Diabetic Microvascular Complications: Emerging Therapies for the Second Century of Diabetes Care

Supported by an unrestricted educational grant from Eli Lilly and Company
Sunday, June 6, 2004
7:00 – 9:30 pm

Chair:
Andrew JM Boulton, MD, FRCP

Faculty:
Andrew JM Boulton, MD, FRCP
Richard Donnelly, MD, PhD
Roy Freeman, MD
Rayaz A Malik, MB ChB, PhD

The common pathophysiology, diagnosis, and treatment of diabetic microvascular complications (DMC) was outlined, emphasizing diabetic peripheral neuropathy (DPN) and diabetic retinopathy including diabetic macular edema (DR/DME). The three DMC (DPN, DR/DME, and diabetic nephropathy) often present in a clustered fashion. The microvascular hallmarks of DR/DME are replicated in the peripheral nerve. Pathophysiological studies show evidence of hemorrhage in tissues of the eye, peripheral nerve, and kidney. Evidence of microvascular disease manifests before diagnosis of type 2 diabetes and may occur even earlier in type 1 diabetes. Microvascular disease reduces oxygen delivery to nerve tissue, thereby causing neuropathy. Trandolapril is one of the few therapeutic agents to show partial reversal of signs of DPN.[1] Treatment with a protein kinase C (PKC) β inhibitor, which may act on the vasculature, shows improvement of nerve deficits in clinical trials.[2] Screening for DR/DME is essential to its early detection and treatment and may lead to improved patient outcomes. The choice of screening and examination tools for DR/DME are not as important as a coordinated strategy for detecting, monitoring, and referring patients. Although distal symmetric polyneuropathy is the most common form of DPN, the clinician must not overlook other possible etiologies for limb pain. Quantitative sensory testing (QST) is good for diagnosing the typically highly symptomatic small-fiber manifestations of DPN, but patient cooperation is needed for accurate results.[3] Some questionnaires are useful for assessing the risk of future foot ulceration, but symptom scores cannot be used independently of other diagnostic techniques, since a patient’s neuropathy may worsen, yet the symptoms may improve. Visually inspecting the patient’s feet with shoes and socks removed, explaining findings to the patient as the examination is conducted, is an essential diagnostic and patient educational practice. Apart from intensive glycemic control, agents acting upon the PKC pathway currently offer the most hope for intervention in DR/DME. The specificity of the inhibitory action of ruboxistaurin mesylate, a selective PKC β inhibitor, implies hope for its safety as a therapeutic agent, although clinical trial design for DR/DME has been an enormous challenge.[4] Hyperglycemia is probably the single most important factor in the development of neuropathy. One of the most important take-home messages from the UKPDS is that 11.5% of patients met the criteria for being at high risk of foot ulceration at the time of diagnosis. In patients with well-controlled glycemia, further intensifying glycemic control will not result in improvement in DPN. Tricylic antidepressants (TCA) are still recommended for first-line therapy of painful symptoms of DPN. Gabapentin, approved for the treatment of neuropathic pain in the UK, seems to have efficacy equivalent to TCA, but with a more favorable side-effect profile.[5] NSAIDs should be used with caution in patients who also have nephropathy. Further study is needed to assess the benefits and limitations of lamotrigine for managing symptoms of DPN.[6] Several pathogenetic treatments for DPN are in development. The aldose reductase inhibitor epalrestat, marketed in Japan, alleviates symptoms of DPN, increases nerve conduction velocity, and is safe.[7] Fidarestat, another aldose reductase inhibitor currently in development, appears promising.[8] Several large studies of alpha lipoic acid for pathogenetic and symptomatic treatment of DPN have been performed or are ongoing (ALADIN, DEKAN, SYDNEY).[9-11] Ruboxistaurin ameliorates not only DR/DME but also DPN.[2,4,12,13] In future, we hope we’ll see success with one or more pathogenetic agents for DPN.

References

1. Malik RA, Williamson S, Abbott C, et al. Effect of angiotensin-converting-enzyme (ACE) inhibitor trandolapril on human diabetic neuropathy: randomized double-blind controlled trial. Lancet. 1998;352:1978-1981.
2. Litchy W, Dyck P, Tesfaye S, et al. Diabetic peripheral neuropathy (DPN) assessed by neurological examination (NE) and composite scores (CS) is improved with LY333531 treatment. Diabetes. 2002;51(suppl 2):A197.
3. Shy ME, Frohman EM, So YT, et al. Quantitative sensory testing: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003;60:898-904.
4. Milton RC, Aiello LP, Davis MD, et al. Initial results of the protein kinase C β inhibitor diabetic retinopathy study (PKC-DRS). Diabetologia. 2003;46(suppl 2):A42.
5. Backonja M, Glanzman RL. Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clin Ther. 2003;25:81-104.
6. Eisenberg E, Lurie Y, Braker C, et al. Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology. 2001;57:505-509.
7. Okamoto H, Nomura M, Nakaya Y, et al. Effects of epalrestat, an aldose reductase inhibitor, on diabetic neuropathy and gastroparesis. Intern Med. 2003;42:655-664.
8. Hotta N, Toyota T, Matsuoka K, et al. Clinical efficacy of fidarestat, a novel aldose reductase inhibitor, for diabetic peripheral neuropathy: a 52-week multicenter placebo-controlled double-blind parallel group study. Diabetes Care. 2001;24:1776-1782.
9. Ziegler D, Nowak H, Kempler P, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. 2004;21:114-121.
10. Ziegler D, Schatz H, Conrad F, et al. Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial (DEKAN Study). Deutsche Kardiale Autonome Neuropathie. Diabetes Care. 1997;20:369-373.
11. Ametov AS, Barinov A, Dyck PJ, et al. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care. 2003;26:770-776.
12. Aiello LP, Davis MD, Milton RC, et al. Initial results of the protein kinase C β inhibitor diabetic macular edema study (PKC-DMES). Diabetologia. 2003;46(suppl 2):A42.
13. Vinik AI, Tesfaye, S, Zhang D, et al. LY333531 treatment improves diabetic peripheral neuropathy (DPN) with symptoms. Diabetes. 2002;51(suppl 2):A79.