 75 had macroalbuminuria (diabetic nephropathy was in 47 of 75 patients); 66 nondiabetic age- and sex-matched subjects acted as a control group. Blood samples were taken for measurements of sialic acid, lipids, creatinine, and HbA1C. Retinopathy was assessed by funduscopy. The prevalence of cardiovascular disease was based on Minnesota-coded electrocardiograms and the World Health Organization cardiovascular questionnaire. RESULTS: A progressive raise in serum sialic acid was demonstrated with an increasing urinary albumin excretion rate: [median (range)] 2.02 (1.55-2.63); 2.42 (1.47-6.48); 2.67 (1.57-5.86), and 2.95 (1.52-7.86) mmol/l in nondiabetic subjects, NIDDM patients with normoalbuminuria, microalbuminuria, and diabetic nephropathy, respectively (P < 0.05 or less for differences between groups). Multiple linear regression analysis showed that serum cholesterol concentration, serum HDL cholesterol concentration, BMI, albuminuria, smoking, and cardiovascular disease correlate independently with logarithmic (10) serum sialic acid concentration. CONCLUSIONS: Our study revealed a progressive raise in serum sialic acid with increasing urinary albumin excretion rate in NIDDM patients. Furthermore, several modifiable cardiovascular risk factors were associated with serum sialic acid.

Placebo-controlled comparison of captopril, metoprolol, and hydrochlorothiazide therapy in non-insulin-dependent diabetic patients with primary hypertension.

The antihypertensive effect of captopril, metoprolol, and hydrochlorothiazide was compared in 23 non-insulin-dependent (NIDDM) diabetic patients less than or equal to 75 years of age, with borderline to moderate primary hypertension. In a double blind, placebo-controlled cross-over trial the patients were treated with 25 to 50 mg captopril, 50 to 100 mg metoprolol, 12.5 to 25 mg hydrochlorothiazide, and placebo, each given twice daily for 8 weeks. Antidiabetic treatment remained unchanged during the study. After receiving placebo for a 4 week run-in period, arterial blood pressure was 168/101 +/- 93/10 (mean +/- SEM) mm Hg. Diastolic blood pressure was lowered significantly during all active treatment periods compared to the placebo value of 97 +/- 2 mm Hg: captopril, 92 +/- 1 mm Hg; metoprolol, 90 +/- 1 mm Hg; hydrochlorothiazide, 91 +/- 1 mm Hg. Metabolic variables were not significantly altered by captopril and metoprolol, while hydrochlorothiazide treatment increased hemoglobin A1c from 7.5 +/- 0.3 to 8.2 +/- 0.4% (P less than .001), decreased high-density lipoprotein-cholesterol from 1.19 +/- 0.08 to 1.10 +/- 0.06 mmol/L (P less than .05). Glomerular filtration rate, urinary albumin excretion, orthostatic blood pressure response, and digital systolic blood pressure in the lower limb remained unchanged during the active treatment periods. The frequency of subjective adverse effects was acceptable during active treatment and not significantly different compared to placebo. We conclude that antihypertensive treatment for 8 weeks with captopril or metoprolol in NIDDM patients is well-tolerated and causes no deterioration in metabolic control and kidney function, while hydrochlorothiazide causes a slight deterioration in glycemic control and lipid profile.

Pregnancy-induced hypertension and postpartum maternal morbidity.

Prospective evaluation of 80 patients experiencing preeclampsia/eclampsia was conducted. Traditional antepartum clinical presentation, classification, and laboratory evaluation were found to be imprecise for the prediction of postpartum maternal morbidity. Serial urine samples were collected from all patients during the antepartum, intrapartum, and postpartum period. Urine albumin and immunoglobulin G (IgG) concentrations were measured by rate nephelometry. The degree of albumin and IgG excretion before and after standard treatment modalities correlates with the occurrence of postpartum morbidity. The nephelometric urinalysis appears to be of assistance in the evaluation of disease severity, the effectiveness of treatment modalities on renal function, and the identification of patients destined to develop postpartum morbidity. In addition, rapid nephelometric urinalysis makes the collection of 24-hour urine samples unnecessary for evaluation of renal function in pregnancy-induced hypertension.

Insulin detemir and insulin aspart: a promising basal-bolus regimen for type 2 diabetes.

