User login
Do TZDs increase the risk of heart failure for patients with diabetes?
Patients with diabetes who take thiazolidinediones (TZDs) have a higher incidence of congestive heart failure (CHF) than those who do not; the incidence of CHF is similar with the use of pioglitazone (Actos), troglitazone (Rezulin), or rosiglitazone (Avandia) (strength of recommendation [SOR]: B, based on a large retrospective cohort study). However, patients on regimens that include pioglitazone but not insulin have lower rates of CHF than those taking insulin but not pioglitazone (SOR: B, based on a retrospective cohort study). Still, patients starting any TZD should be warned of the possibility of CHF and should be monitored for its development. TZDs are contraindicated for patients with class III and IV CHF (SOR: C, based on expert opinion).
Consider stopping TZDs for patients developing edema or CHF
Richard Hoffman, MD
Chesterfield Family Practice, Richmond, Va
Improved glycemic control decreases the risk of end organ damage and heart failure in patients with diabetes. Thiazolidinediones are very useful drugs, particularly for patients with marked insulin resistance and hyperlipidemia. However, they do precipitate edema and heart failure. The edema can be severe enough to lead to discontinuation of the drug, and the risk of heart failure limits the population in which they can be used. They can be used safely in some cardiac patients but, as noted in the article, they should be avoided or used with caution in patients with CHF. Patients taking a TZD who subsequently develop edema should be carefully evaluated for CHF.
Evidence summary
A retrospective cohort study of health insurance claims compared the incidence of CHF among 5441 patients with diabetes who had taken TZDs (rosiglitazone, troglitazone, or pioglitazone) vs 28,103 who had not. Patients were allowed other oral agents and insulin, and they were followed for up to 6 years. The TZD group had more patients on insulin and with pre-existing comorbidities. Based on Kaplan-Meier estimates, which control for censored information, the incidence of new heart failure at 40 months was 8.2% in the TZD group and 5.3% in the non-TZD group (number needed to harm [NNH]=34.5). Using a multivariate analysis that controlled for the coadministration of insulin, the hazard ratio for TZD use was 1.76 (95% confidence interval [CI], 1.43–2.17).1 The incidence of CHF was 3.24% in the troglitazone group (n=1665), 2.39% in the rosiglitazone group (n=1882), and 1.63% in the pioglitazone group (n=1347). The difference in these rates is not statistically significant. Of the 28,103 patients not on a TZD, 1.41% developed heart failure. Individual agents were not compared with placebo.
A manufacturer-sponsored study that combined data from 4 separate unpublished randomized controlled trials compared the incidence of CHF at 1 year for patients treated with pioglitazone (as monotherapy and in combination with other oral agents) with those treated only with other oral agents. Cardiac failure was noted in 12 of 1857 in the pioglitazone group vs 10 of 1856 subjects in the non-pioglitazone groups (not statistically significant). The paper did not comment on how the patients were recruited, how outcomes were measured, or why the 4 original studies were not published.2
Another manufacturer-sponsored retrospective cohort study of pioglitazone analyzed insurance claims data to compare the incidence of CHF among 1668 adult patients taking pioglitazone (and possibly other medications, but not insulin) vs 1668 adult patients taking insulin (and possibly other medications, but not a TZD). The 2 groups were matched in terms of comorbid conditions, but statistical analysis did not take disease severity into account. The incidence of CHF was 2% of pioglitazone users compared with 4% of patients using insulin (NNH for insulin=50). In addition, CHF-related hospitalizations were 0.7% for CHF in the pioglitazone group vs 2.5% in the insulin group (NNH for insulin=55). Both of these findings are statistically significant.3
Recommendations from others
The American Diabetes Association/American Heart Association recommends that patients be evaluated for heart disease or heart failure before starting TZD therapy and monitored for symptoms thereafter. Patients who are at risk for developing CHF, who already have New York Heart Association class I or II CHF, or who take insulin should begin TZD therapy with low doses that are titrated up gradually. The US Food and Drug Administration has not approved TZDs for patients with class III or IV CHF, as there are no studies in these populations.4
1. Delea TE, Edelsberg JS, Hagiwara M, Oster G, Phillips LS. Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes: a retrospective cohort study. Diabetes Care 2003;26:2983-2989.
2. Belcher G, Lambert C, Goh KL, Edwards G, Valbuena M. Cardiovascular effects of treatment of type 2 diabetes with pioglitazone, metformin and gliclazide. Int J Clin Pract 2004;58:833-837.
3. Rajagopalan R, Rosenson RS, Fernandes AW, Khan M, Murray FT. Association between congestive heart failure and hospitalization in patients with type 2 diabetes mellitus receiving treatment with insulin or pioglitazone: a retrospective data analysis. Clin Ther 2004;26:1400-1410.
4. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association, October 7, 2003. Circulation 2003;108:2941-2948.
Patients with diabetes who take thiazolidinediones (TZDs) have a higher incidence of congestive heart failure (CHF) than those who do not; the incidence of CHF is similar with the use of pioglitazone (Actos), troglitazone (Rezulin), or rosiglitazone (Avandia) (strength of recommendation [SOR]: B, based on a large retrospective cohort study). However, patients on regimens that include pioglitazone but not insulin have lower rates of CHF than those taking insulin but not pioglitazone (SOR: B, based on a retrospective cohort study). Still, patients starting any TZD should be warned of the possibility of CHF and should be monitored for its development. TZDs are contraindicated for patients with class III and IV CHF (SOR: C, based on expert opinion).
Consider stopping TZDs for patients developing edema or CHF
Richard Hoffman, MD
Chesterfield Family Practice, Richmond, Va
Improved glycemic control decreases the risk of end organ damage and heart failure in patients with diabetes. Thiazolidinediones are very useful drugs, particularly for patients with marked insulin resistance and hyperlipidemia. However, they do precipitate edema and heart failure. The edema can be severe enough to lead to discontinuation of the drug, and the risk of heart failure limits the population in which they can be used. They can be used safely in some cardiac patients but, as noted in the article, they should be avoided or used with caution in patients with CHF. Patients taking a TZD who subsequently develop edema should be carefully evaluated for CHF.
Evidence summary
A retrospective cohort study of health insurance claims compared the incidence of CHF among 5441 patients with diabetes who had taken TZDs (rosiglitazone, troglitazone, or pioglitazone) vs 28,103 who had not. Patients were allowed other oral agents and insulin, and they were followed for up to 6 years. The TZD group had more patients on insulin and with pre-existing comorbidities. Based on Kaplan-Meier estimates, which control for censored information, the incidence of new heart failure at 40 months was 8.2% in the TZD group and 5.3% in the non-TZD group (number needed to harm [NNH]=34.5). Using a multivariate analysis that controlled for the coadministration of insulin, the hazard ratio for TZD use was 1.76 (95% confidence interval [CI], 1.43–2.17).1 The incidence of CHF was 3.24% in the troglitazone group (n=1665), 2.39% in the rosiglitazone group (n=1882), and 1.63% in the pioglitazone group (n=1347). The difference in these rates is not statistically significant. Of the 28,103 patients not on a TZD, 1.41% developed heart failure. Individual agents were not compared with placebo.
A manufacturer-sponsored study that combined data from 4 separate unpublished randomized controlled trials compared the incidence of CHF at 1 year for patients treated with pioglitazone (as monotherapy and in combination with other oral agents) with those treated only with other oral agents. Cardiac failure was noted in 12 of 1857 in the pioglitazone group vs 10 of 1856 subjects in the non-pioglitazone groups (not statistically significant). The paper did not comment on how the patients were recruited, how outcomes were measured, or why the 4 original studies were not published.2
Another manufacturer-sponsored retrospective cohort study of pioglitazone analyzed insurance claims data to compare the incidence of CHF among 1668 adult patients taking pioglitazone (and possibly other medications, but not insulin) vs 1668 adult patients taking insulin (and possibly other medications, but not a TZD). The 2 groups were matched in terms of comorbid conditions, but statistical analysis did not take disease severity into account. The incidence of CHF was 2% of pioglitazone users compared with 4% of patients using insulin (NNH for insulin=50). In addition, CHF-related hospitalizations were 0.7% for CHF in the pioglitazone group vs 2.5% in the insulin group (NNH for insulin=55). Both of these findings are statistically significant.3
Recommendations from others
The American Diabetes Association/American Heart Association recommends that patients be evaluated for heart disease or heart failure before starting TZD therapy and monitored for symptoms thereafter. Patients who are at risk for developing CHF, who already have New York Heart Association class I or II CHF, or who take insulin should begin TZD therapy with low doses that are titrated up gradually. The US Food and Drug Administration has not approved TZDs for patients with class III or IV CHF, as there are no studies in these populations.4
Patients with diabetes who take thiazolidinediones (TZDs) have a higher incidence of congestive heart failure (CHF) than those who do not; the incidence of CHF is similar with the use of pioglitazone (Actos), troglitazone (Rezulin), or rosiglitazone (Avandia) (strength of recommendation [SOR]: B, based on a large retrospective cohort study). However, patients on regimens that include pioglitazone but not insulin have lower rates of CHF than those taking insulin but not pioglitazone (SOR: B, based on a retrospective cohort study). Still, patients starting any TZD should be warned of the possibility of CHF and should be monitored for its development. TZDs are contraindicated for patients with class III and IV CHF (SOR: C, based on expert opinion).
Consider stopping TZDs for patients developing edema or CHF
Richard Hoffman, MD
Chesterfield Family Practice, Richmond, Va
Improved glycemic control decreases the risk of end organ damage and heart failure in patients with diabetes. Thiazolidinediones are very useful drugs, particularly for patients with marked insulin resistance and hyperlipidemia. However, they do precipitate edema and heart failure. The edema can be severe enough to lead to discontinuation of the drug, and the risk of heart failure limits the population in which they can be used. They can be used safely in some cardiac patients but, as noted in the article, they should be avoided or used with caution in patients with CHF. Patients taking a TZD who subsequently develop edema should be carefully evaluated for CHF.
