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What is the best medical therapy for new-onset type 2 diabetes?
Sulfonylureas, metformin, thiazolidinediones, and non-sulfonylurea secretagogues differ little in their ability to decrease glycosylated hemoglobin (HbA1c) levels when used as initial monotherapy for diabetes mellitus type 2 (strength of recommendation [SOR]: A, based on systematic reviews); α-glucosidase inhibitors may also be as effective (SOR: B, based on systematic reviews with inconsistent results). Metformin is generally indicated in obese patients because it improves all-cause mortality and diabetes related outcomes (SOR: B, based on a single high-quality randomized controlled trial [RCT]). Insulin is generally not recommended as an initial agent (SOR: C, expert opinion).
Consider the advantages of each class to best meet your patient’s goals
Vincent Lo, MD
San Joaquin Family Medicine Residency, French Camp, Calif
Lifestyle modification is the cornerstone of initial treatment of type 2 diabetes. However, in clinical practice, medications (monotherapy or combination therapy) are often started along with diet and exercise recommendations. Physicians and patients should clearly understand the treatment goals before initiating therapy. Multiple factors often influence treatment goals, such as presence or absence of symptoms, age-related risks from potential hypoglycemia, degree of hyperglycemia, presence of morbidities (renal insufficiency, heart failure, obesity), cost of the medication, as well as patient or physician preferences. Despite their comparable efficacy in the reduction of HbA1c level, each class of oral hypoglycemic medication has a different mechanism of action and adverse side-effect profile. Therefore, physicians must consider the advantages and disadvantages of each class to choose a medication regimen that best meets their patient’s individual treatment goals.
Evidence summary
Oral agents are commonly prescribed for patients with diabetes mellitus type 2 when diet and exercise fail. Options for initiating therapy include sulfonylureas, metformin (Glucophage), α-glucosidase inhibitors, thiazolidinediones, and nonsulfonylurea secretagogues (repaglinide [Prandin] and nateglinide [Starlix]).
A systematic review with 31 placebo-controlled randomized trials (total n=12,185 patients) evaluated changes in HbA1c with monotherapy using 5 different classes of oral agents ( TABLE ).1 Except for the α-glucosidase inhibitor acarbose (Precose), which was less effective, all agents typically reduced HbA1c by 1% to 2%. However, in an additional 19 out of 23 randomized head-to-head studies (total n=5396) included in the same systematic review, all classes showed equal efficacy.
Head-to-head studies are difficult to compare since hypoglycemic medications may reach peak effects at different times. An RCT compared glimepiride (Amaryl), pioglitazone (Actos), and metformin over 12 months of use by 114 patients with diabetes.3 There was no difference among the groups in overall HbA1c reduction. However, glimepiride decreased HbA1c rapidly over 1 month and reached a nadir at 4 months. Pioglitazone did not reduce HbA1c until 6 months and reached its nadir at 7 to 9 months. Metformin produced an intermediate response.
A meta-analysis of head to head studies involving α-glucosidase inhibitors included 8 trials comparing acarbose with sulfonylureas. In pooled results, sulfonylureas trended towards greater HbA1c reduction but did not reach significance (additional HbA1c decrease 0.4%; 95% confidence interval [CI], 0%–0.8%).4
A meta-analysis of head-to-head studies involving metformin showed equal efficacy compared with injected insulin (2 trials, 811 participants), α-glucosidase inhibitors (2 trials, 223 participants), and non-sulfonylurea secretagogues (2 trials, 413 participants).5 In 12 trials with 2067 patients, metformin decreased HbA1c more than sulfonylureas did (standardized mean difference [SMD] –0.14; 95% CI, –0.28 to –0.01). In 3 trials with 246 patients, metformin also produced greater HbA1c decreases than thiazolidinediones (SMD –0.28; 95% CI, –0.52 to –0.03). In the United Kingdom Prospective Diabetes Study (UKPDS), metformin improved diabetes-related outcomes and all-cause mortality in obese patients (relative risk of mortality=0.73; 95% CI, 0.55–0.97; P=.03; number needed to treat [NNT]=19).6
A systematic review with 22 RCTs (total n=7370), ranging in length from 12 weeks to 3 years, compared 2 oral agents with a single oral agent or placebo.1 Combinations of oral agents produced statistically significant additional improvement in HbA1c in 21 of 22 studies. The magnitude of this effect across the studies was on the order of a 1% change in HbA1c, although the data were not subject to a formal meta-analysis.
Inhaled insulin may expand the list of initial therapies for type 2 diabetes. A 12-week manufacturer-sponsored RCT with 134 patients (mean HbA1c=9.5) compared inhaled insulin with rosiglitazone (Avandia).7 More patients using inhaled insulin achieved an HbA1c <8.0 (82.7% vs 58.2%; P=.0003); however, inhaled insulin produced more adverse effects, including cough and hypoglycemia.
TABLE
Oral medications as monotherapy in type 2 diabetes mellitus1,2
| CLASS | DOSING INTERVAL | TYPICAL HBA1C REDUCTION | COST * PER MONTH† | CONTRAINDICATIONS/CAUTIONS |
|---|---|---|---|---|
| Sulfonylureas | 1x daily | 1.4%–1.8% | $ | DKA, caution in hepatic or renal disease |
| Metformin | 1–2x daily | 1.1%–2.0% | $$ | Congestive heart failure, acute or chronic metabolic acidosis, Cr ≥1.5 male, Cr ≥1.4 female, COPD, severe hepatic disease, alcoholism. Use caution in the elderly. |
| α-glucosidase inhibitors | 3x daily | 0.6%–1.0% | $$$ | Cr ≥2.0, abnormal baseline liver function tests, inflammatory bowel disease |
| Thiazolidinediones | 1–2x daily | 1.5%–1.6% | $$$–$$$$ | Class III to IV heart failure, baseline ALT >2.5 |
| Non-sulfonylurea secretagogues | 3x daily | 1.8%–1.9% | $$–$$$ | Caution with liver disease |
| * The “typical” range excludes the studies with the highest and lowest measured effects. | ||||
| † $ = $0 to $25; $$ = $25 to $60; $$$ = $60 to $120; $$$$ = $120 to $180. | ||||
| DKA, diabetic ketoacidosis; Cr, chromium; COPD, chronic obstructive pulmonary disease; ALT, alanine transaminease. | ||||
Recommendations from others
The International Diabetes Federation (IDF) recommends metformin as the initial oral agent unless contraindicated.8 A sulfonylurea is an acceptable alternative in patients who are not overweight. The IDF states that insulin should be added when oral agents fail.
The Institute for Clinical Systems Improvement (ICSI) says that the “single best choice drug for oral agent therapy for type 2 diabetes has not been determined” and must be chosen in the context of age, weight, and other comorbidities.9 The ICSI suggests metformin as an appropriate first agent for obese patients and recommends sulfonylureas or metformin as monotherapy for others because they are both economical and well tolerated. The American Diabetes Association does not specifically recommend a best initial agent or combination of agents for type 2 diabetes.10
1. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes. JAMA 2002;287:360-372.
2. Epocrates Drug Database. Available at: www2.epocrates.com/index.html. Accessed on May 18, 2006.
3. Yamanouchi T, Sakai T, Igarashi K, Ichiyanagi K, Watanabe H, Kawasaki T. Comparison of metabolic effects of pioglitazone, metformin, and glimepiride over 1 year in Japanese patients with newly diagnosed Type 2 diabetes. Diabetic Med 2005;22:980-985.
4. Van de Laar FA, Lucassen PLBJ, Akkermans RP, Van de Lisdonk EH, Rutten GEHM, Can Weel C. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev 2005, Issue 2.
5. Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev 2005, Issue 3.
6. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS34). Lancet 1998;352:854-865.
7. DeFronzo RA, Bergenstal RM, Cefalu WT, et al. Efficacy of inhaled insulin in patients with type 2 diabetes not controlled with diet and exercise. Diabetes Care 2005;28:1922-1928.
8. IDF Clinical Guidelines Task Force. Global guideline for Type 2 diabetes. Brussels: International Diabetes Federation, 2005.
9. Institute for Clinical Systems Improvement (ICSI). Management of type 2 diabetes mellitus. Bloomington, Minn: Institute for Clinical Systems Improvement (ICSI); 2005 Nov. 79 p.
