Cochrane for Clinicians

Putting Evidence into Practice

Are Alpha-glucosidase Inhibitors Effective for Control of Type 2 Diabetes?

Dan Brewer, M.D., University of Tennessee, Knoxville, Tennessee

The Cochrane Abstract on the next page is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Dan Brewer, M.D., presents a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a full critique of the review.

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been reviewed systematically by an AAFP-approved source. The practice recommendations in this activity are available online at http://www.cochrane.org/reviews/en/ab003639.html.

Clinical Scenario

A 55-year-old man with diabetes has used diet to control his glucose levels for the past six years. His A1C level gradually has risen to 7.5 percent, and he wants to discuss options for medical therapy.

Clinical Question

Is monotherapy with alpha-glucosidase inhibitors effective in reducing complications and improving glucose control in patients with diabetes?

Evidence-Based Answer

The use of alpha-glucosidase inhibitors has a modest effect on intermediate diabetes-control endpoints such as postprandial blood glucose, postprandial insulin levels, and A1C levels. There is no evidence, however, of improvement in mortality, morbidity, or quality of life. In comparisons with sulfonylureas, alpha-glucosidase inhibitors had less effect on intermediate diabetes-control endpoints and had a greater incidence of adverse effects. The use of alpha-glucosidase inhibitors had no effect on plasma lipid levels or body weight.1

Practice Pointers

Guidelines allow patients and physicians to choose from several classes of agents and combinations of agents as initial therapy for type 2 diabetes. Most authorities suggest biguanides (of which metformin [Glucophage] is the only available agent) for patients who are overweight and have no contraindication to that class, but no consensus has been reached on any other specific guidance.2

Alpha-glucosidase inhibitors are considered to be less potent than the other classes of medications that are used for type 2 diabetes; however, alpha-glucosidase inhibitors have fewer potential metabolic side effects.3 They inhibit the absorption of complex carbohydrates and are particularly useful for controlling postprandial glucose elevations, with little effect on fasting glucose levels.

In this Cochrane meta-analysis,1 alpha-glucosidase inhibitors were found to reduce glycated hemoglobin by 0.8 percent when compared with placebo (95% confidence interval, -0.9 to -0.6; 28 comparisons). Alpha-glucosidase inhibitors have been shown to have a very low incidence of hypoglycemia, particularly in comparison with sulfonylureas and insulin.

Long-term compliance with alpha-glucosidase inhibitors is low because of gastrointestinal side effects including flatulence and diarrhea. One study4 found that only 31 percent of patients were still taking the medication after three years.

Patients for whom an alpha-glucosidase inhibitor might be appropriate as initial monotherapy include those who have liver or kidney disease that may be a contraindication to other medications and those at high risk of hypoglycemia. It might also be appropriate for those who would prefer to avoid systemic medications. Alpha- glucosidase inhibitor monotherapy would not be appropriate for patients who have very high A1C levels or for those who have difficulty with medication compliance.

This review1 points out that there is little evidence for mortality reduction, cardiovascular morbidity reduction, or improvement in quality of life with any of the available therapies for type 2 diabetes. Some reduction in cardiovascular morbidity was found among obese patients who received metformin in the U.K. Prospective Diabetes Study.5 As a result of this finding, the International Diabetes Federation has issued a guideline stating that metformin should be the initial drug of choice for all adult patients who have no evidence of renal impairment.2

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The Author

Dan Brewer, M.D., is associate professor in the Department of Family Medicine at the University of Tennessee, Knoxville.

Address correspondence to Dan Brewer, M.D., Department of Family Medicine, University of Tennessee, 1924 Alcoa Highway, Knoxville, TN 37920 (e-mail: dbrewer2@utk.edu). Reprints are not available from the author.

REFERENCES

1. Van de Laar FA, Lucassen PL, Akkermans RP, Van de Lisdonk EH, Rutten GE, Van Weel C. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev 2005;(2):CD003639.

2. IDF Clinical Guidelines Task Force. Global guideline for type 2 diabetes. Brussels: International Diabetes Federation, 2005.

3. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002;287:360-72.

4. Holman RR, Cull CA, Turner RC. A randomized double-blind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years (U.K. Prospective Diabetes Study 44) [published correction appears in Diabetes Care 1999;22:1922]. Diabetes Care 1999;22:960-4.

5. U.K. Prospective Diabetes Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (U.K. Prospective Diabetes Study 34) [published correction appears in Lancet 1998;352:1557]. Lancet 1998;352:854-65.

Cochrane Briefs

MARK EBELL, M.D., M.S.

CLARISSA KRIPKE, M.D.

Gabapentin for Pain: Balancing Benefit and Harm

Clinical Question

Is gabapentin (Neurontin) effective for the treatment of acute and chronic pain?

Evidence-Based Answer

At high dosages, gabapentin is moderately effective for neuropathic pain, although adverse effects are experienced as often as benefit.

Practice Pointers

Gabapentin is widely used for the treatment of pain, particularly in patients with chronic neuropathic pain. Wiffen and colleagues performed a systematic review of randomized trials assessing the use of gabapentin in acute, chronic, or cancer pain, and found 15 studies with a total of 1,468 patients. Only one study involved patients with acute pain. The remainder enrolled patients with postherpetic neuralgia (two studies), diabetic neuropathy (seven studies), or cancer-related pain, phantom limb pain, Guillain-Barré syndrome, spinal cord injury, and various neuropathic pains (one study each).