Evidence summary
A retrospective cohort study of health insurance claims compared the incidence of CHF among 5441 patients with diabetes who had taken TZDs (rosiglitazone, troglitazone, or pioglitazone) vs 28,103 who had not. Patients were allowed other oral agents and insulin, and they were followed for up to 6 years. The TZD group had more patients on insulin and with pre-existing comorbidities. Based on Kaplan-Meier estimates, which control for censored information, the incidence of new heart failure at 40 months was 8.2% in the TZD group and 5.3% in the non-TZD group (number needed to harm [NNH]=34.5). Using a multivariate analysis that controlled for the coadministration of insulin, the hazard ratio for TZD use was 1.76 (95% confidence interval [CI], 1.43–2.17).1 The incidence of CHF was 3.24% in the troglitazone group (n=1665), 2.39% in the rosiglitazone group (n=1882), and 1.63% in the pioglitazone group (n=1347). The difference in these rates is not statistically significant. Of the 28,103 patients not on a TZD, 1.41% developed heart failure. Individual agents were not compared with placebo.
A manufacturer-sponsored study that combined data from 4 separate unpublished randomized controlled trials compared the incidence of CHF at 1 year for patients treated with pioglitazone (as monotherapy and in combination with other oral agents) with those treated only with other oral agents. Cardiac failure was noted in 12 of 1857 in the pioglitazone group vs 10 of 1856 subjects in the non-pioglitazone groups (not statistically significant). The paper did not comment on how the patients were recruited, how outcomes were measured, or why the 4 original studies were not published.2
Another manufacturer-sponsored retrospective cohort study of pioglitazone analyzed insurance claims data to compare the incidence of CHF among 1668 adult patients taking pioglitazone (and possibly other medications, but not insulin) vs 1668 adult patients taking insulin (and possibly other medications, but not a TZD). The 2 groups were matched in terms of comorbid conditions, but statistical analysis did not take disease severity into account. The incidence of CHF was 2% of pioglitazone users compared with 4% of patients using insulin (NNH for insulin=50). In addition, CHF-related hospitalizations were 0.7% for CHF in the pioglitazone group vs 2.5% in the insulin group (NNH for insulin=55). Both of these findings are statistically significant.3
Recommendations from others
The American Diabetes Association/American Heart Association recommends that patients be evaluated for heart disease or heart failure before starting TZD therapy and monitored for symptoms thereafter. Patients who are at risk for developing CHF, who already have New York Heart Association class I or II CHF, or who take insulin should begin TZD therapy with low doses that are titrated up gradually. The US Food and Drug Administration has not approved TZDs for patients with class III or IV CHF, as there are no studies in these populations.4
1. Delea TE, Edelsberg JS, Hagiwara M, Oster G, Phillips LS. Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes: a retrospective cohort study. Diabetes Care 2003;26:2983-2989.
2. Belcher G, Lambert C, Goh KL, Edwards G, Valbuena M. Cardiovascular effects of treatment of type 2 diabetes with pioglitazone, metformin and gliclazide. Int J Clin Pract 2004;58:833-837.
3. Rajagopalan R, Rosenson RS, Fernandes AW, Khan M, Murray FT. Association between congestive heart failure and hospitalization in patients with type 2 diabetes mellitus receiving treatment with insulin or pioglitazone: a retrospective data analysis. Clin Ther 2004;26:1400-1410.
4. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association, October 7, 2003. Circulation 2003;108:2941-2948.
1. Delea TE, Edelsberg JS, Hagiwara M, Oster G, Phillips LS. Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes: a retrospective cohort study. Diabetes Care 2003;26:2983-2989.
2. Belcher G, Lambert C, Goh KL, Edwards G, Valbuena M. Cardiovascular effects of treatment of type 2 diabetes with pioglitazone, metformin and gliclazide. Int J Clin Pract 2004;58:833-837.
3. Rajagopalan R, Rosenson RS, Fernandes AW, Khan M, Murray FT. Association between congestive heart failure and hospitalization in patients with type 2 diabetes mellitus receiving treatment with insulin or pioglitazone: a retrospective data analysis. Clin Ther 2004;26:1400-1410.
4. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association, October 7, 2003. Circulation 2003;108:2941-2948.
Evidence-based answers from the Family Physicians Inquiries Network
Does tight control of blood glucose in pregnant women with diabetes improve neonatal outcomes?
In pregnant women with preexisting type 1 diabetes mellitus, maintaining near-normal blood glucose levels decreases the rate of major congenital anomalies (defined as those causing death or a serious handicap necessitating surgical correction or medical treatment). Prolonged preconception control of blood sugar to near normal levels reduces the rate of major congenital anomalies close to those seen in women without diabetes (strength of recommendation [SOR]: A, based on prospective cohort studies and randomized controlled trial [RCT]).
Intensive management reduces the risk of congenital anomalies more than conventional therapy, and lowers the risk of neonatal hypoglycemia (SOR: B, based on RCT). Very tight control does not reduce clinically significant neonatal morbidity but does increase the risk of maternal hypoglycemia (SOR: B, based on a systematic review). Evidence is insufficient about whether or not these statements hold true for women with type 2 diabetes.
In women with impaired glucose tolerance, dietary control reduces neonatal hypoglycemia. To date, studies have not found statistically significant reductions in admission rates to the special care nursery or birth weights above the 90th percentile (SOR: B, systematic review). Evidence is insufficient to suggest improved outcomes with therapy in women with gestational diabetes. Standard recommendations typically recommend tight control in this population as well.
Evidence summary
Two studies show that in type 1 diabetes mellitus, elevated blood glucose levels in early pregnancy (HbA1c=6%–8%) are associated with a threefold increase in fetal malformations.1,2 Maintaining preconception and early pregnancy blood glucose levels in the normal range can reduce this risk. A meta-analysis comparing 16 studies of women with pregestational diabetes—13 of which included only women with type 1 diabetes—found that women receiving preconception care had lower early first trimester HbA1c levels than those who did not (7.9% vs 9.6%) and delivered fewer infants with major congenital anomalies (relative risk [RR]=0.36; 95% confidence interval [CI], 0.22–0.59).2 One limitation of this study was that preconception care was not consistently defined among the included studies.
A 10-year RCT evaluated the outcomes of 270 pregnancies in women who had received either intensive (SQ infusion or multiple daily injections) or conventional insulin regimens prior to pregnancy. Women were advised to use intensive therapy when they were trying to conceive, and all were changed to intensive therapy if pregnancy was confirmed. Women in the intensive therapy group had normal HbA1c levels for an average of 40 months before conception. Women receiving intensive therapy had lower mean HbA1c levels at conception (7.4 ± 1.3 SD vs 8.1 ± 1.7 SD) and fewer major congenital anomalies (0.7% vs 5.9%; number needed to treat=19) than did women in the conventional group. When infants with genetic malformations were excluded from the analysis, rates of congenital malformations were similar in women switched to intensive therapy either before or after conception (3.8% vs 3.6%). No differences were seen between neonatal mortality, spontaneous abortion rates, birth weights, Apgar scores, and hypocalcemia or hypoglycemia rates.3
When tight and very tight control of glucose in pregnant women with pregestational diabetes were compared in a Cochrane systematic review, rates of maternal hypoglycemia in the very tightly controlled group were higher (odds ratio [OR]=25.96; 95% CI, 4.91–137.26).5 An RCT of 118 women with pregestational diabetes compared 4-times-daily vs twice-daily doses of insulin. Infants born to women receiving 4-times-daily insulin had significantly lower rates of neonatal hypoglycemia (RR=0.17; 95% CI, 0.04–0.74). While the trend was toward improved neonatal metabolic effects in the trials, the clinical significance of these findings is not clear.
Whether or not treatment of gestational diabetes improves outcomes is uncertain. A Cochrane systematic review evaluating a small number of trials, with variable quality and inconsistent outcome measures, compared dietary management to routine care in gestational diabetics. While fewer infants with birth weights >4000 g were delivered in the diet therapy group (OR=0.78; 95% CI, 0.45–1.35), the results were not statistically significant. No other important clinical differences were found.6
Another Cochrane systematic review evaluated the effects of dietary treatment of women with impaired glucose tolerance and gestational diabetes. Three trials with a total of 223 women with impaired glucose tolerance found a significant reduction in the rate of neonatal hypoglycemia (RR=0.25; 95% CI, 0.07–0.86). There was no significant change in the rates of cesarean section (RR=0.86; 95% CI, 0.51–1.45), admission to the special care nursery (RR=0.49; 95% CI, 0.19–1.24), or birth weights greater than the 90th percentile (RR=0.55; 95% CI, 0.19–1.61). Inadequate power may well account for the failure to reach significance in these outcomes.7
Recommendations from others
The American College of Obstetrics and Gynecology (ACOG) recommends that women with pregestational diabetes maintain fasting plasma glucose levels between 60–90 mg/dL and 2-hour postprandial levels <120 mg/dL.8 For women with gestational diabetes who are not controlled within these targets on dietary therapy alone, ACOG recommends the additional of insulin therapy.9
The American Diabetes Association recommends that women with pregestational diabetes maintain capillary plasma glucose levels of 80–110 mg/dL before and <155 mg/dL 2 hours after meals before pregnancy and while trying to conceive.10 The ADA does not list target glucose levels for women with pregestational diabetes once they become pregnant. The ADA recommends the use of diet and insulin therapy to maintain preprandial plasma glucose levels of <105 mg/dL and 2-hour postprandial levels below <130 mg/dL in gestational diabetes.11
Glucose control makes a difference for pregnancy outcomes in type I diabetes
Linda French, MD
Michigan State University, East Lansing
It is well accepted that glucose control makes a difference for pregnancy outcomes in women with type 1 diabetes. Since similar studies have not been done in women with preexisting type 2 diabetes, we have to assume that the risk is also high for them. Preconception counseling about glucose control is so important for women with diabetes. Fortunately, because they generally have routine visits for their chronic care, we have an opportunity to initiate discussion of glucose control in relationship to pregnancy planning. Routine diabetes care visits also give us the opportunity to discuss other important preconception topics.