10. American Diabetes Association. Standard of medical care in diabetes-2006. Diabetes Care 2006;29:S4-S42.
Sulfonylureas, metformin, thiazolidinediones, and non-sulfonylurea secretagogues differ little in their ability to decrease glycosylated hemoglobin (HbA1c) levels when used as initial monotherapy for diabetes mellitus type 2 (strength of recommendation [SOR]: A, based on systematic reviews); α-glucosidase inhibitors may also be as effective (SOR: B, based on systematic reviews with inconsistent results). Metformin is generally indicated in obese patients because it improves all-cause mortality and diabetes related outcomes (SOR: B, based on a single high-quality randomized controlled trial [RCT]). Insulin is generally not recommended as an initial agent (SOR: C, expert opinion).
Consider the advantages of each class to best meet your patient’s goals
Vincent Lo, MD
San Joaquin Family Medicine Residency, French Camp, Calif
Lifestyle modification is the cornerstone of initial treatment of type 2 diabetes. However, in clinical practice, medications (monotherapy or combination therapy) are often started along with diet and exercise recommendations. Physicians and patients should clearly understand the treatment goals before initiating therapy. Multiple factors often influence treatment goals, such as presence or absence of symptoms, age-related risks from potential hypoglycemia, degree of hyperglycemia, presence of morbidities (renal insufficiency, heart failure, obesity), cost of the medication, as well as patient or physician preferences. Despite their comparable efficacy in the reduction of HbA1c level, each class of oral hypoglycemic medication has a different mechanism of action and adverse side-effect profile. Therefore, physicians must consider the advantages and disadvantages of each class to choose a medication regimen that best meets their patient’s individual treatment goals.
Evidence summary
Oral agents are commonly prescribed for patients with diabetes mellitus type 2 when diet and exercise fail. Options for initiating therapy include sulfonylureas, metformin (Glucophage), α-glucosidase inhibitors, thiazolidinediones, and nonsulfonylurea secretagogues (repaglinide [Prandin] and nateglinide [Starlix]).
A systematic review with 31 placebo-controlled randomized trials (total n=12,185 patients) evaluated changes in HbA1c with monotherapy using 5 different classes of oral agents ( TABLE ).1 Except for the α-glucosidase inhibitor acarbose (Precose), which was less effective, all agents typically reduced HbA1c by 1% to 2%. However, in an additional 19 out of 23 randomized head-to-head studies (total n=5396) included in the same systematic review, all classes showed equal efficacy.
Head-to-head studies are difficult to compare since hypoglycemic medications may reach peak effects at different times. An RCT compared glimepiride (Amaryl), pioglitazone (Actos), and metformin over 12 months of use by 114 patients with diabetes.3 There was no difference among the groups in overall HbA1c reduction. However, glimepiride decreased HbA1c rapidly over 1 month and reached a nadir at 4 months. Pioglitazone did not reduce HbA1c until 6 months and reached its nadir at 7 to 9 months. Metformin produced an intermediate response.
A meta-analysis of head to head studies involving α-glucosidase inhibitors included 8 trials comparing acarbose with sulfonylureas. In pooled results, sulfonylureas trended towards greater HbA1c reduction but did not reach significance (additional HbA1c decrease 0.4%; 95% confidence interval [CI], 0%–0.8%).4
A meta-analysis of head-to-head studies involving metformin showed equal efficacy compared with injected insulin (2 trials, 811 participants), α-glucosidase inhibitors (2 trials, 223 participants), and non-sulfonylurea secretagogues (2 trials, 413 participants).5 In 12 trials with 2067 patients, metformin decreased HbA1c more than sulfonylureas did (standardized mean difference [SMD] –0.14; 95% CI, –0.28 to –0.01). In 3 trials with 246 patients, metformin also produced greater HbA1c decreases than thiazolidinediones (SMD –0.28; 95% CI, –0.52 to –0.03). In the United Kingdom Prospective Diabetes Study (UKPDS), metformin improved diabetes-related outcomes and all-cause mortality in obese patients (relative risk of mortality=0.73; 95% CI, 0.55–0.97; P=.03; number needed to treat [NNT]=19).6
A systematic review with 22 RCTs (total n=7370), ranging in length from 12 weeks to 3 years, compared 2 oral agents with a single oral agent or placebo.1 Combinations of oral agents produced statistically significant additional improvement in HbA1c in 21 of 22 studies. The magnitude of this effect across the studies was on the order of a 1% change in HbA1c, although the data were not subject to a formal meta-analysis.
Inhaled insulin may expand the list of initial therapies for type 2 diabetes. A 12-week manufacturer-sponsored RCT with 134 patients (mean HbA1c=9.5) compared inhaled insulin with rosiglitazone (Avandia).7 More patients using inhaled insulin achieved an HbA1c <8.0 (82.7% vs 58.2%; P=.0003); however, inhaled insulin produced more adverse effects, including cough and hypoglycemia.
TABLE
Oral medications as monotherapy in type 2 diabetes mellitus1,2
| CLASS | DOSING INTERVAL | TYPICAL HBA1C REDUCTION | COST * PER MONTH† | CONTRAINDICATIONS/CAUTIONS |
|---|---|---|---|---|
| Sulfonylureas | 1x daily | 1.4%–1.8% | $ | DKA, caution in hepatic or renal disease |
| Metformin | 1–2x daily | 1.1%–2.0% | $$ | Congestive heart failure, acute or chronic metabolic acidosis, Cr ≥1.5 male, Cr ≥1.4 female, COPD, severe hepatic disease, alcoholism. Use caution in the elderly. |
| α-glucosidase inhibitors | 3x daily | 0.6%–1.0% | $$$ | Cr ≥2.0, abnormal baseline liver function tests, inflammatory bowel disease |
| Thiazolidinediones | 1–2x daily | 1.5%–1.6% | $$$–$$$$ | Class III to IV heart failure, baseline ALT >2.5 |
| Non-sulfonylurea secretagogues | 3x daily | 1.8%–1.9% | $$–$$$ | Caution with liver disease |
| * The “typical” range excludes the studies with the highest and lowest measured effects. | ||||
| † $ = $0 to $25; $$ = $25 to $60; $$$ = $60 to $120; $$$$ = $120 to $180. | ||||
| DKA, diabetic ketoacidosis; Cr, chromium; COPD, chronic obstructive pulmonary disease; ALT, alanine transaminease. | ||||
Recommendations from others
The International Diabetes Federation (IDF) recommends metformin as the initial oral agent unless contraindicated.8 A sulfonylurea is an acceptable alternative in patients who are not overweight. The IDF states that insulin should be added when oral agents fail.
The Institute for Clinical Systems Improvement (ICSI) says that the “single best choice drug for oral agent therapy for type 2 diabetes has not been determined” and must be chosen in the context of age, weight, and other comorbidities.9 The ICSI suggests metformin as an appropriate first agent for obese patients and recommends sulfonylureas or metformin as monotherapy for others because they are both economical and well tolerated. The American Diabetes Association does not specifically recommend a best initial agent or combination of agents for type 2 diabetes.10
Sulfonylureas, metformin, thiazolidinediones, and non-sulfonylurea secretagogues differ little in their ability to decrease glycosylated hemoglobin (HbA1c) levels when used as initial monotherapy for diabetes mellitus type 2 (strength of recommendation [SOR]: A, based on systematic reviews); α-glucosidase inhibitors may also be as effective (SOR: B, based on systematic reviews with inconsistent results). Metformin is generally indicated in obese patients because it improves all-cause mortality and diabetes related outcomes (SOR: B, based on a single high-quality randomized controlled trial [RCT]). Insulin is generally not recommended as an initial agent (SOR: C, expert opinion).
Consider the advantages of each class to best meet your patient’s goals
Vincent Lo, MD
San Joaquin Family Medicine Residency, French Camp, Calif
Lifestyle modification is the cornerstone of initial treatment of type 2 diabetes. However, in clinical practice, medications (monotherapy or combination therapy) are often started along with diet and exercise recommendations. Physicians and patients should clearly understand the treatment goals before initiating therapy. Multiple factors often influence treatment goals, such as presence or absence of symptoms, age-related risks from potential hypoglycemia, degree of hyperglycemia, presence of morbidities (renal insufficiency, heart failure, obesity), cost of the medication, as well as patient or physician preferences. Despite their comparable efficacy in the reduction of HbA1c level, each class of oral hypoglycemic medication has a different mechanism of action and adverse side-effect profile. Therefore, physicians must consider the advantages and disadvantages of each class to choose a medication regimen that best meets their patient’s individual treatment goals.
