Per Reichard

The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus

BACKGROUND A cause-and-effect relation between blood glucose concentrations and microvascular complications in patients with insulin-dependent diabetes mellitus has not been established. METHODS We randomly assigned 102 patients with insulin-dependent diabetes mellitus, nonproliferative retinopathy, normal serum creatinine concentrations, and unsatisfactory blood glucose control to intensified insulin treatment (48 patients) or standard insulin treatment (54 patients). We then evaluated them for microvascular complications after 18 months and 3, 5, and 7.5 years. RESULTS Mean (+/- SD) glycosylated hemoglobin values were reduced from 9.5 +/- 1.3 percent to 7.1 +/- 0.7 percent in the group receiving intensified treatment and from 9.4 +/- 1.4 percent to 8.5 +/- 0.7 percent in the group receiving standard treatment (P = 0.001). In 12 of the patients receiving intensified treatment (27 percent of those included in the analysis) and 27 of those receiving standard treatment (52 percent), serious retinopathy requiring photocoagulation developed (P = 0.01). Visual acuity decreased in 6 patients receiving intensified treatment (14 percent) and in 18 receiving standard treatment (35 percent) (P = 0.02). Nephropathy (urinary albumin excretion, > 200 micrograms per minute) developed in one patient in the group receiving intensified treatment, as compared with nine patients in the group receiving standard treatment (P = 0.01). No patient in the intensified-treatment group had nephropathy with subnormal glomerular filtration rates, as compared with six patients in the standard-treatment group (P = 0.02). The conduction velocities of the ulnar, tibial, peroneal, and sural nerves decreased significantly more in the standard-treatment group than in the intensified-treatment group. The odds ratio for serious retinopathy was 0.4 (95 percent confidence interval, 0.2 to 1.0; P = 0.04) in the intensified-treatment group as compared with the standard-treatment group. The corresponding odds ratio for nephropathy was 0.1 (95 percent confidence interval, 0 to 0.8; P = 0.04). CONCLUSIONS Long-term intensified insulin treatment, as compared with standard treatment, retards the development of microvascular complications in patients with insulin-dependent diabetes mellitus.

Intensified conventional insulin treatment retards the microvascular complications of insulin‐dependent diabetes mellitus (IDDM): the Stockholm Diabetes Intervention Study (SDIS) after 5 years

Abstract. Ninety‐six patients with insulin‐dependent diabetes mellitus (IDDM) and non‐proliferative retinopathy were randomized to intensified conventional treatment (ICT) (n = 44) or regular treatment (RT) (n = 52), and followed up for 5 years. HbA1c decreased from 9.5 ± 0.2% (mean value ± SEM) to 7.2 ± 0.1% in the ICT group, and from 9.4 ± 0.2% to 8.7 ± 0.1% in the RT group (difference between the groups, P < 0.001). Retinopathy increased in both groups (P < 0.001), but after 5 years it was worse in the RT group (P < 0.05). The urinary albumin excretion rate was higher in the RT group than in the ICT group after 5 years (239.9 ± 129.7 μg min−1 vs. 46.0 ± 26.1 μg min−1, P < 0.05). Eight RT patients developed manifest nephropathy, compared with none in the ICT group (P < 0.01). After 5 years the conduction velocities of the sural (P < 0.05), peroneal (P < 0.01) and tibial (P < 0.001) nerves were lower in the RT group. The respiratory sinus arrhythmia was 12.1 ± 1.2 beats min−1 in the RT group and 16.7 ± 1.4 beats min−1 in the ICT group at the end of the study (P < 0.01). The increases in retinopathy (P < 0.01), nephropathy (P < 0.01) and neuropathy (P < 0.001) were all related to the mean HbA1c value during the study. Smoking habits only influenced the progression of retinopathy (P < 0.05). Serious hypoglycaemia occurred in 34 ICT patients and 29 RT patients (242 and 98 episodes, respectively) (P < 0.05). Whereas weight was stable in the RT group, the body mass index increased by 5.8% in the ICT group (P < 0.01). In conclusion, microvascular complications of diabetes were retarded by intensified conventional insulin treatment. However, such treatment increased the frequency of serious hypoglycaemia, and led to an increase in body weight.

Complications in IDDM are caused by elevated blood glucose level : The Stockholm Diabetes Intervention Study (SDIS) at 10-year follow up

Summary Blood glucose values close to normal reduce the microvascular complications of insulin-dependent diabetes mellitus. The Stockholm study of this effect continued after the initial 7.5-year period in order to see what happened when intensively treated patients were left to control their own treatment while treatment was intensified in the control group. Forty-three patients with insulin-dependent diabetes randomised to intensified conventional treatment (ICT) and 48 patients randomised to standard treatment (ST) were followed-up for 10 years. Vascular complications, treatment side-effects and well-being were studied. Risk factors for complications were sought. HbA1c (normal range 3.9–5.7 %) was reduced from 9.5 ± 1.4 % (mean ± SD) in the ICT group and 9.4 ± 1.2 % in the ST group to a mean (during 10 years) of 7.2 ± 0.6 % and 8.3 ± 1.0 %, respectively (p < 0.001). Serious retinopathy (63 vs 33 %, p = 0.003), nephropathy (26 vs 7 %, p = 0.012) and symptoms of neuropathy (32 vs 14 %, p = 0.041) were more common in the ST group after 10 years. HbA1c and age were the only risk factors for complications. Self-reported well-being increased to a greater degree and severe hypoglycaemia was more common in the ICT group. Cognitive function after 10 years was similar in both treatment groups, and was not related to the number of severe hypoglycaemic episodes. Intensified insulin treatment leads to reduced long-term complications and increased well-being without causing undue side-effects. [Diabetologia (1996) 39: 1483–1488]