- Allopurinol • Lopurin, Zyloprim
- Amitriptyline • Elavil, Endep
- Benzbromarone • Urinorm
- Botulinim toxin A • Botox
- Clindamycin • Cleocin
- Fluoxetine • Prozac
- Fluticasone • Flovent
- Gabapentin • Neurontin
- Metronidazole (intravaginal) • MetroGel
- Probenecid • Benemid, Probalan
- Sumatriptan • Imitrex
- Tizanidine • Zanaflex
- Triamcinolone • Azmacort
- Valproate • Depacon
1. Vaarasmaki MS, Hartikainen A, Anttila M, Pramila S, Koivisto M. Factors predicting peri- and neonatal outcome in diabetic pregnancy. Early Hum Dev 2000;59:61-70.
2. Ray JG, O’Brien TE, Chan WS. Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus: a meta-analysis. QJM 2001;94:435-444.
3. Pregnancy outcomes in the Diabetes Control and Complications Trial. Am J Obstet Gynecol 1996;174:1343-1353.
4. Nachum Z, Ben-Shlomo I, Weiner E, Shalev E. Twice daily versus four times daily insulin dose regimens for diabetes in pregnancy. BMJ 1999;319:1223-1227.
5. Walkinshaw SA. Very tight versus tight control for diabetes in pregnancy (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Last updated 2-15-1999. Accessed on January 4, 2004.
6. Walkinshaw SA. Dietary regulation for ‘gestational diabetes’ (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Last updated 2-25-1999. Accessed on January 4, 2004.
7. West J, Walkinshaw SA. Treatments for gestational diabetes and impaired glucose tolerance in pregnancy (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Last updated 9-12-2002. Accessed on January 4, 2004.
8. ACOG technical bulletin Diabetes and pregnancy. Number 200—December 1994 (replaces No. 92, May 1986). Committee on Technical Bulletins of the American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 1995;48:331-339.
9. Gestational Diabetes. ACOG Pract Bull No. 30. American College of Obstetricians and Gynecologists. Obstet Gynecol 2001;98:525-538.
10. Preconception care of women with diabetes. Diabetes Care 2004;27 Suppl 1:S76-S78.Available at: care.diabetesjournals.org/cgi/content/full/27/suppl_1/s76. Accessed on January 4, 2004.
11. Gestational diabetes mellitus. Diabetes Care 2003;26 Suppl 1:S103-S105.Available at: care.diabetesjournals.org/cgi/content/full/26/suppl_1/s103. Accessed on January 4, 2004.
In pregnant women with preexisting type 1 diabetes mellitus, maintaining near-normal blood glucose levels decreases the rate of major congenital anomalies (defined as those causing death or a serious handicap necessitating surgical correction or medical treatment). Prolonged preconception control of blood sugar to near normal levels reduces the rate of major congenital anomalies close to those seen in women without diabetes (strength of recommendation [SOR]: A, based on prospective cohort studies and randomized controlled trial [RCT]).
Intensive management reduces the risk of congenital anomalies more than conventional therapy, and lowers the risk of neonatal hypoglycemia (SOR: B, based on RCT). Very tight control does not reduce clinically significant neonatal morbidity but does increase the risk of maternal hypoglycemia (SOR: B, based on a systematic review). Evidence is insufficient about whether or not these statements hold true for women with type 2 diabetes.
In women with impaired glucose tolerance, dietary control reduces neonatal hypoglycemia. To date, studies have not found statistically significant reductions in admission rates to the special care nursery or birth weights above the 90th percentile (SOR: B, systematic review). Evidence is insufficient to suggest improved outcomes with therapy in women with gestational diabetes. Standard recommendations typically recommend tight control in this population as well.
Evidence summary
Two studies show that in type 1 diabetes mellitus, elevated blood glucose levels in early pregnancy (HbA1c=6%–8%) are associated with a threefold increase in fetal malformations.1,2 Maintaining preconception and early pregnancy blood glucose levels in the normal range can reduce this risk. A meta-analysis comparing 16 studies of women with pregestational diabetes—13 of which included only women with type 1 diabetes—found that women receiving preconception care had lower early first trimester HbA1c levels than those who did not (7.9% vs 9.6%) and delivered fewer infants with major congenital anomalies (relative risk [RR]=0.36; 95% confidence interval [CI], 0.22–0.59).2 One limitation of this study was that preconception care was not consistently defined among the included studies.
A 10-year RCT evaluated the outcomes of 270 pregnancies in women who had received either intensive (SQ infusion or multiple daily injections) or conventional insulin regimens prior to pregnancy. Women were advised to use intensive therapy when they were trying to conceive, and all were changed to intensive therapy if pregnancy was confirmed. Women in the intensive therapy group had normal HbA1c levels for an average of 40 months before conception. Women receiving intensive therapy had lower mean HbA1c levels at conception (7.4 ± 1.3 SD vs 8.1 ± 1.7 SD) and fewer major congenital anomalies (0.7% vs 5.9%; number needed to treat=19) than did women in the conventional group. When infants with genetic malformations were excluded from the analysis, rates of congenital malformations were similar in women switched to intensive therapy either before or after conception (3.8% vs 3.6%). No differences were seen between neonatal mortality, spontaneous abortion rates, birth weights, Apgar scores, and hypocalcemia or hypoglycemia rates.3
When tight and very tight control of glucose in pregnant women with pregestational diabetes were compared in a Cochrane systematic review, rates of maternal hypoglycemia in the very tightly controlled group were higher (odds ratio [OR]=25.96; 95% CI, 4.91–137.26).5 An RCT of 118 women with pregestational diabetes compared 4-times-daily vs twice-daily doses of insulin. Infants born to women receiving 4-times-daily insulin had significantly lower rates of neonatal hypoglycemia (RR=0.17; 95% CI, 0.04–0.74). While the trend was toward improved neonatal metabolic effects in the trials, the clinical significance of these findings is not clear.
Whether or not treatment of gestational diabetes improves outcomes is uncertain. A Cochrane systematic review evaluating a small number of trials, with variable quality and inconsistent outcome measures, compared dietary management to routine care in gestational diabetics. While fewer infants with birth weights >4000 g were delivered in the diet therapy group (OR=0.78; 95% CI, 0.45–1.35), the results were not statistically significant. No other important clinical differences were found.6
Another Cochrane systematic review evaluated the effects of dietary treatment of women with impaired glucose tolerance and gestational diabetes. Three trials with a total of 223 women with impaired glucose tolerance found a significant reduction in the rate of neonatal hypoglycemia (RR=0.25; 95% CI, 0.07–0.86). There was no significant change in the rates of cesarean section (RR=0.86; 95% CI, 0.51–1.45), admission to the special care nursery (RR=0.49; 95% CI, 0.19–1.24), or birth weights greater than the 90th percentile (RR=0.55; 95% CI, 0.19–1.61). Inadequate power may well account for the failure to reach significance in these outcomes.7
Recommendations from others
The American College of Obstetrics and Gynecology (ACOG) recommends that women with pregestational diabetes maintain fasting plasma glucose levels between 60–90 mg/dL and 2-hour postprandial levels <120 mg/dL.8 For women with gestational diabetes who are not controlled within these targets on dietary therapy alone, ACOG recommends the additional of insulin therapy.9
The American Diabetes Association recommends that women with pregestational diabetes maintain capillary plasma glucose levels of 80–110 mg/dL before and <155 mg/dL 2 hours after meals before pregnancy and while trying to conceive.10 The ADA does not list target glucose levels for women with pregestational diabetes once they become pregnant. The ADA recommends the use of diet and insulin therapy to maintain preprandial plasma glucose levels of <105 mg/dL and 2-hour postprandial levels below <130 mg/dL in gestational diabetes.11
Glucose control makes a difference for pregnancy outcomes in type I diabetes
Linda French, MD
Michigan State University, East Lansing
It is well accepted that glucose control makes a difference for pregnancy outcomes in women with type 1 diabetes. Since similar studies have not been done in women with preexisting type 2 diabetes, we have to assume that the risk is also high for them. Preconception counseling about glucose control is so important for women with diabetes. Fortunately, because they generally have routine visits for their chronic care, we have an opportunity to initiate discussion of glucose control in relationship to pregnancy planning. Routine diabetes care visits also give us the opportunity to discuss other important preconception topics.
- Allopurinol • Lopurin, Zyloprim
- Amitriptyline • Elavil, Endep
- Benzbromarone • Urinorm
- Botulinim toxin A • Botox
- Clindamycin • Cleocin
- Fluoxetine • Prozac
- Fluticasone • Flovent
- Gabapentin • Neurontin
- Metronidazole (intravaginal) • MetroGel
- Probenecid • Benemid, Probalan
- Sumatriptan • Imitrex
- Tizanidine • Zanaflex
- Triamcinolone • Azmacort
- Valproate • Depacon
In pregnant women with preexisting type 1 diabetes mellitus, maintaining near-normal blood glucose levels decreases the rate of major congenital anomalies (defined as those causing death or a serious handicap necessitating surgical correction or medical treatment). Prolonged preconception control of blood sugar to near normal levels reduces the rate of major congenital anomalies close to those seen in women without diabetes (strength of recommendation [SOR]: A, based on prospective cohort studies and randomized controlled trial [RCT]).
Intensive management reduces the risk of congenital anomalies more than conventional therapy, and lowers the risk of neonatal hypoglycemia (SOR: B, based on RCT). Very tight control does not reduce clinically significant neonatal morbidity but does increase the risk of maternal hypoglycemia (SOR: B, based on a systematic review). Evidence is insufficient about whether or not these statements hold true for women with type 2 diabetes.
In women with impaired glucose tolerance, dietary control reduces neonatal hypoglycemia. To date, studies have not found statistically significant reductions in admission rates to the special care nursery or birth weights above the 90th percentile (SOR: B, systematic review). Evidence is insufficient to suggest improved outcomes with therapy in women with gestational diabetes. Standard recommendations typically recommend tight control in this population as well.
Evidence summary
Two studies show that in type 1 diabetes mellitus, elevated blood glucose levels in early pregnancy (HbA1c=6%–8%) are associated with a threefold increase in fetal malformations.1,2 Maintaining preconception and early pregnancy blood glucose levels in the normal range can reduce this risk. A meta-analysis comparing 16 studies of women with pregestational diabetes—13 of which included only women with type 1 diabetes—found that women receiving preconception care had lower early first trimester HbA1c levels than those who did not (7.9% vs 9.6%) and delivered fewer infants with major congenital anomalies (relative risk [RR]=0.36; 95% confidence interval [CI], 0.22–0.59).2 One limitation of this study was that preconception care was not consistently defined among the included studies.