This trial compared the efficacy and safety of basal-bolus therapy using either the soluble basal insulin analogue insulin detemir (IDet) in combination with meal-time rapid-acting analogue insulin aspart (IAsp), or NPH insulin (NPH) in combination with meal-time regular human insulin (HSI). This was a 22-week, multinational, open-labelled, symmetrically randomised, parallel group trial including 395 people with type 2 diabetes (IDet + IAsp: 195, NPH + HSI: 200). At 22 weeks, HbA1c was comparable between treatments (IDet + IAsp: 7.46%, NPH + HSI: 7.52%, P = 0.515) with decreases from baseline of 0.65% and 0.58%, respectively. Treatment with IDet + IAsp was associated with a significantly lower within-person variation in self-measured fasting plasma glucose (FPG) (SD:1.20 versus 1.54 mmol/L, p < 0.001), as well as a lower body weight gain (0.51 versus 1.13 kg, p = 0.038) than with NPH + HSI. The risk of nocturnal hypoglycaemia was 38% lower with IDet + IAsp than with NPH + HSI, but statistical significance was not attained (P = 0.14). The overall safety profile was similar between the two treatments. Basal-bolus treatment with IDet + IAsp is an effective and well tolerated insulin regimen in people with type 2 diabetes, resulting in glycaemic control comparable to that of NPH + HSI, but with the advantages of less weight gain and a lower day-to-day within-person variation in FPG.

Induction of parturition in swine with prostaglandin F(2)alpha, estradiol benzoate and oxytocin.

Pregnant sows and gilts were administered either 0, 2.5, 5, 10 or 20 mg prostaglandin F(2)alpha (PGF(2)alpha) intramuscularly on Day 112 or 113 of gestation at 0800 h in an effort to induce parturition. The average interval from PGF(2)alpha injection to farrowing was 55.1 +/- 5.7, 29.4 +/- 3.1, 32.1 +/- 4.6, 27.8 +/- 1.8 and 26.9 +/- 1.1 h for 0, 2.5, 5, 10 and 20 mg, respectively. All PGF(2)alpha treatments increased (P < 0.01) over controls the number of sows farrowing 23 to 33 h after injection. The average gestation length was significantly shorter in treated gilts; however, no detrimental effect on pig performance or pig survivability was observed. A second trial evaluated the effect of a 10-mg dose of PGF(2)alpha on the induction of parturition in sows in order to obtain a majority of sows farrowing within normal working hours (0700 to 1700 h). The interval from injection to farrowing was decreased (P < 0.05) by PGF(2)alpha treatment (66.2 +/- 5.3 vs 28.1 +/- 2.2 h). Fifty-seven percent (P < 0.05) of PGF(2)alpha-treated sows farrowed between 0700 and 1700 h as compared to 13.6% for control sows. A third trial was conducted to examine a sequential treatment of PGF(2)alpha and oxytocin to control the time of parturition more precisely. Sows receiving only 10 mg of PGF(2)alpha farrowed on an average 31.1 +/- 1.4 h after injection. The injection of 40 IU oxytocin 24 to 28 h after PGF(2)alpha decreased (P < 0.05) the interval from PGF(2)alpha to farrowing (28.1 +/- 0.9 h). The addition of oxytocin increased (P < 0.05) the number of sows farrowing within 3 h of injection (33 vs 86% for PGF(2)alpha and PGF(2)alpha + oxytocin treatments, respectively). A fourth trial was designed to determine if the addition of exogenous estradiol benzoate (EB) to a sequential treatment of PGF(2)alpha and oxytocin would improve the predictability and synchronization of the induced parturition. Sows were assigned to receive either saline, 10 mg PGF(2)alpha + 40 IU oxytocin or 10 mg PGF(2)alpha + 5 mg EB + 40 IU oxytocin. The addition of EB reduced (P < 0.01) the variance in the interval from oxytocin to farrowing and added precision to the predicted time of induced parturition.

[Sustained ventricular tachycardia in older children. Spontaneous regression in 3 cases]. / Tachycardie ventriculaire en salve soutenue du grand enfant. Guérison spontanée de 3 cas.

Extensively described since Gallvardin's reports, the electrical features of salves of ventricular tachycardia in an apparently healthy heart are now well known. The usual benign nature of this arrhythmia is acknowledged, seldom contradicted by isolated clinical cases. Although chronicity is the rule in young adults, there have been a few publications concerning the natural history of these tachycardias in the paediatric age group. The authors report three cases of episodic sustained ventricular tachycardia in older children, presenting at an average of 7 years of age (range 5 to 9 years) and followed up for an average of 7 years (range: 5.5 to 9 years). These three children were treated for an average of 4.5 years (range: 3 to 5.5 years). All treatment was finally withdrawn when stable permanent sinus rhythm without ventricular extrasystoles was restored and confirmed over an average period of 2 years (range 10 months to 3.5 years), an average of 4 (range 3 to 7) successive normal Holter recordings at several months' interval. The outcome in children to spontaneous regression after several years would seem to make radiofrequency ablation more dangerous than useful given the benign nature of the arrhythmia and its good response to pharmacological intervention.