Evidence summary
Oral agents are commonly prescribed for patients with diabetes mellitus type 2 when diet and exercise fail. Options for initiating therapy include sulfonylureas, metformin (Glucophage), α-glucosidase inhibitors, thiazolidinediones, and nonsulfonylurea secretagogues (repaglinide [Prandin] and nateglinide [Starlix]).
A systematic review with 31 placebo-controlled randomized trials (total n=12,185 patients) evaluated changes in HbA1c with monotherapy using 5 different classes of oral agents ( TABLE ).1 Except for the α-glucosidase inhibitor acarbose (Precose), which was less effective, all agents typically reduced HbA1c by 1% to 2%. However, in an additional 19 out of 23 randomized head-to-head studies (total n=5396) included in the same systematic review, all classes showed equal efficacy.
Head-to-head studies are difficult to compare since hypoglycemic medications may reach peak effects at different times. An RCT compared glimepiride (Amaryl), pioglitazone (Actos), and metformin over 12 months of use by 114 patients with diabetes.3 There was no difference among the groups in overall HbA1c reduction. However, glimepiride decreased HbA1c rapidly over 1 month and reached a nadir at 4 months. Pioglitazone did not reduce HbA1c until 6 months and reached its nadir at 7 to 9 months. Metformin produced an intermediate response.
A meta-analysis of head to head studies involving α-glucosidase inhibitors included 8 trials comparing acarbose with sulfonylureas. In pooled results, sulfonylureas trended towards greater HbA1c reduction but did not reach significance (additional HbA1c decrease 0.4%; 95% confidence interval [CI], 0%–0.8%).4
A meta-analysis of head-to-head studies involving metformin showed equal efficacy compared with injected insulin (2 trials, 811 participants), α-glucosidase inhibitors (2 trials, 223 participants), and non-sulfonylurea secretagogues (2 trials, 413 participants).5 In 12 trials with 2067 patients, metformin decreased HbA1c more than sulfonylureas did (standardized mean difference [SMD] –0.14; 95% CI, –0.28 to –0.01). In 3 trials with 246 patients, metformin also produced greater HbA1c decreases than thiazolidinediones (SMD –0.28; 95% CI, –0.52 to –0.03). In the United Kingdom Prospective Diabetes Study (UKPDS), metformin improved diabetes-related outcomes and all-cause mortality in obese patients (relative risk of mortality=0.73; 95% CI, 0.55–0.97; P=.03; number needed to treat [NNT]=19).6
A systematic review with 22 RCTs (total n=7370), ranging in length from 12 weeks to 3 years, compared 2 oral agents with a single oral agent or placebo.1 Combinations of oral agents produced statistically significant additional improvement in HbA1c in 21 of 22 studies. The magnitude of this effect across the studies was on the order of a 1% change in HbA1c, although the data were not subject to a formal meta-analysis.
Inhaled insulin may expand the list of initial therapies for type 2 diabetes. A 12-week manufacturer-sponsored RCT with 134 patients (mean HbA1c=9.5) compared inhaled insulin with rosiglitazone (Avandia).7 More patients using inhaled insulin achieved an HbA1c <8.0 (82.7% vs 58.2%; P=.0003); however, inhaled insulin produced more adverse effects, including cough and hypoglycemia.
TABLE
Oral medications as monotherapy in type 2 diabetes mellitus1,2
| CLASS | DOSING INTERVAL | TYPICAL HBA1C REDUCTION | COST * PER MONTH† | CONTRAINDICATIONS/CAUTIONS |
|---|---|---|---|---|
| Sulfonylureas | 1x daily | 1.4%–1.8% | $ | DKA, caution in hepatic or renal disease |
| Metformin | 1–2x daily | 1.1%–2.0% | $$ | Congestive heart failure, acute or chronic metabolic acidosis, Cr ≥1.5 male, Cr ≥1.4 female, COPD, severe hepatic disease, alcoholism. Use caution in the elderly. |
| α-glucosidase inhibitors | 3x daily | 0.6%–1.0% | $$$ | Cr ≥2.0, abnormal baseline liver function tests, inflammatory bowel disease |
| Thiazolidinediones | 1–2x daily | 1.5%–1.6% | $$$–$$$$ | Class III to IV heart failure, baseline ALT >2.5 |
| Non-sulfonylurea secretagogues | 3x daily | 1.8%–1.9% | $$–$$$ | Caution with liver disease |
| * The “typical” range excludes the studies with the highest and lowest measured effects. | ||||
| † $ = $0 to $25; $$ = $25 to $60; $$$ = $60 to $120; $$$$ = $120 to $180. | ||||
| DKA, diabetic ketoacidosis; Cr, chromium; COPD, chronic obstructive pulmonary disease; ALT, alanine transaminease. | ||||
Recommendations from others
The International Diabetes Federation (IDF) recommends metformin as the initial oral agent unless contraindicated.8 A sulfonylurea is an acceptable alternative in patients who are not overweight. The IDF states that insulin should be added when oral agents fail.
The Institute for Clinical Systems Improvement (ICSI) says that the “single best choice drug for oral agent therapy for type 2 diabetes has not been determined” and must be chosen in the context of age, weight, and other comorbidities.9 The ICSI suggests metformin as an appropriate first agent for obese patients and recommends sulfonylureas or metformin as monotherapy for others because they are both economical and well tolerated. The American Diabetes Association does not specifically recommend a best initial agent or combination of agents for type 2 diabetes.10
1. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes. JAMA 2002;287:360-372.
2. Epocrates Drug Database. Available at: www2.epocrates.com/index.html. Accessed on May 18, 2006.
3. Yamanouchi T, Sakai T, Igarashi K, Ichiyanagi K, Watanabe H, Kawasaki T. Comparison of metabolic effects of pioglitazone, metformin, and glimepiride over 1 year in Japanese patients with newly diagnosed Type 2 diabetes. Diabetic Med 2005;22:980-985.
4. Van de Laar FA, Lucassen PLBJ, Akkermans RP, Van de Lisdonk EH, Rutten GEHM, Can Weel C. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev 2005, Issue 2.
5. Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev 2005, Issue 3.
6. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS34). Lancet 1998;352:854-865.
7. DeFronzo RA, Bergenstal RM, Cefalu WT, et al. Efficacy of inhaled insulin in patients with type 2 diabetes not controlled with diet and exercise. Diabetes Care 2005;28:1922-1928.
8. IDF Clinical Guidelines Task Force. Global guideline for Type 2 diabetes. Brussels: International Diabetes Federation, 2005.
9. Institute for Clinical Systems Improvement (ICSI). Management of type 2 diabetes mellitus. Bloomington, Minn: Institute for Clinical Systems Improvement (ICSI); 2005 Nov. 79 p.
10. American Diabetes Association. Standard of medical care in diabetes-2006. Diabetes Care 2006;29:S4-S42.
1. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes. JAMA 2002;287:360-372.
2. Epocrates Drug Database. Available at: www2.epocrates.com/index.html. Accessed on May 18, 2006.
3. Yamanouchi T, Sakai T, Igarashi K, Ichiyanagi K, Watanabe H, Kawasaki T. Comparison of metabolic effects of pioglitazone, metformin, and glimepiride over 1 year in Japanese patients with newly diagnosed Type 2 diabetes. Diabetic Med 2005;22:980-985.
4. Van de Laar FA, Lucassen PLBJ, Akkermans RP, Van de Lisdonk EH, Rutten GEHM, Can Weel C. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev 2005, Issue 2.
5. Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev 2005, Issue 3.
6. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS34). Lancet 1998;352:854-865.
7. DeFronzo RA, Bergenstal RM, Cefalu WT, et al. Efficacy of inhaled insulin in patients with type 2 diabetes not controlled with diet and exercise. Diabetes Care 2005;28:1922-1928.
8. IDF Clinical Guidelines Task Force. Global guideline for Type 2 diabetes. Brussels: International Diabetes Federation, 2005.