A 10-year RCT evaluated the outcomes of 270 pregnancies in women who had received either intensive (SQ infusion or multiple daily injections) or conventional insulin regimens prior to pregnancy. Women were advised to use intensive therapy when they were trying to conceive, and all were changed to intensive therapy if pregnancy was confirmed. Women in the intensive therapy group had normal HbA1c levels for an average of 40 months before conception. Women receiving intensive therapy had lower mean HbA1c levels at conception (7.4 ± 1.3 SD vs 8.1 ± 1.7 SD) and fewer major congenital anomalies (0.7% vs 5.9%; number needed to treat=19) than did women in the conventional group. When infants with genetic malformations were excluded from the analysis, rates of congenital malformations were similar in women switched to intensive therapy either before or after conception (3.8% vs 3.6%). No differences were seen between neonatal mortality, spontaneous abortion rates, birth weights, Apgar scores, and hypocalcemia or hypoglycemia rates.3
When tight and very tight control of glucose in pregnant women with pregestational diabetes were compared in a Cochrane systematic review, rates of maternal hypoglycemia in the very tightly controlled group were higher (odds ratio [OR]=25.96; 95% CI, 4.91–137.26).5 An RCT of 118 women with pregestational diabetes compared 4-times-daily vs twice-daily doses of insulin. Infants born to women receiving 4-times-daily insulin had significantly lower rates of neonatal hypoglycemia (RR=0.17; 95% CI, 0.04–0.74). While the trend was toward improved neonatal metabolic effects in the trials, the clinical significance of these findings is not clear.
Whether or not treatment of gestational diabetes improves outcomes is uncertain. A Cochrane systematic review evaluating a small number of trials, with variable quality and inconsistent outcome measures, compared dietary management to routine care in gestational diabetics. While fewer infants with birth weights >4000 g were delivered in the diet therapy group (OR=0.78; 95% CI, 0.45–1.35), the results were not statistically significant. No other important clinical differences were found.6
Another Cochrane systematic review evaluated the effects of dietary treatment of women with impaired glucose tolerance and gestational diabetes. Three trials with a total of 223 women with impaired glucose tolerance found a significant reduction in the rate of neonatal hypoglycemia (RR=0.25; 95% CI, 0.07–0.86). There was no significant change in the rates of cesarean section (RR=0.86; 95% CI, 0.51–1.45), admission to the special care nursery (RR=0.49; 95% CI, 0.19–1.24), or birth weights greater than the 90th percentile (RR=0.55; 95% CI, 0.19–1.61). Inadequate power may well account for the failure to reach significance in these outcomes.7
Recommendations from others
The American College of Obstetrics and Gynecology (ACOG) recommends that women with pregestational diabetes maintain fasting plasma glucose levels between 60–90 mg/dL and 2-hour postprandial levels <120 mg/dL.8 For women with gestational diabetes who are not controlled within these targets on dietary therapy alone, ACOG recommends the additional of insulin therapy.9
The American Diabetes Association recommends that women with pregestational diabetes maintain capillary plasma glucose levels of 80–110 mg/dL before and <155 mg/dL 2 hours after meals before pregnancy and while trying to conceive.10 The ADA does not list target glucose levels for women with pregestational diabetes once they become pregnant. The ADA recommends the use of diet and insulin therapy to maintain preprandial plasma glucose levels of <105 mg/dL and 2-hour postprandial levels below <130 mg/dL in gestational diabetes.11
Glucose control makes a difference for pregnancy outcomes in type I diabetes
Linda French, MD
Michigan State University, East Lansing
It is well accepted that glucose control makes a difference for pregnancy outcomes in women with type 1 diabetes. Since similar studies have not been done in women with preexisting type 2 diabetes, we have to assume that the risk is also high for them. Preconception counseling about glucose control is so important for women with diabetes. Fortunately, because they generally have routine visits for their chronic care, we have an opportunity to initiate discussion of glucose control in relationship to pregnancy planning. Routine diabetes care visits also give us the opportunity to discuss other important preconception topics.
- Allopurinol • Lopurin, Zyloprim
- Amitriptyline • Elavil, Endep
- Benzbromarone • Urinorm
- Botulinim toxin A • Botox
- Clindamycin • Cleocin
- Fluoxetine • Prozac
- Fluticasone • Flovent
- Gabapentin • Neurontin
- Metronidazole (intravaginal) • MetroGel
- Probenecid • Benemid, Probalan
- Sumatriptan • Imitrex
- Tizanidine • Zanaflex
- Triamcinolone • Azmacort
- Valproate • Depacon
1. Vaarasmaki MS, Hartikainen A, Anttila M, Pramila S, Koivisto M. Factors predicting peri- and neonatal outcome in diabetic pregnancy. Early Hum Dev 2000;59:61-70.
2. Ray JG, O’Brien TE, Chan WS. Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus: a meta-analysis. QJM 2001;94:435-444.
3. Pregnancy outcomes in the Diabetes Control and Complications Trial. Am J Obstet Gynecol 1996;174:1343-1353.
4. Nachum Z, Ben-Shlomo I, Weiner E, Shalev E. Twice daily versus four times daily insulin dose regimens for diabetes in pregnancy. BMJ 1999;319:1223-1227.
5. Walkinshaw SA. Very tight versus tight control for diabetes in pregnancy (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Last updated 2-15-1999. Accessed on January 4, 2004.
6. Walkinshaw SA. Dietary regulation for ‘gestational diabetes’ (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Last updated 2-25-1999. Accessed on January 4, 2004.
7. West J, Walkinshaw SA. Treatments for gestational diabetes and impaired glucose tolerance in pregnancy (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Last updated 9-12-2002. Accessed on January 4, 2004.
8. ACOG technical bulletin Diabetes and pregnancy. Number 200—December 1994 (replaces No. 92, May 1986). Committee on Technical Bulletins of the American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 1995;48:331-339.
9. Gestational Diabetes. ACOG Pract Bull No. 30. American College of Obstetricians and Gynecologists. Obstet Gynecol 2001;98:525-538.
10. Preconception care of women with diabetes. Diabetes Care 2004;27 Suppl 1:S76-S78.Available at: care.diabetesjournals.org/cgi/content/full/27/suppl_1/s76. Accessed on January 4, 2004.
11. Gestational diabetes mellitus. Diabetes Care 2003;26 Suppl 1:S103-S105.Available at: care.diabetesjournals.org/cgi/content/full/26/suppl_1/s103. Accessed on January 4, 2004.
1. Vaarasmaki MS, Hartikainen A, Anttila M, Pramila S, Koivisto M. Factors predicting peri- and neonatal outcome in diabetic pregnancy. Early Hum Dev 2000;59:61-70.
2. Ray JG, O’Brien TE, Chan WS. Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus: a meta-analysis. QJM 2001;94:435-444.
3. Pregnancy outcomes in the Diabetes Control and Complications Trial. Am J Obstet Gynecol 1996;174:1343-1353.
4. Nachum Z, Ben-Shlomo I, Weiner E, Shalev E. Twice daily versus four times daily insulin dose regimens for diabetes in pregnancy. BMJ 1999;319:1223-1227.
5. Walkinshaw SA. Very tight versus tight control for diabetes in pregnancy (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Last updated 2-15-1999. Accessed on January 4, 2004.
6. Walkinshaw SA. Dietary regulation for ‘gestational diabetes’ (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Last updated 2-25-1999. Accessed on January 4, 2004.
7. West J, Walkinshaw SA. Treatments for gestational diabetes and impaired glucose tolerance in pregnancy (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd. Last updated 9-12-2002. Accessed on January 4, 2004.
8. ACOG technical bulletin Diabetes and pregnancy. Number 200—December 1994 (replaces No. 92, May 1986). Committee on Technical Bulletins of the American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 1995;48:331-339.
9. Gestational Diabetes. ACOG Pract Bull No. 30. American College of Obstetricians and Gynecologists. Obstet Gynecol 2001;98:525-538.
10. Preconception care of women with diabetes. Diabetes Care 2004;27 Suppl 1:S76-S78.Available at: care.diabetesjournals.org/cgi/content/full/27/suppl_1/s76. Accessed on January 4, 2004.
11. Gestational diabetes mellitus. Diabetes Care 2003;26 Suppl 1:S103-S105.Available at: care.diabetesjournals.org/cgi/content/full/26/suppl_1/s103. Accessed on January 4, 2004.
Evidence-based answers from the Family Physicians Inquiries Network
Do ACE inhibitors prevent nephropathy in type 2 diabetes without proteinuria?
Angiotensin-converting enzyme (ACE) inhibitors make a significant difference for patients with diabetes as a whole. If patients both with and without microalbuminuria are included together, ACE inhibitors significantly reduce the progression of the albumin excretion rate (strength of recommendation [SOR]: A, based on multiple randomized controlled trials) and the development of overt nephropathy (SOR: A, based on 1 randomized controlled trial).
However, studying diabetes without microalbuminuria separately, the effect of ACE inhibitors on progression to nephropathy does not reach statistical significance. This applies to both type 1 and 2 diabetes (SOR: A, based on randomized controlled trials with heterogenous results). Results are contradictory regarding whether ACE inhibition delays new onset of diabetic microalbuminuria.
