Long-Term Trials in Type 1 Diabetic Patients
Three pivotal long-term prospective studies that included type 1 diabetic patients either with mild retinopathy or without evidence of diabetic complications have been published (Table 4.1). The results of the Stockholm Diabetes Intervention Study (SDIS) over 10 years [138], the Oslo Study over eight years [139], and the DCCT over five years [140] demonstrate that long-term near-normoglycemia retards the deterioration in motor and sensory NCV. In the DCCT, intensive insulin therapy reduced the appearance of nerve conduction deficits after five years by approximately 50%. The risk for the development of clinical neuropathy was reduced by 64% within five years (5% vs 13% for the intensive therapy [IT] vs the conventional therapy [CT] group) [109]. Most attributes of nerve conduction remained stable or showed modest improvement in patients on IT, whereas they generally deteriorated in those on CT. Among patients in the primary prevention cohort (for retinopathy) without neuropathy at baseline, the IT group had significantly higher NCVs at five years compared with the CT group, the most prominent difference being noted for the peroneal motor NCV, which was 4.1 m/s faster [140]. A comparable effect was observed in the subgroup of patients with possible or definite neuropathy at baseline and in the secondary intervention cohort. Thus, the magnitude of treatment effect was relatively independent of the presence or absence of clinical neuropathy at baseline. Abnormal R-R interval variation at deep breathing as a measure of cardiovascular autonomic neuropathy (CAN) was significantly more frequent in the CT group than the IT group (14.8% vs 7.6%) in the secondary intervention cohort at 5-6 years [141]. The corresponding percentages for any abnormality among R-R interval variation, Valsalva ratio, and postural testing in the secondary intervention cohort at 5-6 years were 16.2% and 8.2%, respectively. These differences were considerably smaller and did not reach statistical significance in the primary prevention cohort. Overall, less than 3% of the DCCT subjects reported symptoms consistent with autonomic dysfunction. Thus, intensive therapy can slow the progression and development of autonomic dysfunction in type 1 diabetic patients with retinopathy.
The Epidemiology of Diabetes Interventions and Complications (EDIC) study, a long-term observational continuation of the DCCT in which the CT patients were offered IT, showed that the reduction in the risk of progressive retinopathy and nephropathy resulting from IT persists for four years, despite a narrowing in the difference in mean HbA1c between the groups, which decreased from 9.1% to 8.2% in the original CT group and increased from 7.2.% to 7.9% in the IT group [142]. However, no data were reported for neuropathy.
In the Oslo Study, a difference in HbA1 of 1% was associated with changes in peroneal motor NCV of 1.2 m/s, in tibial motor NCV of 1.3 m/s, and in sural sensory NCV of 1.4 m/s during the eight-year follow-up period [139], In the SD1S the mean differences in NCV between the IT and CT groups after 10 years were 5.1 m/s for the peroneal nerve. 6.0 m/s for the tibial nerve, and 8.9 m/s for the sural nerve. Pin-prick sensitivity deteriorated significantly in the CT vs the IT groups, and the rates of neuropathic symptoms were 14% vs 32% after 10 years for IT vs CT, respectively [138], However, these studies do not provide information about the reversibility of established nerve conduction deficits. Fur-thermore, in the Oslo Study the original randomization to the three treatment groups was abolished, and the patients were retrospectively allocated to new groups according to their mean HbA1 over eight years. A certain degree of deterioration and development of deficits in NCV was also observed in the well-controlled groups, suggesting that, using the current methods of intensive insulin therapy, complete prevention of neuropathy is difficult to achieve. Moreover, in the DCCT, intensive therapy was associated with a three-fold increased risk of severe hypoglycemia and mean weight gain of 4.6 kg within five years. In the SDIS, a two-fold increased risk of severe hypoglycemia was observed for intensive therapy (Table 4.2).
Long-term Trials In Type 2 Diabetic Patients
The UKPDS showed a lower rate of impaired vibration perception threshold (VPT>25 V) after 15 years for IT with a sulfonylurea or insulin vs CT with diet (31% vs 52%). However, only 217 patients were available for assessment of VPT after 15 years, out of 3836 available at baseline. Thus, a bias due to the small sample size may have influenced this result. Moreover, the only additional time point at which VPT reached a significant difference between IT and CT was the nine-year follow-up, whereas the results after three, six, and 12 years did not differ between the groups. Likewise, the rates of absent knee and ankle reflexes as well as the heart rate responses to deep breathing did not differ between the groups. IT was associated with an increased risk of weight gain and hypoglycemia [110] (Table 4.2).
In the Kumamoto Study of insulin-treated type 2 diabetic patients, after six years NCV in the median motor and sensory nerves was significantly slower in patients given conventional insulin injection therapy (CT) compared with those given multiple insulin injections (IT), but unfortunately NCV was not measured in the lower limbs, where it would be more likely to reflect an effect on polyneuropathy. This is particularly important in view of the fact that VPT in the upper but not the lower limbs was significantly improved in IT as compared with CT. Similar to the findings of the UKPDS. HRV at rest and during deep breathing and posture-related change in blood pressure did not differ between the groups after six years [143]. The 10-year follow-up of the Kumamoto Study showed a relative risk reduction in the progression of clinical neuropathy by 64% in the IT group compared to the CT group. Moreover, IT prolonged the period in which patients were free of clinical neuropathy by 2.2 years, and was more cost-effective, mainly because of reduced costs for management of diabetic complications [144].
In the Steno type 2 Study, intensified multifactorial intervention including the use of intensive diabetes treatment, ACE inhibitors, antioxidants, statins, aspirin, and smoking cessation in patients with microalbuminuria had no effect on the progression of polyneuropathy after 3.8 years. By contrast, a positive effect of this approach was seen on HRV. It cannot be deduced from this study that this effect was due to improved glycemic control, because any of the other interventions, particularly the administration of ACE inhibitors and antioxidants, or even smoking cessation, may have been responsible for this result [145].
In the Veterans Administration Cooperative Study on type 2 diabetes mellitus (VA CSDM), no significant effect of IT (four-step plan of multiple insulin injections) compared to CT (one morning insulin injection per day) on peripheral neuropathy, abnormal Valsalva ratio and/or R-R interval variation, or erectile dysfunction could be demonstrated after two years, despite a difference in HbA1c between the groups comparable with those in the above studies [146].
In conclusion, these trials have shown heterogeneous effects of intensive diabetes therapy on the progression of distal symmetric polyneuropathy and autonomic neuropathy. It cannot be concluded unequivocally from these results that improved glycemic control prevents the development or retards the progression of polyneuropathy in type 2 diabetic patients treated for periods of 2-15 years. In the UKPDS intensive therapy was associated with an increased risk of weight gain and mild or severe hypoglycemia.
Pancreas Transplantation in Type 1 Diabetic Patients
Pancreas transplantation is the most effective method of achieving long-term normoglycemia in type 1 diabetic patients, but is usually limited to patients with end-stage diabetic nephropathy in combination with a renal graft. Other indications have been questioned [147]. Several long-term studies in patients with established diabetic polyneuropathy who underwent successful pancreatic transplantation have been published (Table 4.3). Kennedy et al. [148] have shown that 42 months after transplantation the neuropathy was only slightly improved, but a significant difference was seen in the mean motor and sensory nerve conduction in the transplanted