9. Institute for Clinical Systems Improvement (ICSI). Management of type 2 diabetes mellitus. Bloomington, Minn: Institute for Clinical Systems Improvement (ICSI); 2005 Nov. 79 p.
10. American Diabetes Association. Standard of medical care in diabetes-2006. Diabetes Care 2006;29:S4-S42.
Evidence-based answers from the Family Physicians Inquiries Network
What treatments are safe and effective for mild to moderate hypertension in pregnancy?
There is considerable debate concerning the treatment of mild to moderate essential hypertension during pregnancy. Evidence suggests that because of the potential risk of fetal intrauterine growth restriction, treatment of hypertension should be delayed until maternal blood pressure reaches 150–160 mm Hg systolic or 100–110 mm Hg diastolic, as long as the mother has no preexisting end organ damage.
Methyldopa has been the drug of choice for oral treatment, as it is the only medication to have any extended follow-up study. However, a recent meta-analysis raised the possibility of increased fetal mortality (strength of recommendation [SOR]: A, based on systematic review of randomized controlled trials).
Labetalol is an effective alternative, but concerns remain that treatment with any beta-blocker increases the risk that infants will be small for gestational age (SGA) (SOR: B, based on small randomized controlled trials with inconsistent results).
There is limited evidence that calcium channel blockers and diuretics are safe alternatives, although evidence is insufficient to prove a clear benefit (SOR: B, based on limited randomized controlled trials). Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), due to similar mechanisms of action, are contraindicated in pregnancy (SOR: B, based on multiple case studies). No other class of anti-hypertensive medications is proven to be harmful in pregnancy.
Evidence summary
Treatment of maternal hypertension during pregnancy is based on maternal and fetal outcomes. Multiple meta-analyses of randomized controlled trials show that the major maternal outcomes improved by treating mild to moderate hypertension are decreased progression to severe hypertension (number needed to treat [NNT]=12; 95% confidence interval [CI], 9–17) and decreased need for additional antihypertensive therapy.1,2 The relative risk (RR) for preventing preeclampsia was 0.99 (95% CI, 0.84–1.18). The risk of preterm delivery was 1.00 (95% CI, 0.87–1.15).
The data for fetal outcomes are important, as the maternal benefits of treatment remain small.3 Much of the debate centers on decreasing uteroplacental perfusion, which may lead to decreased fetal growth. One meta-analysis reviewed 45 trials to evaluate the potential increase in SGA infants caused by any antihypertensive treatment, through quantifying the fall in mean arterial pressure. The analysis found an average decrease in birthweight of 145 g for a 10 mm Hg fall in mean arterial pressurewith no increased perinatal morbidity.4 The clinical significance of this is unclear.
In comparing one agent with another, methyldopa was the most commonly tested agent, with 14 randomized controlled trials of more than 1010 subjects demonstrating its efficacy at reducing blood pressure. Other antihypertensive agents appear better than methyldopa in terms of reducing the risk of infant mortality (RR=0.49; 95% CI, 0.24–0.99),1 but the studies were small and used weak methods, and this finding may be due to bias.5 Meta-analyses of beta-blocker trials show a borderline increase in SGA infants, with no related increase in perinatal mortality, as well as a decrease in the incidence of respiratory distress syndrome.6
Diuretics are effective antihypertensives, especially when combined with other agents, but they are known to decrease the circulating plasma volume, potentially decreasing uteroplacental perfusion. They are generally viewed as safe, as long as the mother is not already at increased risk for perfusion abnormalities (eg, preeclamptic states).7 Calcium channel blockers, though generally regarded as safe and effective, have mostly been evaluated for use late in pregnancy, so their benefit-to-risk ratio remains uncertain.8ACE inhibitors and, by extension, ARBs, due to their similar mechanisms of action, are contraindicated in pregnancy, having been linked to miscarriage, fetal death, fetal renal failure, and malformation.5,9-11
Recommendations from others
The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin states there is no evidence that antihypertensive treatment for mild to moderate hypertension improves maternal or fetal outcomes, even for women who are already receiving hypertension treatment at the time of pregnancy. ACOG suggests treatment may be stopped during pregnancy, or not initiated until blood pressures reach 150–160 mm Hg systolic or 100–110 mm Hg diastolic, unless the mother has underlying renal or cardiovascular disease.9
The National High Blood Pressure Education Program recommends the same guidelines as ACOG,10 whereas the Canadian Hypertension Society consensus panel has chosen 140/90 mm Hg as the level at which treatment should be initiated.11
The British Medical Journal Clinical Evidence Guidelines reiterate that the evidence does not support the benefit of treating mild to moderate hypertension, except in reducing the progression to severe hypertension.5 Methyldopa is consistently the drug of choice in all those making a specific recommendation,9-11 although it should be noted these recommendations were published before the 2003 Cochrane Review.1
Benefits from treatment do not outweigh risks unless maternal BP moderately high
James Holt, MD
East Tennessee State University, Johnson City
I have always felt uneasy with treatment of mild to moderate hypertension in pregnancy, as chronic hypertension must be differentiated from preeclampsia; and the treatments seem counterintuitive. I often see new obstetric patients well into the third trimester, and how I should initially treat an elevated blood pressure has been unclear. Adding the welfare of the unborn baby raises the stakes further.
This Clinical Inquiry helps my decision about initiating treatment, as the benefits from treatment do not outweigh the risks to mother and fetus unless the maternal blood pressure is moderately high, and the recommended thresholds for treatment are rather high for women with no end organ damage. If I must treat her, it appears the best (but not perfect) option is methyldopa.
1. Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev 2003;(1):CD002252.-
2. Magee LA, Duley L. Oral beta blockers for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev. 2003;(1):CD002863.-
3. Ferrer RL, Sibai BM, Mulrow CD, Chiquette E, Stevens KR, Cornell J. Management of mild chronic hypertension during pregnancy: a review. Obstet Gynecol 2000;96:849-860.
4. von Dadelszen P, Ornstein MP, Bull SB, Logan AG, Koren G, Magee LA. Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis. Lancet 2000;355:87-92.
5. Duley L. Childbirth and pregnancy—pre-eclampsia and hypertension. Clin Evid [online], Issue 9, August 2003. London: BMJ Publishing Group; 2003. Available at: clinicalevidence.com. Accessed on August 29, 2003.
6. Magee LA, Elran E, Bull SB, Logan A, Koren G. Risks and benefits of beta-receptor blockers for pregnancy hypertension: overview of the randomized trials. Eur J Obstet Gynecol Reprod Biol 2000;88:15-26.
7. Management of Chronic Hypertension During Pregnancy. Evidence Report/Technology Assessment: Number 14. AHRQ Publication No. 00-E010, August 2000. Rockville, Md: Agency for Healthcare Research and Quality; 2000. Available at: www.ahrq.gov/clinic/epcsums/pregsum.htm. Accessed on May 5, 2004.
8. Magee LA, Ornstein MP, von Dadelszen P. Fortnightly review: management of hypertension in pregnancy. BMJ 1999;318:1332-1336.
9. Gilstrap LC, Ramin SM. ACOG Practice Bulletin No. 29: Chronic hypertension in pregnancy. Obstet Gynecol 2001;98:177-185.
10. National. Heart Lung and Blood Institute. National High Blood Pressure Education Program: Working Group Report on High Blood Pressure in Pregnancy. Bethesda, Md: NHLBI; 2000. Available at: www.nhlbi.nih.gov/health/prof/heart/hbp/hbp_preg.pdf. Accessed on May 5, 2004.
11. Rey E, LeLorier J, Burgess E, Lange IR, Leduc L. Report of Canadian Hypertension Society Consensus Conference: 3. Pharmacologic treatment of hypertensive disorders in pregnancy. CMAJ 1997;157:1245-1254.
There is considerable debate concerning the treatment of mild to moderate essential hypertension during pregnancy. Evidence suggests that because of the potential risk of fetal intrauterine growth restriction, treatment of hypertension should be delayed until maternal blood pressure reaches 150–160 mm Hg systolic or 100–110 mm Hg diastolic, as long as the mother has no preexisting end organ damage.
Methyldopa has been the drug of choice for oral treatment, as it is the only medication to have any extended follow-up study. However, a recent meta-analysis raised the possibility of increased fetal mortality (strength of recommendation [SOR]: A, based on systematic review of randomized controlled trials).