Evidence summary
There are 3 prospective randomized controlled trials studying the effect of ACE inhibitors on albumin excretion for patients with diabetes who do not have microalbuminuria. A 2-year randomized controlled trial compared lisinopril (Prinivil; Zestril) 10 mg/d with placebo in 530 normotensive adults (aged 20–59 years) with insulin-dependent diabetes, defined as those diagnosed with diabetes before age 36 and using continuous insulin therapy within 1 year of diagnosis. At the beginning of the study, 90 patients had microalbuminuria—defined as an albumin excretion rate (AER) >29 mg/24 hr—and 440 patients did not. When the results for all patients who had and did not have microalbuminuria were combined, there was a significantly smaller rise in the AER for the lisinopril group vs the placebo group (3.2 mg/24 hr lower; P=.03). However, for the patients without initial microalbuminuria, the reduction in the rise of AER with lisinopril was not significant (1.4 mg/24 hr lower; P=.10). The decreased rate of developing new microalbuminuria was also not significant (relative risk reduction [RRR]=12.7%; P=.10).1
A subsequent trial compared enalapril (Vasotec) 10 mg/d with placebo in 194 normotensive patients (aged 40–60) with type 2 diabetes and without microalbuminuria, defined as AER >30 mg/24 hr. Over the 6-year course of the study, the AER in the placebo group rose from 10.8 mg/24 hr to 26.5 mg/24 hr. The AER of the treatment group dropped from 11.6 mg/24 hr initially to 9.7 mg/24 hr at 2 years, then rose to 15.8 mg/24 hr at 6 years. Enalapril significantly slowed the rise in AER (RRR=0.4; P=.001). Nineteen percent of the placebo group developed microalbuminuria, compared with 6.5% of those taking enalapril (absolute risk reduction[ARR]=12.5%; number needed to treat=8; P=.042). While this study described a modest and statistically significant renal protective effect of enalapril, it did not use an intention-to-treat analysis.2
MICRO-HOPE, a subset of the HOPE trial, studied ramipril (Altace) 10 mg/d vs placebo in 2437 patients with diabetes who did not have clinical proteinuria. Patients were aged 55 years or older and had either a previous cardiovascular event or at least 1 other cardiovascular risk factor. There were 1140 patients with microalbuminuria, defined as an albumin/creatinine ratio 2 mg/mmol, and 2437 patients without. After 4.5 years, 10% of patients had developed overt nephropathy, defined as albumin/creatinine >36 mg/mmol.
When all patients in the study were examined together, ramipril provided significant renal protection over placebo (RRR=24%; ARR=1%; P=.027). It also lowered the risk of MI by 22%, stroke by 33%, and cardiovascular death by 37%. But in a separate analysis of the patients without microalbuminuria, ramipril did not significantly reduce overt nephropathy (P=.50). Ramipril also did not significantly reduce the risk of developing new microalbuminuria in this group (RRR=9%; P=.17). Further, for patients without microalbuminuria, ramipril did not reduce the combined outcomes of myocardial infarction, stroke, or cardiovascular death (odds ratio=0.85; 95% CI, 0.70–1.02).3
Recommendations from others
We could find no guidelines recommending for or against the use of ACE inhibitors for patients with diabetes without microalbuminuria.
ACE inhibitors should still be used in most patients with type 2 diabetes
Joseph Saseen, PharmD, FCCP, BCPS
University of Colorado Health Sciences Center, Denver
ACE inhibitors do not prevent the development of type 2 diabetic nephropathy. In contrast to type 1 diabetes, cardiovascular disease is the primary cause of death in type 2. The HOPE study demonstrated that ACE inhibitor therapy significantly reduces cardiovascular events in type 2 diabetes independent of hypertension status.4 These benefits are so compelling that the American Diabetes Association strongly recommends ACE inhibitor therapy for type 2 diabetics aged ≥55 years with 1 additional risk factor.5 Despite not preventing the development of nephropathy, ACE inhibitors should be used for most patients with type 2 diabetes for cardiovascular risk reduction.
1. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. The EUCLID Study Group. Lancet 1997;349:1787-1792.
2. Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 1998;128:982-988.
3. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000;355:253-259.
4. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-153.
5. Arauz-Pacheco C, Parrott MA, Raskin P. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care 2003;26 Suppl 1:S80-S82.
Angiotensin-converting enzyme (ACE) inhibitors make a significant difference for patients with diabetes as a whole. If patients both with and without microalbuminuria are included together, ACE inhibitors significantly reduce the progression of the albumin excretion rate (strength of recommendation [SOR]: A, based on multiple randomized controlled trials) and the development of overt nephropathy (SOR: A, based on 1 randomized controlled trial).
However, studying diabetes without microalbuminuria separately, the effect of ACE inhibitors on progression to nephropathy does not reach statistical significance. This applies to both type 1 and 2 diabetes (SOR: A, based on randomized controlled trials with heterogenous results). Results are contradictory regarding whether ACE inhibition delays new onset of diabetic microalbuminuria.
Evidence summary
There are 3 prospective randomized controlled trials studying the effect of ACE inhibitors on albumin excretion for patients with diabetes who do not have microalbuminuria. A 2-year randomized controlled trial compared lisinopril (Prinivil; Zestril) 10 mg/d with placebo in 530 normotensive adults (aged 20–59 years) with insulin-dependent diabetes, defined as those diagnosed with diabetes before age 36 and using continuous insulin therapy within 1 year of diagnosis. At the beginning of the study, 90 patients had microalbuminuria—defined as an albumin excretion rate (AER) >29 mg/24 hr—and 440 patients did not. When the results for all patients who had and did not have microalbuminuria were combined, there was a significantly smaller rise in the AER for the lisinopril group vs the placebo group (3.2 mg/24 hr lower; P=.03). However, for the patients without initial microalbuminuria, the reduction in the rise of AER with lisinopril was not significant (1.4 mg/24 hr lower; P=.10). The decreased rate of developing new microalbuminuria was also not significant (relative risk reduction [RRR]=12.7%; P=.10).1
A subsequent trial compared enalapril (Vasotec) 10 mg/d with placebo in 194 normotensive patients (aged 40–60) with type 2 diabetes and without microalbuminuria, defined as AER >30 mg/24 hr. Over the 6-year course of the study, the AER in the placebo group rose from 10.8 mg/24 hr to 26.5 mg/24 hr. The AER of the treatment group dropped from 11.6 mg/24 hr initially to 9.7 mg/24 hr at 2 years, then rose to 15.8 mg/24 hr at 6 years. Enalapril significantly slowed the rise in AER (RRR=0.4; P=.001). Nineteen percent of the placebo group developed microalbuminuria, compared with 6.5% of those taking enalapril (absolute risk reduction[ARR]=12.5%; number needed to treat=8; P=.042). While this study described a modest and statistically significant renal protective effect of enalapril, it did not use an intention-to-treat analysis.2
MICRO-HOPE, a subset of the HOPE trial, studied ramipril (Altace) 10 mg/d vs placebo in 2437 patients with diabetes who did not have clinical proteinuria. Patients were aged 55 years or older and had either a previous cardiovascular event or at least 1 other cardiovascular risk factor. There were 1140 patients with microalbuminuria, defined as an albumin/creatinine ratio 2 mg/mmol, and 2437 patients without. After 4.5 years, 10% of patients had developed overt nephropathy, defined as albumin/creatinine >36 mg/mmol.
When all patients in the study were examined together, ramipril provided significant renal protection over placebo (RRR=24%; ARR=1%; P=.027). It also lowered the risk of MI by 22%, stroke by 33%, and cardiovascular death by 37%. But in a separate analysis of the patients without microalbuminuria, ramipril did not significantly reduce overt nephropathy (P=.50). Ramipril also did not significantly reduce the risk of developing new microalbuminuria in this group (RRR=9%; P=.17). Further, for patients without microalbuminuria, ramipril did not reduce the combined outcomes of myocardial infarction, stroke, or cardiovascular death (odds ratio=0.85; 95% CI, 0.70–1.02).3
Recommendations from others
We could find no guidelines recommending for or against the use of ACE inhibitors for patients with diabetes without microalbuminuria.
ACE inhibitors should still be used in most patients with type 2 diabetes
Joseph Saseen, PharmD, FCCP, BCPS
University of Colorado Health Sciences Center, Denver
ACE inhibitors do not prevent the development of type 2 diabetic nephropathy. In contrast to type 1 diabetes, cardiovascular disease is the primary cause of death in type 2. The HOPE study demonstrated that ACE inhibitor therapy significantly reduces cardiovascular events in type 2 diabetes independent of hypertension status.4 These benefits are so compelling that the American Diabetes Association strongly recommends ACE inhibitor therapy for type 2 diabetics aged ≥55 years with 1 additional risk factor.5 Despite not preventing the development of nephropathy, ACE inhibitors should be used for most patients with type 2 diabetes for cardiovascular risk reduction.
Angiotensin-converting enzyme (ACE) inhibitors make a significant difference for patients with diabetes as a whole. If patients both with and without microalbuminuria are included together, ACE inhibitors significantly reduce the progression of the albumin excretion rate (strength of recommendation [SOR]: A, based on multiple randomized controlled trials) and the development of overt nephropathy (SOR: A, based on 1 randomized controlled trial).
However, studying diabetes without microalbuminuria separately, the effect of ACE inhibitors on progression to nephropathy does not reach statistical significance. This applies to both type 1 and 2 diabetes (SOR: A, based on randomized controlled trials with heterogenous results). Results are contradictory regarding whether ACE inhibition delays new onset of diabetic microalbuminuria.
Evidence summary
There are 3 prospective randomized controlled trials studying the effect of ACE inhibitors on albumin excretion for patients with diabetes who do not have microalbuminuria. A 2-year randomized controlled trial compared lisinopril (Prinivil; Zestril) 10 mg/d with placebo in 530 normotensive adults (aged 20–59 years) with insulin-dependent diabetes, defined as those diagnosed with diabetes before age 36 and using continuous insulin therapy within 1 year of diagnosis. At the beginning of the study, 90 patients had microalbuminuria—defined as an albumin excretion rate (AER) >29 mg/24 hr—and 440 patients did not. When the results for all patients who had and did not have microalbuminuria were combined, there was a significantly smaller rise in the AER for the lisinopril group vs the placebo group (3.2 mg/24 hr lower; P=.03). However, for the patients without initial microalbuminuria, the reduction in the rise of AER with lisinopril was not significant (1.4 mg/24 hr lower; P=.10). The decreased rate of developing new microalbuminuria was also not significant (relative risk reduction [RRR]=12.7%; P=.10).1
A subsequent trial compared enalapril (Vasotec) 10 mg/d with placebo in 194 normotensive patients (aged 40–60) with type 2 diabetes and without microalbuminuria, defined as AER >30 mg/24 hr. Over the 6-year course of the study, the AER in the placebo group rose from 10.8 mg/24 hr to 26.5 mg/24 hr. The AER of the treatment group dropped from 11.6 mg/24 hr initially to 9.7 mg/24 hr at 2 years, then rose to 15.8 mg/24 hr at 6 years. Enalapril significantly slowed the rise in AER (RRR=0.4; P=.001). Nineteen percent of the placebo group developed microalbuminuria, compared with 6.5% of those taking enalapril (absolute risk reduction[ARR]=12.5%; number needed to treat=8; P=.042). While this study described a modest and statistically significant renal protective effect of enalapril, it did not use an intention-to-treat analysis.2
MICRO-HOPE, a subset of the HOPE trial, studied ramipril (Altace) 10 mg/d vs placebo in 2437 patients with diabetes who did not have clinical proteinuria. Patients were aged 55 years or older and had either a previous cardiovascular event or at least 1 other cardiovascular risk factor. There were 1140 patients with microalbuminuria, defined as an albumin/creatinine ratio 2 mg/mmol, and 2437 patients without. After 4.5 years, 10% of patients had developed overt nephropathy, defined as albumin/creatinine >36 mg/mmol.