Gabapentin was found ineffective for acute pain. The studies of neuropathic pain used a wide variety of dosages, typically 900 to 2,400 mg per day, and in one case up to 3,600 mg per day (the maximum recommended dosage according to the package labeling is 1,800 mg per day).

Data could be combined for six studies of neuropathic pain. In these trials, 42 percent of patients improved with gabapentin versus 19 percent with placebo, giving a combined number needed to treat (NNT) of 4 (i.e., four patients must be treated for one patient to experience an improvement in pain). However, adverse effects were common at the high dosages used in these studies, with 24 percent of patients experiencing dizziness, 20 percent somnolence, 10 percent headache, 10 percent diarrhea, and 7 percent confusion. The overall number needed to harm for adverse effects was also 4. Thus, for every patient who experiences a reduction in pain, another experiences an adverse effect.

The modest benefit of gabapentin for neuropathic pain must be balanced against its adverse effects. Whether this trade-off is worthwhile should be decided by the individual patient. The authors of this review report that based on preliminary data tricyclic antidepressants (NNT = 2) and carbamazepine (Tegretol; NNT = 1.7) are at least as effective as gabapentin and are less expensive (although generic gabapentin costs about one half as much as Neurontin). It is important that physicians carefully assess the balance between benefit and harm for their patients after a therapeutic trial rather than continuing a course of medication indefinitely.

Wiffen PJ, et al. Gabapentin for acute and chronic pain. Cochrane Database Syst Rev 2005;(3):CD005452.

Adalimumab for Rheumatoid Arthritis?

Clinical Question

Is adalimumab (Humira) safe and effective for rheumatoid arthritis?

Evidence-Based Answer

Combined with methotrexate, subcutaneous adalimumab at a dosage of 40 mg every two weeks slows the progression of rheumatoid arthritis at one year. The combination is more effective than adalimumab monotherapy. Limited evidence suggests that adalimumab is also safe and effective when combined with other disease-modifying antirheumatic drugs (DMARDs).

Practice Pointers

Management of rheumatoid arthritis has shifted toward initiation of DMARDs within three months of diagnosis.1 Adalimumab is a new anti-tumor necrosis factor (TNF) medication that is similar to etanercept (Enbrel) and infliximab (Remicade). It is approved for reducing symptoms and inhibiting structural-damage progression of rheumatoid arthritis in adults with moderately or severely active rheumatoid arthritis who have had an inadequate response to one or more other DMARDs. Adalimumab can be used alone or in combination with methotrexate or other DMARDs.

To assess the safety and effectiveness of adalimumab, Navarro-Sarabia and colleagues conducted a review of controlled trials of adalimumab compared with placebo as monotherapy or in combination with other drugs. Six trials were included, with a total of 2,381 patients. Improvements were assessed using the American College of Rheumatology (ACR) scores ACR 20, ACR 50, and ACR 70 (representing the percentage improvement in tender and swollen joints, pain, health assessment results, and active phase reactants).2 Results were given in terms of the number of patients needed to receive treatment (NNT) for one patient to have a response.

At 24 weeks, the NNT with adalimumab (40 mg subcutaneously every two weeks) plus methotrexate for one patient to have an ACR 20 improvement ranged from 2 to 5. The NNT for an ACR 50 response ranged from 2 to 6, and the NNT for an ACR 70 improvement ranged from 5 to 13. After 52 weeks, the results were similar. Adalimumab monotherapy also was effective, but the size of the effect was lower. The number of patients needed to be treated to harm one patient with serious infection was 30.

The British Society of Rheumatology guidelines3 state that patients with rheumatoid arthritis are candidates for anti-TNF therapy if they have active, ongoing disease that has failed to respond to two of the following standard DMARD regimens: methotrexate and intramuscular gold, hydroxychloroquine (Plaquenil), sulfasalazine (Azulfidine), penicillamine (Cuprimine), azathioprine (Imuran), or leflunomide (Arava). No anti-TNF therapy has been shown to be more effective than any other. Adverse effects of anti-TNF therapy include serious infection and reactivation of latent tuberculosis. Anti-TNF medications may increase the risk of malignancy, systemic lupus erythematosus, cardiovascular disease, demyelinating or neurologic disease, and hematologic complications.

Management of rheumatoid arthritis is an area of rapidly developing research and changing treatment recommendations, and management decisions generally should be made with a consultant who is following these changes closely.

REFERENCES

1. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum 2002;46:328-46.

2. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727-35.

3. Ledingham J, Deighton C. Update on the British Society for Rheumatology guidelines for prescribing TNFa blockers in adults with rheumatoid arthritis. Rheumatology 2005;44:157-63.

Navarro-Sarabia F, et al. Adalimumab for treating rheumatoid arthritis. Cochrane Database Syst Rev 2005;(3):CD005113.

The series coordinator for AFP is Clarissa Kripke, M.D., Department of Family and Community Medicine, University of California, San Francisco.

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