Labetalol is an effective alternative, but concerns remain that treatment with any beta-blocker increases the risk that infants will be small for gestational age (SGA) (SOR: B, based on small randomized controlled trials with inconsistent results).
There is limited evidence that calcium channel blockers and diuretics are safe alternatives, although evidence is insufficient to prove a clear benefit (SOR: B, based on limited randomized controlled trials). Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), due to similar mechanisms of action, are contraindicated in pregnancy (SOR: B, based on multiple case studies). No other class of anti-hypertensive medications is proven to be harmful in pregnancy.
Evidence summary
Treatment of maternal hypertension during pregnancy is based on maternal and fetal outcomes. Multiple meta-analyses of randomized controlled trials show that the major maternal outcomes improved by treating mild to moderate hypertension are decreased progression to severe hypertension (number needed to treat [NNT]=12; 95% confidence interval [CI], 9–17) and decreased need for additional antihypertensive therapy.1,2 The relative risk (RR) for preventing preeclampsia was 0.99 (95% CI, 0.84–1.18). The risk of preterm delivery was 1.00 (95% CI, 0.87–1.15).
The data for fetal outcomes are important, as the maternal benefits of treatment remain small.3 Much of the debate centers on decreasing uteroplacental perfusion, which may lead to decreased fetal growth. One meta-analysis reviewed 45 trials to evaluate the potential increase in SGA infants caused by any antihypertensive treatment, through quantifying the fall in mean arterial pressure. The analysis found an average decrease in birthweight of 145 g for a 10 mm Hg fall in mean arterial pressurewith no increased perinatal morbidity.4 The clinical significance of this is unclear.
In comparing one agent with another, methyldopa was the most commonly tested agent, with 14 randomized controlled trials of more than 1010 subjects demonstrating its efficacy at reducing blood pressure. Other antihypertensive agents appear better than methyldopa in terms of reducing the risk of infant mortality (RR=0.49; 95% CI, 0.24–0.99),1 but the studies were small and used weak methods, and this finding may be due to bias.5 Meta-analyses of beta-blocker trials show a borderline increase in SGA infants, with no related increase in perinatal mortality, as well as a decrease in the incidence of respiratory distress syndrome.6
Diuretics are effective antihypertensives, especially when combined with other agents, but they are known to decrease the circulating plasma volume, potentially decreasing uteroplacental perfusion. They are generally viewed as safe, as long as the mother is not already at increased risk for perfusion abnormalities (eg, preeclamptic states).7 Calcium channel blockers, though generally regarded as safe and effective, have mostly been evaluated for use late in pregnancy, so their benefit-to-risk ratio remains uncertain.8ACE inhibitors and, by extension, ARBs, due to their similar mechanisms of action, are contraindicated in pregnancy, having been linked to miscarriage, fetal death, fetal renal failure, and malformation.5,9-11
Recommendations from others
The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin states there is no evidence that antihypertensive treatment for mild to moderate hypertension improves maternal or fetal outcomes, even for women who are already receiving hypertension treatment at the time of pregnancy. ACOG suggests treatment may be stopped during pregnancy, or not initiated until blood pressures reach 150–160 mm Hg systolic or 100–110 mm Hg diastolic, unless the mother has underlying renal or cardiovascular disease.9
The National High Blood Pressure Education Program recommends the same guidelines as ACOG,10 whereas the Canadian Hypertension Society consensus panel has chosen 140/90 mm Hg as the level at which treatment should be initiated.11
The British Medical Journal Clinical Evidence Guidelines reiterate that the evidence does not support the benefit of treating mild to moderate hypertension, except in reducing the progression to severe hypertension.5 Methyldopa is consistently the drug of choice in all those making a specific recommendation,9-11 although it should be noted these recommendations were published before the 2003 Cochrane Review.1
Benefits from treatment do not outweigh risks unless maternal BP moderately high
James Holt, MD
East Tennessee State University, Johnson City
I have always felt uneasy with treatment of mild to moderate hypertension in pregnancy, as chronic hypertension must be differentiated from preeclampsia; and the treatments seem counterintuitive. I often see new obstetric patients well into the third trimester, and how I should initially treat an elevated blood pressure has been unclear. Adding the welfare of the unborn baby raises the stakes further.
This Clinical Inquiry helps my decision about initiating treatment, as the benefits from treatment do not outweigh the risks to mother and fetus unless the maternal blood pressure is moderately high, and the recommended thresholds for treatment are rather high for women with no end organ damage. If I must treat her, it appears the best (but not perfect) option is methyldopa.
There is considerable debate concerning the treatment of mild to moderate essential hypertension during pregnancy. Evidence suggests that because of the potential risk of fetal intrauterine growth restriction, treatment of hypertension should be delayed until maternal blood pressure reaches 150–160 mm Hg systolic or 100–110 mm Hg diastolic, as long as the mother has no preexisting end organ damage.
Methyldopa has been the drug of choice for oral treatment, as it is the only medication to have any extended follow-up study. However, a recent meta-analysis raised the possibility of increased fetal mortality (strength of recommendation [SOR]: A, based on systematic review of randomized controlled trials).
Labetalol is an effective alternative, but concerns remain that treatment with any beta-blocker increases the risk that infants will be small for gestational age (SGA) (SOR: B, based on small randomized controlled trials with inconsistent results).
There is limited evidence that calcium channel blockers and diuretics are safe alternatives, although evidence is insufficient to prove a clear benefit (SOR: B, based on limited randomized controlled trials). Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), due to similar mechanisms of action, are contraindicated in pregnancy (SOR: B, based on multiple case studies). No other class of anti-hypertensive medications is proven to be harmful in pregnancy.
Evidence summary
Treatment of maternal hypertension during pregnancy is based on maternal and fetal outcomes. Multiple meta-analyses of randomized controlled trials show that the major maternal outcomes improved by treating mild to moderate hypertension are decreased progression to severe hypertension (number needed to treat [NNT]=12; 95% confidence interval [CI], 9–17) and decreased need for additional antihypertensive therapy.1,2 The relative risk (RR) for preventing preeclampsia was 0.99 (95% CI, 0.84–1.18). The risk of preterm delivery was 1.00 (95% CI, 0.87–1.15).
The data for fetal outcomes are important, as the maternal benefits of treatment remain small.3 Much of the debate centers on decreasing uteroplacental perfusion, which may lead to decreased fetal growth. One meta-analysis reviewed 45 trials to evaluate the potential increase in SGA infants caused by any antihypertensive treatment, through quantifying the fall in mean arterial pressure. The analysis found an average decrease in birthweight of 145 g for a 10 mm Hg fall in mean arterial pressurewith no increased perinatal morbidity.4 The clinical significance of this is unclear.
In comparing one agent with another, methyldopa was the most commonly tested agent, with 14 randomized controlled trials of more than 1010 subjects demonstrating its efficacy at reducing blood pressure. Other antihypertensive agents appear better than methyldopa in terms of reducing the risk of infant mortality (RR=0.49; 95% CI, 0.24–0.99),1 but the studies were small and used weak methods, and this finding may be due to bias.5 Meta-analyses of beta-blocker trials show a borderline increase in SGA infants, with no related increase in perinatal mortality, as well as a decrease in the incidence of respiratory distress syndrome.6
Diuretics are effective antihypertensives, especially when combined with other agents, but they are known to decrease the circulating plasma volume, potentially decreasing uteroplacental perfusion. They are generally viewed as safe, as long as the mother is not already at increased risk for perfusion abnormalities (eg, preeclamptic states).7 Calcium channel blockers, though generally regarded as safe and effective, have mostly been evaluated for use late in pregnancy, so their benefit-to-risk ratio remains uncertain.8ACE inhibitors and, by extension, ARBs, due to their similar mechanisms of action, are contraindicated in pregnancy, having been linked to miscarriage, fetal death, fetal renal failure, and malformation.5,9-11
Recommendations from others
The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin states there is no evidence that antihypertensive treatment for mild to moderate hypertension improves maternal or fetal outcomes, even for women who are already receiving hypertension treatment at the time of pregnancy. ACOG suggests treatment may be stopped during pregnancy, or not initiated until blood pressures reach 150–160 mm Hg systolic or 100–110 mm Hg diastolic, unless the mother has underlying renal or cardiovascular disease.9
The National High Blood Pressure Education Program recommends the same guidelines as ACOG,10 whereas the Canadian Hypertension Society consensus panel has chosen 140/90 mm Hg as the level at which treatment should be initiated.11
The British Medical Journal Clinical Evidence Guidelines reiterate that the evidence does not support the benefit of treating mild to moderate hypertension, except in reducing the progression to severe hypertension.5 Methyldopa is consistently the drug of choice in all those making a specific recommendation,9-11 although it should be noted these recommendations were published before the 2003 Cochrane Review.1
Benefits from treatment do not outweigh risks unless maternal BP moderately high
James Holt, MD
East Tennessee State University, Johnson City
I have always felt uneasy with treatment of mild to moderate hypertension in pregnancy, as chronic hypertension must be differentiated from preeclampsia; and the treatments seem counterintuitive. I often see new obstetric patients well into the third trimester, and how I should initially treat an elevated blood pressure has been unclear. Adding the welfare of the unborn baby raises the stakes further.