When all patients in the study were examined together, ramipril provided significant renal protection over placebo (RRR=24%; ARR=1%; P=.027). It also lowered the risk of MI by 22%, stroke by 33%, and cardiovascular death by 37%. But in a separate analysis of the patients without microalbuminuria, ramipril did not significantly reduce overt nephropathy (P=.50). Ramipril also did not significantly reduce the risk of developing new microalbuminuria in this group (RRR=9%; P=.17). Further, for patients without microalbuminuria, ramipril did not reduce the combined outcomes of myocardial infarction, stroke, or cardiovascular death (odds ratio=0.85; 95% CI, 0.70–1.02).3
Recommendations from others
We could find no guidelines recommending for or against the use of ACE inhibitors for patients with diabetes without microalbuminuria.
ACE inhibitors should still be used in most patients with type 2 diabetes
Joseph Saseen, PharmD, FCCP, BCPS
University of Colorado Health Sciences Center, Denver
ACE inhibitors do not prevent the development of type 2 diabetic nephropathy. In contrast to type 1 diabetes, cardiovascular disease is the primary cause of death in type 2. The HOPE study demonstrated that ACE inhibitor therapy significantly reduces cardiovascular events in type 2 diabetes independent of hypertension status.4 These benefits are so compelling that the American Diabetes Association strongly recommends ACE inhibitor therapy for type 2 diabetics aged ≥55 years with 1 additional risk factor.5 Despite not preventing the development of nephropathy, ACE inhibitors should be used for most patients with type 2 diabetes for cardiovascular risk reduction.
1. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. The EUCLID Study Group. Lancet 1997;349:1787-1792.
2. Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 1998;128:982-988.
3. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000;355:253-259.
4. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-153.
5. Arauz-Pacheco C, Parrott MA, Raskin P. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care 2003;26 Suppl 1:S80-S82.
1. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. The EUCLID Study Group. Lancet 1997;349:1787-1792.
2. Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 1998;128:982-988.
3. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000;355:253-259.
4. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-153.
5. Arauz-Pacheco C, Parrott MA, Raskin P. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care 2003;26 Suppl 1:S80-S82.
Evidence-based answers from the Family Physicians Inquiries Network
What is the best treatment for bronchiolitis?
Nebulized epinephrine decreases oxygen requirements, respiratory rate, wheezing, and retractions and may lower hospitalization rates and length of stay (Grade of Recommendation: A, based on consistent randomized controlled trials [RCTs] and systematic reviews). At best, other beta-2 agonists provide modest short-term improvement in mild to moderate bronchiolitis (Grade of Recommendation: A, consistent RCTs and systematic reviews), and may be indicated in patients with preexisting asthma. Discontinue bronchodilators if patients do not respond quickly, because the bronchodilators may cause respiratory deterioration (Grade of Recommendation: D, expert opinion). Supplemental oxygen for low oxygen saturation and suctioning may improve respiratory status (Grade of Recommendation: D, expert opinion). Chest physiotherapy (Grade of Recommendation: D, expert opinion), cool mist (Grade of Recommendation: D, expert opinion), and aerosolized saline (Grade of Recommendation: A, based on RCTs) are not recommended. Steroids, routine antibiotics, ribavirin, and pooled immunoglobulins play no role in previously healthy children (Grade of Recommendation: A, systematic review, RCT and meta-analysis). See the Table for a summary of therapeutic interventions for bronchiolitis.
TABLE
Therapeutic interventions for bronchiolitis
| Intervention | Usefulness | Grade of recommendation | Notes |
|---|---|---|---|
| Nebulized epinephrine | Beneficial | A | Should be discontinued promptly in the absence of response |
| Beta-2 agonists | Not beneficial | A | May be useful in patients with preexisting asthma |
| Corticosteroids | Not beneficial | A | Not shown to impact clinical score or length of hospital stay |
| Supplemental oxygen, suctioning | Beneficial | D | Initiate at 91% and wean at 94% |
Evidence summary
Most trials of bronchiolitis treatment suffer from 2 constraints: possible inclusion of patients with asthma and inconsistent outcome measures. Five trials of nebulized epinephrine, involving 225 children, have been published in the last decade. All have shown clinical improvement in measures such as respiratory rate, wheezing, retractions, hospital admission rates, and length of stay.1
Data from other clinical trials, meta-analyses, and a comprehensive Cochrane systematic review do not support the routine use of selective beta-2 agonists. Studies with unselected patients noted some benefit, which may reflect the inclusion of asthmatic children, or the effects of suctioning in combination with inhalational therapy. Large proportions of patients admitted to hospital with bronchiolitis receive bronchodilators, and many physicians continue to advocate their use.2 The cost of routine bronchodilators for children with bronchiolitis may be as high as $37.5 million per year.2
One systematic review and 8 RCTs found conflicting evidence on the effects of corticosteroids.3 Steroid therapy, given as inhalations, intravenously, orally, or intramuscularly, does not have a consistent effect on clinical status or on length of stay.4
A 1997 systematic review showed that ribavirin had no significant effect on mortality or the risk of respiratory deterioration in children admitted to hospital with respiratory syncytial virus (RSV) bronchiolitis.3 In fact, cohort studies and randomized trials have shown that ribavirin use is associated with an increase in the number of days of mechanical ventilation, intensive care unit stay, and hospitalizations.4
Passive immunotherapy with pooled immunoglobulins remains controversial and is undergoing intense study.4 Three RCTs failed to show any effect on length of hospital stay, and subsequent studies of an RSV-specific humanized monoclonal antibody (palivizumab) have not shown improvements in outcome.
The evidence supporting the use of supplemental oxygen and suctioning of respiratory secretions is limited to expert opinion.5
Recommendations from others
Most pediatric infectious diseases specialists surveyed in Europe recommend bronchodilators. However, bronchodilators are seldom used to treat bronchiolitis in the United Kingdom.2 The present consensus from the American Academy of Pediatrics6 states that ribavirin should be considered in infants with underlying congenital heart disease, lung disease, or immunosuppression, or for infants requiring mechanical ventilation.
Harold A. Williamson, Jr, MD, MSPH
Department of Family and Community Medicine, University of Missouri– Columbia
Wheezing children are usually hospitalized when they have hypoxemia, lethargy, and fatigue associated with tachypnea and decreased oral intake. Because of the difficulty in differentiating between “bronchiolitis” and a first episode of “asthma,” many wheezing children will continue to receive bronchodilators. Discontinuing bronchodilators seems prudent if oxygenation and respiratory rate do not improve after 6 hours. Supportive care with fluids, oxygen, and suctioning of secretions is usually all that is required in even moderately sick patients. As in other situations involving sick children, the temptation to intervene is overwhelming, hence the many ineffective treatments available. RSV is by far the most common viral pathogen causing bronchiolitis; effective immunization for RSV would probably markedly decrease hospitalizations from bronchiolitis.
1. Schindler M. Do bronchodilators have an effect on bronchiolitis? Crit Care 2002;6:111-2.
2. Kellner JD, Ohlsson A, Gadomski AM, et al. Bronchodilators for bronchiolitis (Cochrane Review). In:The Cochrane Library, Issue 2, 2002. Oxford, England: Update Software.
3. Wang E. What are the effects of treatment for children with bronchiolitis? Clin Evid 2001 December.;
4. Barr F, Graham B. Respiratory syncytial virus. Up To Date 2001 June.;
5. National Guideline Clearinghouse.Evidence based clinical practice guidelines for the infant with bronchiolitis. Cincinnati, OH: Cincinnati Children’s Hospital Medical Center; 2001 Nov 28.
6. Committee on Infect Diseases, American Academy of Pediatrics. Reassessment of the indications for ribavirin therapy in respiratory syncytial virus infections. Pediatrics 1996;97:137.-
Nebulized epinephrine decreases oxygen requirements, respiratory rate, wheezing, and retractions and may lower hospitalization rates and length of stay (Grade of Recommendation: A, based on consistent randomized controlled trials [RCTs] and systematic reviews). At best, other beta-2 agonists provide modest short-term improvement in mild to moderate bronchiolitis (Grade of Recommendation: A, consistent RCTs and systematic reviews), and may be indicated in patients with preexisting asthma. Discontinue bronchodilators if patients do not respond quickly, because the bronchodilators may cause respiratory deterioration (Grade of Recommendation: D, expert opinion). Supplemental oxygen for low oxygen saturation and suctioning may improve respiratory status (Grade of Recommendation: D, expert opinion). Chest physiotherapy (Grade of Recommendation: D, expert opinion), cool mist (Grade of Recommendation: D, expert opinion), and aerosolized saline (Grade of Recommendation: A, based on RCTs) are not recommended. Steroids, routine antibiotics, ribavirin, and pooled immunoglobulins play no role in previously healthy children (Grade of Recommendation: A, systematic review, RCT and meta-analysis). See the Table for a summary of therapeutic interventions for bronchiolitis.
