Managing Diabetic Neuropathy in Primary Care: Aggressive Prevention Is Key

Diabetic neuropathy is the most common complication of diabetes, affecting up to 70% of patients; it is both insidious and underdiagnosed.1 The problem of underdiagnosis is particularly pernicious in type 2 diabetes. Most patients in whom type 2 diabetes is diagnosed in clinical practice do not actually have “new-onset” diabetes; the disease develops slowly over many years. Similarly, type 2 diabetic patients may present with neuropathic symptoms, such as paresthesia, at the time of diagnosis, suggesting that neuropathy develops at an early stage of the disease, perhaps years before laboratory confirmation of hyperglycemia.2 Evidence indicates that diabetic neuropathy is a direct consequence of persistent hyperglycemia, and that prevention is paramount: once it occurs, neuropathic damage is not reversed by current treatments, and symptomatic palliation remains a therapeutic challenge.^2,3

Neuropathic damage can have a devastating impact on quality of life. Almost 50% of all nontraumatic lower-extremity amputations worldwide are caused by diabetes.4 The lifetime risk for amputation in patients with diabetes is estimated to be 10% to 15%, 10 to 30 times higher than the risk for the general population.⁴ In patients with diabetes, peripheral sensory neuropathy and peripheral vascular disease are independent risk factors for lower‑extremity amputations.5

Glycemic control durably reduces the risk for development of diabetic neuropathy

Clinical trials have shown that good glycemic control provides a sustained reduction of risk for development of diabetic neuropathy. The Diabetes Control and Complications Trial (DCCT) compared intensive therapy with standard care on the development of neuropathy in type 1 diabetes.6^,7 At study entry, patients were free of neuropathy, not requiring treatment or medication. Intensive therapy, designed to attain A1C levels in the near-normal range, reduced the risk of developing confirmed clinical neuropathy by 60% to 64% over 6.5 years. Both study cohorts from the DCCT were evaluated annually for a further 8 years in the observational Epidemiology of Diabetes Intervention and Complications (EDIC) study.8 Significant differences were identified in the prevalence of neuropathy at the onset of the EDIC study, favoring intensive therapy over conventional care. The group difference in the prevalence of neuropathy persisted over 8 years of EDIC follow-up, with risk reductions observed for both neuropathic symptoms (51%, P <.0001) and neuropathic signs (43%, P <.0001). Neuropathic risk reduction persisted in the former intensive care cohort even though the A1C levels were almost identical for the intensive and conventional care groups by EDIC study year 8. The value of antecedent glycemic control in reducing the risk for development of neuropathy can be long lasting, as illustrated by the approximately 14 years of follow-up in these studies.

However, it is important to note that at the end of the DCCT, the cumulative incidence of neuropathy (15% to 21%) and abnormal nerve conduction (40% to 52%) was substantial despite relatively good glycemic control (A1C = 7.4%) in the intensive therapy group.⁷ These findings highlighted the crucial importance of rigorous glycemic control (A1C <7.0%) in risk reduction for neuropathy, and also raised the possibility that other risk factors, in addition to hyperglycemia, were involved in the development of neuropathy.

Risk reduction requires an intensive multifactorial approach

Intensive targeting of all modifiable risk factors offers the best approach to risk reduction for diabetic neuropathy. The Steno‑2 clinical trial compared the effects of standard versus intensive multifactorial intervention in subjects with type 2 diabetes and microalbuminuria.9^,10 Intensive therapy included the pharmacologic targeting of hyperglycemia, hypertension, dyslipidemia, and microalbuminuria. All patients were prescribed an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II‑receptor blocker (ARB), irrespective of blood pressure level.