Hypoglycaemic episodes during intensified insulin treatment: increased frequency but no effect on cognitive function

Abstract. Ninety‐seven patients with insulin dependent diabetes mellitus (IDDM) were randomized to intensified conventional treatment (ICT, n = 44) or regular treatment (RT, n = 53). The mean HbA1c level (± SEM) was reduced from 9.5 ± 0.2% to 7.4 ± 0.1% in the ICT group (P < 0.001), and from 9.4 ± 0.2% to 9.0 ± 0.2% (P < 0.01) in the RT group. The difference between the groups was significant (P < 0.001). During a period of 3 years, 57% of the ICT patients (95% confidence interval 44‐73%) and 23% of the RT patients (95% CI, 11‐34%) (P < 0.001) had at least one episode of serious hypoglycaemia, with the need for third‐party assistance or resulting in coma. Eighteen of the 32 ICT patients who initially had adrenergic symptoms during hypoglycaemia changed to predominantly neuroglycopenic symptoms. This was the case with only 8 of 38 RT patients (P < 0.01). The change in symptoms was related to the increased frequency of serious hypoglycaemia, but neither symptoms nor frequency of hypoglycaemia bore any relationship to insulin dose, body mass index, duration of diabetes or autonomic nerve function. The results of several neuropsychological tests did not differ between the groups at baseline, and did not change during the study. There were no signs of deteriorating cognitive function in the patients with serious hypoglycaemic episodes.

Metabolic control and complications over 3 years in patients with insulin dependent diabetes (IDDM): the Stockholm Diabetes Intervention Study (SDIS).

Abstract. In a planned 5‐year study, 97 patients with insulin dependent diabetes mellitus (IDDM), non‐proliferative retinopathy and unsatisfactory blood glucose control were monitored for 3 years. The patients were randomized to an intensified conventional treatment (ICT, n=44) or a regular treatment (RT, n=53) group. HbA1c (normal range 3.9‐5.7%) was reduced from 9.5 ± 0.2 (mean value±SEM) to 7.4 ± 0.1% in the ICT group (P=0.0001), and from 9.4 ± 0.2 to 9.0 ± 0.2% in the RT group (P=0.004). Nerve conduction velocities in the sural and peroneal nerves (P=0.01‐0.0001) were impaired in the RT group, but not in the ICT group. Retinopathy increased in both groups. The condition of 22 ICT patients (50%, 95% confidence interval 34‐66%) and 37 RT patients (73%, 61‐84%) deteriorated with regard to at least one microvascular complication (retinopathy, nephropathy, neuropathy) (P=0.024). Lower HbA1c levels during the study significantly reduced the risk of deterioration (P=0.01). In total, 57% of the ICT patients had at least one episode of serious hypoglycaemia, compared with 23% in the RT group (P=0.001). The patients in the ICT group also gained weight (P=0.0001). Improved blood glucose control slowed down the progression of microangiopathy during a 3‐year period in patients with non‐proliferative retinopathy, but at the price of an increased frequency of serious hypoglycaemic episodes, and some gain in body weight.

Intensified conventional insulin treatment and neuropsychological impairment.

OBJECTIVE--To assess whether intensified insulin treatment, with an increased frequency of hypoglycaemic episodes, leads to cognitive deterioration. DESIGN--Prospective randomised trial of intensified conventional treatment and standard treatment. SETTING--Outpatient clinic for patients with insulin dependent diabetes. SUBJECTS--96 patients with insulin dependent diabetes, high blood glucose concentrations, and non-proliferative retinopathy were randomised to intensified conventional treatment (n = 44) or standard treatment (n = 52). MAIN OUTCOME MEASURES--Glycated haemoglobin concentration (metabolic control); the number of hypoglycaemic episodes reported by patients at each visit; results of computerised neuropsychological tests performed at entry and after five years. RESULTS--Mean glycated haemoglobin concentration during the study was 7.2% (SE 0.1%) with intensified conventional treatment and 8.7 (0.1%) with standard treatment (p less than 0.001). During five years 34 (77%, 95% confidence interval 53% to 100%) of the patients given intensified treatment and 29 (56%, 36% to 75%) of the others had at least one episode of serious hypoglycaemia (p less than 0.05). The intensified conventional treatment group had a mean of 1.1 episodes of serious hypoglycaemia per patient per year compared with 0.4 episodes in the standard treatment group. Results of the neuropsychological tests were similar in the two groups after five years. CONCLUSIONS--Intensified conventional insulin treatment led to lower blood glucose concentrations and a higher frequency of hypoglycaemic episodes, but patients showed no signs of cognitive deterioration.

Capillary Loss and Leakage after Five Years of Intensified Insulin Treatment in Patients with Insulin-dependent Diabetes Mellitus

Ninety-six patients with insulin-dependent diabetes mellitus were randomized to intensified conventional treatment (n = 44) or regular treatment (n = 52) programs and followed for 5 years. Hemoglobin A1c was reduced from 9.5% +/- 0.1% to 7.2% +/- 0.1% in the intensified conventional treatment group and from 9.4% +/- 0.2% to 8.7% +/- 0.1% in the regular treatment group (mean +/- standard error) (P less than 0.001). Capillary loss and leakage of fluorescein as evaluated with fluorescein angiography increased significantly in the regular treatment group (P less than 0.05; P less than 0.01) but not in the intensified conventional treatment group. Capillary loss (P less than 0.01) and leakage (P less than 0.001) were related to metabolic control as measured by Hb A1c but not to duration of diabetes or smoking habits. Capillary loss (P less than 0.05) but not leakage was related to the initial diastolic blood pressure.