TABLE
Therapeutic interventions for bronchiolitis
| Intervention | Usefulness | Grade of recommendation | Notes |
|---|---|---|---|
| Nebulized epinephrine | Beneficial | A | Should be discontinued promptly in the absence of response |
| Beta-2 agonists | Not beneficial | A | May be useful in patients with preexisting asthma |
| Corticosteroids | Not beneficial | A | Not shown to impact clinical score or length of hospital stay |
| Supplemental oxygen, suctioning | Beneficial | D | Initiate at 91% and wean at 94% |
Evidence summary
Most trials of bronchiolitis treatment suffer from 2 constraints: possible inclusion of patients with asthma and inconsistent outcome measures. Five trials of nebulized epinephrine, involving 225 children, have been published in the last decade. All have shown clinical improvement in measures such as respiratory rate, wheezing, retractions, hospital admission rates, and length of stay.1
Data from other clinical trials, meta-analyses, and a comprehensive Cochrane systematic review do not support the routine use of selective beta-2 agonists. Studies with unselected patients noted some benefit, which may reflect the inclusion of asthmatic children, or the effects of suctioning in combination with inhalational therapy. Large proportions of patients admitted to hospital with bronchiolitis receive bronchodilators, and many physicians continue to advocate their use.2 The cost of routine bronchodilators for children with bronchiolitis may be as high as $37.5 million per year.2
One systematic review and 8 RCTs found conflicting evidence on the effects of corticosteroids.3 Steroid therapy, given as inhalations, intravenously, orally, or intramuscularly, does not have a consistent effect on clinical status or on length of stay.4
A 1997 systematic review showed that ribavirin had no significant effect on mortality or the risk of respiratory deterioration in children admitted to hospital with respiratory syncytial virus (RSV) bronchiolitis.3 In fact, cohort studies and randomized trials have shown that ribavirin use is associated with an increase in the number of days of mechanical ventilation, intensive care unit stay, and hospitalizations.4
Passive immunotherapy with pooled immunoglobulins remains controversial and is undergoing intense study.4 Three RCTs failed to show any effect on length of hospital stay, and subsequent studies of an RSV-specific humanized monoclonal antibody (palivizumab) have not shown improvements in outcome.
The evidence supporting the use of supplemental oxygen and suctioning of respiratory secretions is limited to expert opinion.5
Recommendations from others
Most pediatric infectious diseases specialists surveyed in Europe recommend bronchodilators. However, bronchodilators are seldom used to treat bronchiolitis in the United Kingdom.2 The present consensus from the American Academy of Pediatrics6 states that ribavirin should be considered in infants with underlying congenital heart disease, lung disease, or immunosuppression, or for infants requiring mechanical ventilation.
Harold A. Williamson, Jr, MD, MSPH
Department of Family and Community Medicine, University of Missouri– Columbia
Wheezing children are usually hospitalized when they have hypoxemia, lethargy, and fatigue associated with tachypnea and decreased oral intake. Because of the difficulty in differentiating between “bronchiolitis” and a first episode of “asthma,” many wheezing children will continue to receive bronchodilators. Discontinuing bronchodilators seems prudent if oxygenation and respiratory rate do not improve after 6 hours. Supportive care with fluids, oxygen, and suctioning of secretions is usually all that is required in even moderately sick patients. As in other situations involving sick children, the temptation to intervene is overwhelming, hence the many ineffective treatments available. RSV is by far the most common viral pathogen causing bronchiolitis; effective immunization for RSV would probably markedly decrease hospitalizations from bronchiolitis.
Nebulized epinephrine decreases oxygen requirements, respiratory rate, wheezing, and retractions and may lower hospitalization rates and length of stay (Grade of Recommendation: A, based on consistent randomized controlled trials [RCTs] and systematic reviews). At best, other beta-2 agonists provide modest short-term improvement in mild to moderate bronchiolitis (Grade of Recommendation: A, consistent RCTs and systematic reviews), and may be indicated in patients with preexisting asthma. Discontinue bronchodilators if patients do not respond quickly, because the bronchodilators may cause respiratory deterioration (Grade of Recommendation: D, expert opinion). Supplemental oxygen for low oxygen saturation and suctioning may improve respiratory status (Grade of Recommendation: D, expert opinion). Chest physiotherapy (Grade of Recommendation: D, expert opinion), cool mist (Grade of Recommendation: D, expert opinion), and aerosolized saline (Grade of Recommendation: A, based on RCTs) are not recommended. Steroids, routine antibiotics, ribavirin, and pooled immunoglobulins play no role in previously healthy children (Grade of Recommendation: A, systematic review, RCT and meta-analysis). See the Table for a summary of therapeutic interventions for bronchiolitis.
TABLE
Therapeutic interventions for bronchiolitis
| Intervention | Usefulness | Grade of recommendation | Notes |
|---|---|---|---|
| Nebulized epinephrine | Beneficial | A | Should be discontinued promptly in the absence of response |
| Beta-2 agonists | Not beneficial | A | May be useful in patients with preexisting asthma |
| Corticosteroids | Not beneficial | A | Not shown to impact clinical score or length of hospital stay |
| Supplemental oxygen, suctioning | Beneficial | D | Initiate at 91% and wean at 94% |
Evidence summary
Most trials of bronchiolitis treatment suffer from 2 constraints: possible inclusion of patients with asthma and inconsistent outcome measures. Five trials of nebulized epinephrine, involving 225 children, have been published in the last decade. All have shown clinical improvement in measures such as respiratory rate, wheezing, retractions, hospital admission rates, and length of stay.1
Data from other clinical trials, meta-analyses, and a comprehensive Cochrane systematic review do not support the routine use of selective beta-2 agonists. Studies with unselected patients noted some benefit, which may reflect the inclusion of asthmatic children, or the effects of suctioning in combination with inhalational therapy. Large proportions of patients admitted to hospital with bronchiolitis receive bronchodilators, and many physicians continue to advocate their use.2 The cost of routine bronchodilators for children with bronchiolitis may be as high as $37.5 million per year.2
One systematic review and 8 RCTs found conflicting evidence on the effects of corticosteroids.3 Steroid therapy, given as inhalations, intravenously, orally, or intramuscularly, does not have a consistent effect on clinical status or on length of stay.4
A 1997 systematic review showed that ribavirin had no significant effect on mortality or the risk of respiratory deterioration in children admitted to hospital with respiratory syncytial virus (RSV) bronchiolitis.3 In fact, cohort studies and randomized trials have shown that ribavirin use is associated with an increase in the number of days of mechanical ventilation, intensive care unit stay, and hospitalizations.4
Passive immunotherapy with pooled immunoglobulins remains controversial and is undergoing intense study.4 Three RCTs failed to show any effect on length of hospital stay, and subsequent studies of an RSV-specific humanized monoclonal antibody (palivizumab) have not shown improvements in outcome.
The evidence supporting the use of supplemental oxygen and suctioning of respiratory secretions is limited to expert opinion.5
Recommendations from others
Most pediatric infectious diseases specialists surveyed in Europe recommend bronchodilators. However, bronchodilators are seldom used to treat bronchiolitis in the United Kingdom.2 The present consensus from the American Academy of Pediatrics6 states that ribavirin should be considered in infants with underlying congenital heart disease, lung disease, or immunosuppression, or for infants requiring mechanical ventilation.
Harold A. Williamson, Jr, MD, MSPH
Department of Family and Community Medicine, University of Missouri– Columbia
Wheezing children are usually hospitalized when they have hypoxemia, lethargy, and fatigue associated with tachypnea and decreased oral intake. Because of the difficulty in differentiating between “bronchiolitis” and a first episode of “asthma,” many wheezing children will continue to receive bronchodilators. Discontinuing bronchodilators seems prudent if oxygenation and respiratory rate do not improve after 6 hours. Supportive care with fluids, oxygen, and suctioning of secretions is usually all that is required in even moderately sick patients. As in other situations involving sick children, the temptation to intervene is overwhelming, hence the many ineffective treatments available. RSV is by far the most common viral pathogen causing bronchiolitis; effective immunization for RSV would probably markedly decrease hospitalizations from bronchiolitis.
1. Schindler M. Do bronchodilators have an effect on bronchiolitis? Crit Care 2002;6:111-2.
2. Kellner JD, Ohlsson A, Gadomski AM, et al. Bronchodilators for bronchiolitis (Cochrane Review). In:The Cochrane Library, Issue 2, 2002. Oxford, England: Update Software.
3. Wang E. What are the effects of treatment for children with bronchiolitis? Clin Evid 2001 December.;
4. Barr F, Graham B. Respiratory syncytial virus. Up To Date 2001 June.;
5. National Guideline Clearinghouse.Evidence based clinical practice guidelines for the infant with bronchiolitis. Cincinnati, OH: Cincinnati Children’s Hospital Medical Center; 2001 Nov 28.
6. Committee on Infect Diseases, American Academy of Pediatrics. Reassessment of the indications for ribavirin therapy in respiratory syncytial virus infections. Pediatrics 1996;97:137.-
1. Schindler M. Do bronchodilators have an effect on bronchiolitis? Crit Care 2002;6:111-2.
2. Kellner JD, Ohlsson A, Gadomski AM, et al. Bronchodilators for bronchiolitis (Cochrane Review). In:The Cochrane Library, Issue 2, 2002. Oxford, England: Update Software.
3. Wang E. What are the effects of treatment for children with bronchiolitis? Clin Evid 2001 December.;
4. Barr F, Graham B. Respiratory syncytial virus. Up To Date 2001 June.;
5. National Guideline Clearinghouse.Evidence based clinical practice guidelines for the infant with bronchiolitis. Cincinnati, OH: Cincinnati Children’s Hospital Medical Center; 2001 Nov 28.
6. Committee on Infect Diseases, American Academy of Pediatrics. Reassessment of the indications for ribavirin therapy in respiratory syncytial virus infections. Pediatrics 1996;97:137.-
Evidence-based answers from the Family Physicians Inquiries Network
Is there a role for theophylline in treating patients with asthma?
With adults, oral theophylline may help lower the dosage of inhaled steroids needed to control chronic asthma. It offers no benefit for acute asthma exacerbations. For children, intravenous aminophylline may improve the clinical course of severe asthma attacks. Side effects and toxicity limit use of these medications in most settings. (Grade of recommendation: A, based on systematic reviews and randomized control trials [RCTs]).