This Clinical Inquiry helps my decision about initiating treatment, as the benefits from treatment do not outweigh the risks to mother and fetus unless the maternal blood pressure is moderately high, and the recommended thresholds for treatment are rather high for women with no end organ damage. If I must treat her, it appears the best (but not perfect) option is methyldopa.
1. Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev 2003;(1):CD002252.-
2. Magee LA, Duley L. Oral beta blockers for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev. 2003;(1):CD002863.-
3. Ferrer RL, Sibai BM, Mulrow CD, Chiquette E, Stevens KR, Cornell J. Management of mild chronic hypertension during pregnancy: a review. Obstet Gynecol 2000;96:849-860.
4. von Dadelszen P, Ornstein MP, Bull SB, Logan AG, Koren G, Magee LA. Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis. Lancet 2000;355:87-92.
5. Duley L. Childbirth and pregnancy—pre-eclampsia and hypertension. Clin Evid [online], Issue 9, August 2003. London: BMJ Publishing Group; 2003. Available at: clinicalevidence.com. Accessed on August 29, 2003.
6. Magee LA, Elran E, Bull SB, Logan A, Koren G. Risks and benefits of beta-receptor blockers for pregnancy hypertension: overview of the randomized trials. Eur J Obstet Gynecol Reprod Biol 2000;88:15-26.
7. Management of Chronic Hypertension During Pregnancy. Evidence Report/Technology Assessment: Number 14. AHRQ Publication No. 00-E010, August 2000. Rockville, Md: Agency for Healthcare Research and Quality; 2000. Available at: www.ahrq.gov/clinic/epcsums/pregsum.htm. Accessed on May 5, 2004.
8. Magee LA, Ornstein MP, von Dadelszen P. Fortnightly review: management of hypertension in pregnancy. BMJ 1999;318:1332-1336.
9. Gilstrap LC, Ramin SM. ACOG Practice Bulletin No. 29: Chronic hypertension in pregnancy. Obstet Gynecol 2001;98:177-185.
10. National. Heart Lung and Blood Institute. National High Blood Pressure Education Program: Working Group Report on High Blood Pressure in Pregnancy. Bethesda, Md: NHLBI; 2000. Available at: www.nhlbi.nih.gov/health/prof/heart/hbp/hbp_preg.pdf. Accessed on May 5, 2004.
11. Rey E, LeLorier J, Burgess E, Lange IR, Leduc L. Report of Canadian Hypertension Society Consensus Conference: 3. Pharmacologic treatment of hypertensive disorders in pregnancy. CMAJ 1997;157:1245-1254.
1. Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev 2003;(1):CD002252.-
2. Magee LA, Duley L. Oral beta blockers for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev. 2003;(1):CD002863.-
3. Ferrer RL, Sibai BM, Mulrow CD, Chiquette E, Stevens KR, Cornell J. Management of mild chronic hypertension during pregnancy: a review. Obstet Gynecol 2000;96:849-860.
4. von Dadelszen P, Ornstein MP, Bull SB, Logan AG, Koren G, Magee LA. Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis. Lancet 2000;355:87-92.
5. Duley L. Childbirth and pregnancy—pre-eclampsia and hypertension. Clin Evid [online], Issue 9, August 2003. London: BMJ Publishing Group; 2003. Available at: clinicalevidence.com. Accessed on August 29, 2003.
6. Magee LA, Elran E, Bull SB, Logan A, Koren G. Risks and benefits of beta-receptor blockers for pregnancy hypertension: overview of the randomized trials. Eur J Obstet Gynecol Reprod Biol 2000;88:15-26.
7. Management of Chronic Hypertension During Pregnancy. Evidence Report/Technology Assessment: Number 14. AHRQ Publication No. 00-E010, August 2000. Rockville, Md: Agency for Healthcare Research and Quality; 2000. Available at: www.ahrq.gov/clinic/epcsums/pregsum.htm. Accessed on May 5, 2004.
8. Magee LA, Ornstein MP, von Dadelszen P. Fortnightly review: management of hypertension in pregnancy. BMJ 1999;318:1332-1336.
9. Gilstrap LC, Ramin SM. ACOG Practice Bulletin No. 29: Chronic hypertension in pregnancy. Obstet Gynecol 2001;98:177-185.
10. National. Heart Lung and Blood Institute. National High Blood Pressure Education Program: Working Group Report on High Blood Pressure in Pregnancy. Bethesda, Md: NHLBI; 2000. Available at: www.nhlbi.nih.gov/health/prof/heart/hbp/hbp_preg.pdf. Accessed on May 5, 2004.
11. Rey E, LeLorier J, Burgess E, Lange IR, Leduc L. Report of Canadian Hypertension Society Consensus Conference: 3. Pharmacologic treatment of hypertensive disorders in pregnancy. CMAJ 1997;157:1245-1254.
Evidence-based answers from the Family Physicians Inquiries Network
Are tympanostomy tubes indicated for recurrent acute otitis media?
For children with recurrent acute otitis media (here defined as 3 or more episodes in 6 months, or 4 or more in a year), tympanostomy tubes are indicated if middle-ear effusion is present. Tubes reduce the frequency of recurrent acute otitis media by 2 to 3 episodes per year in these patients (strength of recommendation [SOR]: A; based on randomized controlled trials).
Further benefits include improved quality of life for both child and caregiver and greater parental satisfaction (SOR: B; based on trials that included patients with recurrent acute otitis media or otitis media with effusion).
Tympanostomy tubes do not decrease the number of recurrent acute otitis media episodes in children without middle-ear effusion (SOR: A, based on randomized controlled trials). These children run the risk of adverse outcomes of tube placement, including transient or recurrent otorrhea, tympanosclerosis, focal atrophy, perforation, and cholesteatoma (SOR: A; based on meta-analysis).
Evidence summary
Several randomized controlled trials and a meta-analysis demonstrated that the children most likely to benefit from tympanostomy tubes are those more than 6 months old with middle-ear effusion who have had 3 or more episodes of acute otitis media in 6 months, or 4 or more episodes in 12 months.1-4 Data are inadequate to determine the lowest rate of recurrence that would suggest a benefit from tube placement.