Subjects were followed over 7.8 years. At study end, the decline in A1C levels, systolic and diastolic blood pressure, fasting cholesterol and triglyceride levels, and urinary albumin excretion rate were all significantly greater in the intensive therapy group than in the conventional care group. A1C levels were on average 9.0% for conventional therapy and between 7% and 8% for intensive care. The relative risk reductions for subjects receiving intensive therapy were 61% for nephropathy, 58% for retinopathy, and 63% for autonomic neuropathy. There was no effect of intensified intervention on peripheral sensory neuropathy. Intensive care provided an absolute risk reduction of 20% in cardiovascular disease events. After 7.8 years the number needed to treat to prevent one event was 5.0 for macrovascular complications, 5.3 for diabetic nephropathy, 6.2 for retinopathy progression, and 4.2 for autonomic neuropathy progression.11

Although the majority of subjects in the intensive‑therapy group attained targets for cholesterol (<175 mg/dL), triglycerides (<150 mg/dL), and diastolic blood pressure (<80 mm Hg), only 15% of subjects reached A1C levels <6.5%. These results suggest that intensive control of blood pressure and atherogenic lipids will provide some degree of protection from neuropathy, even if glycemic control is less than ideal.

Modifiable risk factors and prevention of neuropathy were also studied in patients with type 1 diabetes in the European Diabetes Prospective Complications Study.12 Distal symmetric neuropathy was assessed at baseline and at study endpoint, with a follow-up of approximately 7 years. At study conclusion, neuropathy had developed in 23.5% of patients without neuropathy at baseline. The cumulative incidence of neuropathy was related to the A1C value and the duration of diabetes. Patients in whom neuropathy developed had diabetes for 3.3 years longer, and had higher A1C values (8.4% ± 1.9% versus 7.9% ± 1.8%) at baseline than those in whom neuropathy did not develop.

Risk factors significantly associated with the development of neuropathy after adjustment for A1C and duration of diabetes were the presence of hypertension, albuminuria (either microalbuminuria or macroalbuminuria), any retinopathy, history of cardiovascular disease, and history of smoking at baseline. Obesity and elevated triglyceride levels were also associated with the development of neuropathy.

Intensive polypharmaceutical risk reduction for diabetic neuropathy

Early detection and aggressive prevention of diabetic neuropathy should begin at the first office visit of a newly diagnosed patient with type 1 or type 2 diabetes; symptoms should be checked on a yearly basis thereafter. Screening for neuropathy is also advisable in any overweight patient who may be at risk, but not yet diagnosed, for type 2 diabetes. Although achieving tight glycemic control is challenging, modification of other risk factors also contributes to risk reduction for the development of neuropathy. LDL- and HDL‑cholesterol and triglycerides should be treated to American Diabetes Association (ADA) targets.13 ACE inhibitors and/or ARBs should be used aggressively to bring blood pressure within the normotensive range.

Neuropathic complications can be prevented or delayed by sustained glycemic control. In type 2 diabetes, the successive failure of lifestyle modification and oral antihyperglycemic agents burdens patients with prolonged periods of uncontrolled hyperglycemia. To aggressively manage hyperglycemia in type 2 diabetes, the ADA and the European Association for the Study of Diabetes now recommend that the first intervention post-diagnosis should be concurrent metformin therapy and lifestyle modification.14 A1C levels should then be measured no less frequently than every 3 months and dual therapy with antihyperglycemic agents should begin at the first A1C measurement of 7.0% or more. When metabolic goals are not achieved or maintained, the algorithm provided in the guidelines calls for thiazolidinediones, sulfonylureas, or insulin to be added to metformin and lifestyle management. Postprandial glycemic excursions are a frequent phenomenon in actively treated patients with type 2 diabetes and can occur even in the presence of apparently good metabolic control.15 Postprandial hyperglycemia should be suspected and addressed if A1C goals are not met despite adequate control of fasting glucose levels.¹¹ Post-meal hyperglycemia can be targeted with a rapid-acting insulinotropic agent or an incretin mimetic.

The attainment of strict glycemic control has been limited by an increased risk of hypoglycemia. However, the risk for serious hyperglycemia is low when using either a thiazolidinedione or exenatide (incretin mimetic) in combination with metformin. The antihyperglycemic armamentarium should be used at full strength to provide stringent glycemic control, thereby reducing the risk of developing diabetic neuropathy and its irreversible and devastating sequelae.