[Vagal hyperreactivity and sudden infant death. Study of 15 families]. / Hyperréactivité vagale et mort subite dans la fratrie. Etude des 15 familles.

Prone sleep position is obviously the main risk factor for sudden infant death. Other risk factors, such as vagal overactivity particularly in the familial form, are still discussed. We here report 15 families characterized by the coexistence of vagal overactivity and sudden infant death. At least, 1 child for each family had documented [Holter or occulo-cardiac reflex (OCR)] vagal overactivity. In 5 families 2 children were affected; in 2 families 3 children were affected and in 1 family 4 children were affected. Sudden death occurred in the elderly of the family in 8 cases, in the twin in 3 cases, in the 2nd in 3 cases and in the 5th child in 1 case. Within the 15 families, at least 1 parent had experienced vagally-induced fainting or syncope in 10 cases. Familial pattern of vagal overactivity is underlined. Possible links between vagal overactivity, risk factor for suddden death and sudden death are discussed. We suggest an Holter-ECG and OCR follow-up for sudden infant death siblings with history of familial vagal overactivity (3 examinations during the 1st year of life, at 1, 3 and 9 months).

Risk factors for development of incipient and overt diabetic nephropathy in patients with non-insulin dependent diabetes mellitus: prospective, observational study.

OBJECTIVE: To evaluate putative risk factors for the development of incipient diabetic nephropathy (persistent microalbuminuria) and overt diabetic nephropathy (persistent macroalbuminuria) in patients with non-insulin dependent diabetes. DESIGN: Prospective, observational study of a cohort of white, non-insulin dependent diabetic patients followed for a median period of 5.8 years. SETTING: Outpatient clinic in tertiary referral centre. SUBJECTS: 191 patients aged under 66 years with non-insulin dependent diabetes and normoalbuminuria (urinary albumin excretion rate < 30 mg/24 h) who attended the clinic during 1987. MAIN OUTCOME MEASURES: Incipient and overt diabetic nephropathy. RESULTS: Fifteen patients were lost to follow up. Thirty six of the 176 remaining developed persistent microalbuminuria (30-299 mg/24 h in two out of three consecutive 24 hour urine collections) and five developed persistent macroalbuminuria (> or = mg/24 h in two out of three consecutive collections) during follow up. The five year cumulative incidence of incipient diabetic nephropathy was 23% (95% confidence interval 17% to 30%). Cox's multiple stepwise regression analysis revealed the following risk factors for the development of incipient or overt diabetic nephropathy: increased baseline log urinary albumin excretion rate (relative risk 11.1 (3.4 to 35.9); P < 0.0001); male sex (2.6 (1.2 to 5.4); P < 0.02); presence of retinopathy (2.4 (1.3 to 4.7); P < 0.01); increased serum cholesterol concentration (1.4 (1.1 to 1.7); P < 0.01); haemoglobin A1c concentration (1.2 (1.0 to 1.4); P < 0.05); and age (1.07 (1.02 to 1.12); P < 0.01). Known duration of diabetes, body mass index, arterial blood pressure, serum creatinine concentration, pre-existing coronary heart disease, and history of smoking were not risk factors. CONCLUSION: Several potentially modifiable risk factors predict the development of incipient and overt diabetic nephropathy in normoalbuminuric patients with non-insulin dependent diabetes.

[Albuminuria and glycemic control. The significance for mortality in non-insulin-dependent diabetes mellitus]. / Albuminuri og glykaemisk kontrol. Betydningen for dødelighed hos ikkeinsulinkroevende diabetikere.

The impact of microalbuminuria and macroalbuminuria on mortality was evaluated prospectively in 328 Caucasian patients with non-insulin-dependent diabetes mellitus (NIDDM) followed for five years. One hundred and ninety-one patients with normoalbuminuria (albumin excretion rate (AER) < 30 mg/24 h), 86 patients with microalbuminuria (AER 30-299 mg/24 h), and 51 patients with macroalbuminuria (AER > or = 300 mg/24 h) all less than 66 years old at start of the study were followed from 1987 until death or until 1 January 1993. Eight percent of patients with normoalbuminuria, 20% of patients with microalbuminuria, and 35% of patients with macroalbuminuria had died, predominantly from cardiovascular disease. Significant predictors of all-cause mortality included preexisting coronary heart disease, AER, HbA1c level and age. Significant predictors of cardiovascular mortality included preexisting coronary heart disease, macroalbuminuria, HbA1c level and systolic blood pressure. Abnormally elevated urinary albumin excretion and poor glycaemic control indicate a substantially increased all-cause, mainly cardiovascular, mortality risk in NIDDM patients.