A meta-analysis of 5 randomized trials comparing no surgery with placement of tubes for recurrent acute otitis media with or without middle-ear effusion showed that the placement of tubes resulted in a mean absolute decrease in acute otitis media incidence of 1.0 per year (95% confidence interval [CI], 0.4–1.6), and a decrease in the prevalence of middle-ear effusion by 115 days per year (95% CI, 11–220).4 The benefit of tubes for recurrent acute otitis media was demonstrated only in studies in which middle-ear effusion was present:2,3 one found 3.01 (95% CI, 2.18–3.84) fewer acute episodes per year;1,4 the other found 2.27 (95% CI, 1.03–3.51) fewer.2,4
One randomized controlled trial of 264 children, aged 7 to 35 months, with a history of recurrent acute otitis media but free of middle-ear effusion, compared tubes with medical therapy and found no difference in recurrence over 2 years.3 The medical therapy arm received prophylaxis with either amoxicillin or placebo. The amoxicillin arm had 0.6 fewer episodes of acute otitis media per year compared with the other 2, a statistically significant 40% decrease (relative risk reduction=0.4).3
The average time with otitis media of any type (acute otitis media, otitis media with effusion, or ottorhea) also decreased—15.0% in the placebo group, 10.0% in the amoxicillin group, and 6.6% in the tympanostomy tube group (amoxicillin vs. placebo, P=.03; tubes vs. placebo, P<.001).3 Higher dropout rates occurred in the amoxicillin and medical treatment groups.3
In prospective studies of patients receiving tubes for recurrent acute otitis media and otitis media with effusion, measures of quality of life—physical suffering, emotional distress, activity limitation, hearing loss, speech development, caregiver concern/worry, parental post-tube satisfaction,4,5,6 and an ear symptom score6 —improved after tube placement. Within several weeks of tube placement, 79% of children had improved quality of life, 17% had trivial change, and 4% were worse.4
A meta-analysis reporting sequelae of tympanostomy tubes found an absolute complication rate of 26% for transient otorrhea and 4% for chronic otorrhea.4
Compared with nonsurgical treatment, complication rates for tube placement were reported in 0.7% of surgically treated ears.7 Complications included:
- tympanosclerosis (relative risk [RR]=3.5 [95% CI, 2.6–4.9])
- focal atrophy (RR=1.7 [95% CI, 1.1–2.7])
- perforation (RR=3.5 [95% CI, 1.5–7.1])
- 2% with short-term tubes
- 16% with long-term tubes
- cholesteatoma (RR=2.6 [95% CI, 1.5–4.4]).
Recommendations from others
The Institute for Clinical Systems Improvement 2001 guidelines for recurrent acute otitis media treatment in children recommends initial antibiotic prophylaxis with amoxicillin (20 mg/kg/day) for 2 to 6 months (based on randomized controlled trial data). If there are 2 recurrences of acute otitis media during that time, then referral to an otorhinolaryngologist for possible tympanostomy tube placement is recommended.8
Michael Fisher, MD
University of North Carolina, Chapel Hill
Of the remaining challenges to the care of children with recurrent acute otitis media, 2 major issues are accurate diagnosis and the lack of information about long-term results. Diagnosis is difficult and requires pneumotoscopy and/or tympanometry. Without those techniques, a red drum (unless it is bulging) has a <40% positive predictive value for recurrent acute otitis media with effusion. On the other hand, with pneumotoscopy or tympanometry, the positive predictive value is 78% to 85%.
We don’t want to refer children unnecessarily for tubes. Delaying referral up to 9 months in children aged 6 to 36 months with middle-ear effusion does not seem to hurt language acquisition at 3 years of age. At this point, I know of no long-term follow-up studies of randomized controlled trials of >4 years to assess differences in language acquisition and hearing.
1. Gebhart DE. Tympanostomy tubes in the otitis media prone child. Laryngoscope 1981;91:849-866.
2. Gonzalez C, Arnold JE, Woody EA, et al. Prevention of recurrent acute otitis media: chemoprophylaxis versus tympanostomy tubes. Laryngoscope 1986;96:1330-1334.
3. Casselbrant ML, Kaleida PH, Rockette HE, et al. Efficacy of antimicrobial prophylaxis and of tympanostomy tube insertion for prevention of recurrent acute otitis media: results of a randomized clinical trial. Pediatr Infect Dis J 1992;11:278-286.
4. Rosenfeld RM. Surgical prevention of otitis media. Vaccine 2000;19:S134-S139.
5. Rosenfeld RM, Bhaya MH, Bower CM, et al. Impact of tympanostomy tubes on child quality of life. Arch Otolaryngol Head Neck Surg 2000;126:585-592.
6. Richards M, Giannoni C. Quality-of-life outcomes after surgical intervention for otitis media. Arch Otolaryngol Head Neck Surg 2002;128:776-782.
7. Kay DJ, Nelson M, Rosenfeld RM. Meta-analysis of tympanostomy tube sequelae. Otolaryngol Head Neck Surg 2001;124:374-380.
8. Diagnosis and treatment of otitis media in children. Bloomington, Minn: Institute for Clinical Systems Improvement (ICSI), 2001.
For children with recurrent acute otitis media (here defined as 3 or more episodes in 6 months, or 4 or more in a year), tympanostomy tubes are indicated if middle-ear effusion is present. Tubes reduce the frequency of recurrent acute otitis media by 2 to 3 episodes per year in these patients (strength of recommendation [SOR]: A; based on randomized controlled trials).
Further benefits include improved quality of life for both child and caregiver and greater parental satisfaction (SOR: B; based on trials that included patients with recurrent acute otitis media or otitis media with effusion).
Tympanostomy tubes do not decrease the number of recurrent acute otitis media episodes in children without middle-ear effusion (SOR: A, based on randomized controlled trials). These children run the risk of adverse outcomes of tube placement, including transient or recurrent otorrhea, tympanosclerosis, focal atrophy, perforation, and cholesteatoma (SOR: A; based on meta-analysis).
Evidence summary
Several randomized controlled trials and a meta-analysis demonstrated that the children most likely to benefit from tympanostomy tubes are those more than 6 months old with middle-ear effusion who have had 3 or more episodes of acute otitis media in 6 months, or 4 or more episodes in 12 months.1-4 Data are inadequate to determine the lowest rate of recurrence that would suggest a benefit from tube placement.
A meta-analysis of 5 randomized trials comparing no surgery with placement of tubes for recurrent acute otitis media with or without middle-ear effusion showed that the placement of tubes resulted in a mean absolute decrease in acute otitis media incidence of 1.0 per year (95% confidence interval [CI], 0.4–1.6), and a decrease in the prevalence of middle-ear effusion by 115 days per year (95% CI, 11–220).4 The benefit of tubes for recurrent acute otitis media was demonstrated only in studies in which middle-ear effusion was present:2,3 one found 3.01 (95% CI, 2.18–3.84) fewer acute episodes per year;1,4 the other found 2.27 (95% CI, 1.03–3.51) fewer.2,4
One randomized controlled trial of 264 children, aged 7 to 35 months, with a history of recurrent acute otitis media but free of middle-ear effusion, compared tubes with medical therapy and found no difference in recurrence over 2 years.3 The medical therapy arm received prophylaxis with either amoxicillin or placebo. The amoxicillin arm had 0.6 fewer episodes of acute otitis media per year compared with the other 2, a statistically significant 40% decrease (relative risk reduction=0.4).3
The average time with otitis media of any type (acute otitis media, otitis media with effusion, or ottorhea) also decreased—15.0% in the placebo group, 10.0% in the amoxicillin group, and 6.6% in the tympanostomy tube group (amoxicillin vs. placebo, P=.03; tubes vs. placebo, P<.001).3 Higher dropout rates occurred in the amoxicillin and medical treatment groups.3
In prospective studies of patients receiving tubes for recurrent acute otitis media and otitis media with effusion, measures of quality of life—physical suffering, emotional distress, activity limitation, hearing loss, speech development, caregiver concern/worry, parental post-tube satisfaction,4,5,6 and an ear symptom score6 —improved after tube placement. Within several weeks of tube placement, 79% of children had improved quality of life, 17% had trivial change, and 4% were worse.4
A meta-analysis reporting sequelae of tympanostomy tubes found an absolute complication rate of 26% for transient otorrhea and 4% for chronic otorrhea.4
Compared with nonsurgical treatment, complication rates for tube placement were reported in 0.7% of surgically treated ears.7 Complications included:
- tympanosclerosis (relative risk [RR]=3.5 [95% CI, 2.6–4.9])
- focal atrophy (RR=1.7 [95% CI, 1.1–2.7])
- perforation (RR=3.5 [95% CI, 1.5–7.1])
- 2% with short-term tubes
- 16% with long-term tubes
- cholesteatoma (RR=2.6 [95% CI, 1.5–4.4]).
Recommendations from others
The Institute for Clinical Systems Improvement 2001 guidelines for recurrent acute otitis media treatment in children recommends initial antibiotic prophylaxis with amoxicillin (20 mg/kg/day) for 2 to 6 months (based on randomized controlled trial data). If there are 2 recurrences of acute otitis media during that time, then referral to an otorhinolaryngologist for possible tympanostomy tube placement is recommended.8
Michael Fisher, MD
University of North Carolina, Chapel Hill
Of the remaining challenges to the care of children with recurrent acute otitis media, 2 major issues are accurate diagnosis and the lack of information about long-term results. Diagnosis is difficult and requires pneumotoscopy and/or tympanometry. Without those techniques, a red drum (unless it is bulging) has a <40% positive predictive value for recurrent acute otitis media with effusion. On the other hand, with pneumotoscopy or tympanometry, the positive predictive value is 78% to 85%.
We don’t want to refer children unnecessarily for tubes. Delaying referral up to 9 months in children aged 6 to 36 months with middle-ear effusion does not seem to hurt language acquisition at 3 years of age. At this point, I know of no long-term follow-up studies of randomized controlled trials of >4 years to assess differences in language acquisition and hearing.
For children with recurrent acute otitis media (here defined as 3 or more episodes in 6 months, or 4 or more in a year), tympanostomy tubes are indicated if middle-ear effusion is present. Tubes reduce the frequency of recurrent acute otitis media by 2 to 3 episodes per year in these patients (strength of recommendation [SOR]: A; based on randomized controlled trials).
Further benefits include improved quality of life for both child and caregiver and greater parental satisfaction (SOR: B; based on trials that included patients with recurrent acute otitis media or otitis media with effusion).
Tympanostomy tubes do not decrease the number of recurrent acute otitis media episodes in children without middle-ear effusion (SOR: A, based on randomized controlled trials). These children run the risk of adverse outcomes of tube placement, including transient or recurrent otorrhea, tympanosclerosis, focal atrophy, perforation, and cholesteatoma (SOR: A; based on meta-analysis).
Evidence summary
Several randomized controlled trials and a meta-analysis demonstrated that the children most likely to benefit from tympanostomy tubes are those more than 6 months old with middle-ear effusion who have had 3 or more episodes of acute otitis media in 6 months, or 4 or more episodes in 12 months.1-4 Data are inadequate to determine the lowest rate of recurrence that would suggest a benefit from tube placement.
A meta-analysis of 5 randomized trials comparing no surgery with placement of tubes for recurrent acute otitis media with or without middle-ear effusion showed that the placement of tubes resulted in a mean absolute decrease in acute otitis media incidence of 1.0 per year (95% confidence interval [CI], 0.4–1.6), and a decrease in the prevalence of middle-ear effusion by 115 days per year (95% CI, 11–220).4 The benefit of tubes for recurrent acute otitis media was demonstrated only in studies in which middle-ear effusion was present:2,3 one found 3.01 (95% CI, 2.18–3.84) fewer acute episodes per year;1,4 the other found 2.27 (95% CI, 1.03–3.51) fewer.2,4
One randomized controlled trial of 264 children, aged 7 to 35 months, with a history of recurrent acute otitis media but free of middle-ear effusion, compared tubes with medical therapy and found no difference in recurrence over 2 years.3 The medical therapy arm received prophylaxis with either amoxicillin or placebo. The amoxicillin arm had 0.6 fewer episodes of acute otitis media per year compared with the other 2, a statistically significant 40% decrease (relative risk reduction=0.4).3
The average time with otitis media of any type (acute otitis media, otitis media with effusion, or ottorhea) also decreased—15.0% in the placebo group, 10.0% in the amoxicillin group, and 6.6% in the tympanostomy tube group (amoxicillin vs. placebo, P=.03; tubes vs. placebo, P<.001).3 Higher dropout rates occurred in the amoxicillin and medical treatment groups.3
In prospective studies of patients receiving tubes for recurrent acute otitis media and otitis media with effusion, measures of quality of life—physical suffering, emotional distress, activity limitation, hearing loss, speech development, caregiver concern/worry, parental post-tube satisfaction,4,5,6 and an ear symptom score6 —improved after tube placement. Within several weeks of tube placement, 79% of children had improved quality of life, 17% had trivial change, and 4% were worse.4
A meta-analysis reporting sequelae of tympanostomy tubes found an absolute complication rate of 26% for transient otorrhea and 4% for chronic otorrhea.4
Compared with nonsurgical treatment, complication rates for tube placement were reported in 0.7% of surgically treated ears.7 Complications included:
- tympanosclerosis (relative risk [RR]=3.5 [95% CI, 2.6–4.9])
- focal atrophy (RR=1.7 [95% CI, 1.1–2.7])
- perforation (RR=3.5 [95% CI, 1.5–7.1])
- 2% with short-term tubes
- 16% with long-term tubes
- cholesteatoma (RR=2.6 [95% CI, 1.5–4.4]).
Recommendations from others
The Institute for Clinical Systems Improvement 2001 guidelines for recurrent acute otitis media treatment in children recommends initial antibiotic prophylaxis with amoxicillin (20 mg/kg/day) for 2 to 6 months (based on randomized controlled trial data). If there are 2 recurrences of acute otitis media during that time, then referral to an otorhinolaryngologist for possible tympanostomy tube placement is recommended.8
Michael Fisher, MD
University of North Carolina, Chapel Hill
Of the remaining challenges to the care of children with recurrent acute otitis media, 2 major issues are accurate diagnosis and the lack of information about long-term results. Diagnosis is difficult and requires pneumotoscopy and/or tympanometry. Without those techniques, a red drum (unless it is bulging) has a <40% positive predictive value for recurrent acute otitis media with effusion. On the other hand, with pneumotoscopy or tympanometry, the positive predictive value is 78% to 85%.
We don’t want to refer children unnecessarily for tubes. Delaying referral up to 9 months in children aged 6 to 36 months with middle-ear effusion does not seem to hurt language acquisition at 3 years of age. At this point, I know of no long-term follow-up studies of randomized controlled trials of >4 years to assess differences in language acquisition and hearing.
1. Gebhart DE. Tympanostomy tubes in the otitis media prone child. Laryngoscope 1981;91:849-866.
2. Gonzalez C, Arnold JE, Woody EA, et al. Prevention of recurrent acute otitis media: chemoprophylaxis versus tympanostomy tubes. Laryngoscope 1986;96:1330-1334.
3. Casselbrant ML, Kaleida PH, Rockette HE, et al. Efficacy of antimicrobial prophylaxis and of tympanostomy tube insertion for prevention of recurrent acute otitis media: results of a randomized clinical trial. Pediatr Infect Dis J 1992;11:278-286.
4. Rosenfeld RM. Surgical prevention of otitis media. Vaccine 2000;19:S134-S139.
5. Rosenfeld RM, Bhaya MH, Bower CM, et al. Impact of tympanostomy tubes on child quality of life. Arch Otolaryngol Head Neck Surg 2000;126:585-592.
6. Richards M, Giannoni C. Quality-of-life outcomes after surgical intervention for otitis media. Arch Otolaryngol Head Neck Surg 2002;128:776-782.
7. Kay DJ, Nelson M, Rosenfeld RM. Meta-analysis of tympanostomy tube sequelae. Otolaryngol Head Neck Surg 2001;124:374-380.
8. Diagnosis and treatment of otitis media in children. Bloomington, Minn: Institute for Clinical Systems Improvement (ICSI), 2001.
1. Gebhart DE. Tympanostomy tubes in the otitis media prone child. Laryngoscope 1981;91:849-866.
2. Gonzalez C, Arnold JE, Woody EA, et al. Prevention of recurrent acute otitis media: chemoprophylaxis versus tympanostomy tubes. Laryngoscope 1986;96:1330-1334.
3. Casselbrant ML, Kaleida PH, Rockette HE, et al. Efficacy of antimicrobial prophylaxis and of tympanostomy tube insertion for prevention of recurrent acute otitis media: results of a randomized clinical trial. Pediatr Infect Dis J 1992;11:278-286.
4. Rosenfeld RM. Surgical prevention of otitis media. Vaccine 2000;19:S134-S139.
5. Rosenfeld RM, Bhaya MH, Bower CM, et al. Impact of tympanostomy tubes on child quality of life. Arch Otolaryngol Head Neck Surg 2000;126:585-592.
6. Richards M, Giannoni C. Quality-of-life outcomes after surgical intervention for otitis media. Arch Otolaryngol Head Neck Surg 2002;128:776-782.
7. Kay DJ, Nelson M, Rosenfeld RM. Meta-analysis of tympanostomy tube sequelae. Otolaryngol Head Neck Surg 2001;124:374-380.
8. Diagnosis and treatment of otitis media in children. Bloomington, Minn: Institute for Clinical Systems Improvement (ICSI), 2001.
Evidence-based answers from the Family Physicians Inquiries Network