Evidence summary
Several systematic reviews help clarify theophylline’s role in asthma management. When compared with placebo in the management of acute exacerbations, theophylline confers no added benefit to beta-agonist therapy (with or without steroids) in improving pulmonary function or reducing hospitalization rates. Side effects occurred more often in the theophylline group: palpitations/arrhythmias (OR = 2.9; 95% CI: 1.5 to 5.7) and vomiting (OR = 4.2; 95% CI: 2.4 to 7.4).1 For moderately severe asthma in patients already receiving inhaled corticosteroids (ICS), theophylline as maintenance therapy equaled long-acting beta-2-agonists in increasing FEV 1 and PEFR, but was less effective in controlling night time symptoms. Use of long-acting beta-agonists resulted in fewer side effects (RR = 0.38; 95%CI: 0.25-0.57).2 When added to low-dose ICS for maintenance, theophylline was as effective as high-dose ICS alone in improving FEV 1 , decreasing day and night symptoms, and reducing the need for rescue medications and the incidence of attacks. This suggests theophylline has utility as a steroid sparing agent.3
Intravenous aminophylline does appear to be clinically beneficial for children with severe exacerbations, defined as an FEV 1 of 35%-40% of predicted value. Critically ill children receiving aminophylline in addition to usual care exhibited an improved FEV 1 at 24 hours (mean difference = 8.4%; 95% CI: 0.82 to 15.92) and reduced symptom scores at 6 hours.4 The largest RCT of aminophylline in children demonstrated a reduced intubation rate (NNT = 14 CI: 7.8-77).5 Children receiving aminophylline experienced more vomiting (RR = 3.69; 95%CI: 2.15-6.33). Treatment with aminophylline did not reduce length of hospital stay or the number of rescue nebulizers needed (Table).4
TABLE
Theophylline use in asthma
| Adults | Children | |
|---|---|---|
| Acute Treatment | No added benefit to corticosteroids and beta-agonist therapy; increased GI and cardiac side effects. | 24 hours of IV aminophylline improves symptom scores without reducing LOS or nebulizer requirements; may reduce intubation |
| Maintenance Therapy | ||
| Mild | No clinical benefit | Not recommended |
| Moderate | Performs worse than long-acting beta-agonists and has more side effects; may limit the need for high-dose ICS if not using long beta agonists. | No advantage over long-acting beta agonists when added to ICS. More side effects |
| Severe | Same for moderate; does not limit the need for oral corticosteroids in this setting. | Same as moderate |
| LOS = length of stay; ICS = inhaled corticosteroids. | ||
Recommendations from others
Three evidence-supported guidelines concur that theophylline has a limited role as maintenance therapy for moderate-to-severe persistent asthma when symptom control with ICS alone is not adequate. Much stronger evidence supports the use of long-acting beta-2-agonists or leukotriene modifiers in this setting.6-8 The guidelines do not recommend using theophylline to treat acute asthma exacerbations; nor do they address using theophylline in children.
Read a Clinical Commentary by M. Lee Chambliss, MD, MSPH, at www.fpin.org.
1. Wilson AJ, Gibson, PG, Coughlan J. The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
2. Parameswaran K, Belda J, Rowe BH. The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
3. Evans DJ, Taylor DA, Zetterstrom O, et al. N Engl J Med 1997;337:1412-8.
4. Mitra A, Bassler D, Ducharme FM. The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
5. Yung M, South M. Arch Dis Child 1998;79:405-410.
6. Management of Chronic Asthma. Evidence Report/Technology Assessment. Number 44. AHQR Publication Number 01-E043, September 2001.
7. Global Initiative for Asthma, National Heart, Lung and Blood Institute, (U.S.)/World Health Organization. 1995 Jan (revised 1998).
8. Expert Panel Report 2:Guidelines for the diagnosis and management of asthma. National Asthma Education and Prevention Program/National Heart, Lung and Blood Institute (U.S.). 1997 Jul, (reprinted 1998 Apr, 1999 Mar).
With adults, oral theophylline may help lower the dosage of inhaled steroids needed to control chronic asthma. It offers no benefit for acute asthma exacerbations. For children, intravenous aminophylline may improve the clinical course of severe asthma attacks. Side effects and toxicity limit use of these medications in most settings. (Grade of recommendation: A, based on systematic reviews and randomized control trials [RCTs]).
Evidence summary
Several systematic reviews help clarify theophylline’s role in asthma management. When compared with placebo in the management of acute exacerbations, theophylline confers no added benefit to beta-agonist therapy (with or without steroids) in improving pulmonary function or reducing hospitalization rates. Side effects occurred more often in the theophylline group: palpitations/arrhythmias (OR = 2.9; 95% CI: 1.5 to 5.7) and vomiting (OR = 4.2; 95% CI: 2.4 to 7.4).1 For moderately severe asthma in patients already receiving inhaled corticosteroids (ICS), theophylline as maintenance therapy equaled long-acting beta-2-agonists in increasing FEV 1 and PEFR, but was less effective in controlling night time symptoms. Use of long-acting beta-agonists resulted in fewer side effects (RR = 0.38; 95%CI: 0.25-0.57).2 When added to low-dose ICS for maintenance, theophylline was as effective as high-dose ICS alone in improving FEV 1 , decreasing day and night symptoms, and reducing the need for rescue medications and the incidence of attacks. This suggests theophylline has utility as a steroid sparing agent.3
Intravenous aminophylline does appear to be clinically beneficial for children with severe exacerbations, defined as an FEV 1 of 35%-40% of predicted value. Critically ill children receiving aminophylline in addition to usual care exhibited an improved FEV 1 at 24 hours (mean difference = 8.4%; 95% CI: 0.82 to 15.92) and reduced symptom scores at 6 hours.4 The largest RCT of aminophylline in children demonstrated a reduced intubation rate (NNT = 14 CI: 7.8-77).5 Children receiving aminophylline experienced more vomiting (RR = 3.69; 95%CI: 2.15-6.33). Treatment with aminophylline did not reduce length of hospital stay or the number of rescue nebulizers needed (Table).4
TABLE
Theophylline use in asthma
| Adults | Children | |
|---|---|---|
| Acute Treatment | No added benefit to corticosteroids and beta-agonist therapy; increased GI and cardiac side effects. | 24 hours of IV aminophylline improves symptom scores without reducing LOS or nebulizer requirements; may reduce intubation |
| Maintenance Therapy | ||
| Mild | No clinical benefit | Not recommended |
| Moderate | Performs worse than long-acting beta-agonists and has more side effects; may limit the need for high-dose ICS if not using long beta agonists. | No advantage over long-acting beta agonists when added to ICS. More side effects |
| Severe | Same for moderate; does not limit the need for oral corticosteroids in this setting. | Same as moderate |
| LOS = length of stay; ICS = inhaled corticosteroids. | ||
Recommendations from others
Three evidence-supported guidelines concur that theophylline has a limited role as maintenance therapy for moderate-to-severe persistent asthma when symptom control with ICS alone is not adequate. Much stronger evidence supports the use of long-acting beta-2-agonists or leukotriene modifiers in this setting.6-8 The guidelines do not recommend using theophylline to treat acute asthma exacerbations; nor do they address using theophylline in children.
Read a Clinical Commentary by M. Lee Chambliss, MD, MSPH, at www.fpin.org.
With adults, oral theophylline may help lower the dosage of inhaled steroids needed to control chronic asthma. It offers no benefit for acute asthma exacerbations. For children, intravenous aminophylline may improve the clinical course of severe asthma attacks. Side effects and toxicity limit use of these medications in most settings. (Grade of recommendation: A, based on systematic reviews and randomized control trials [RCTs]).
Evidence summary
Several systematic reviews help clarify theophylline’s role in asthma management. When compared with placebo in the management of acute exacerbations, theophylline confers no added benefit to beta-agonist therapy (with or without steroids) in improving pulmonary function or reducing hospitalization rates. Side effects occurred more often in the theophylline group: palpitations/arrhythmias (OR = 2.9; 95% CI: 1.5 to 5.7) and vomiting (OR = 4.2; 95% CI: 2.4 to 7.4).1 For moderately severe asthma in patients already receiving inhaled corticosteroids (ICS), theophylline as maintenance therapy equaled long-acting beta-2-agonists in increasing FEV 1 and PEFR, but was less effective in controlling night time symptoms. Use of long-acting beta-agonists resulted in fewer side effects (RR = 0.38; 95%CI: 0.25-0.57).2 When added to low-dose ICS for maintenance, theophylline was as effective as high-dose ICS alone in improving FEV 1 , decreasing day and night symptoms, and reducing the need for rescue medications and the incidence of attacks. This suggests theophylline has utility as a steroid sparing agent.3
Intravenous aminophylline does appear to be clinically beneficial for children with severe exacerbations, defined as an FEV 1 of 35%-40% of predicted value. Critically ill children receiving aminophylline in addition to usual care exhibited an improved FEV 1 at 24 hours (mean difference = 8.4%; 95% CI: 0.82 to 15.92) and reduced symptom scores at 6 hours.4 The largest RCT of aminophylline in children demonstrated a reduced intubation rate (NNT = 14 CI: 7.8-77).5 Children receiving aminophylline experienced more vomiting (RR = 3.69; 95%CI: 2.15-6.33). Treatment with aminophylline did not reduce length of hospital stay or the number of rescue nebulizers needed (Table).4
TABLE
Theophylline use in asthma
| Adults | Children | |
|---|---|---|
| Acute Treatment | No added benefit to corticosteroids and beta-agonist therapy; increased GI and cardiac side effects. | 24 hours of IV aminophylline improves symptom scores without reducing LOS or nebulizer requirements; may reduce intubation |
| Maintenance Therapy | ||
| Mild | No clinical benefit | Not recommended |
| Moderate | Performs worse than long-acting beta-agonists and has more side effects; may limit the need for high-dose ICS if not using long beta agonists. | No advantage over long-acting beta agonists when added to ICS. More side effects |
| Severe | Same for moderate; does not limit the need for oral corticosteroids in this setting. | Same as moderate |
| LOS = length of stay; ICS = inhaled corticosteroids. | ||
Recommendations from others
Three evidence-supported guidelines concur that theophylline has a limited role as maintenance therapy for moderate-to-severe persistent asthma when symptom control with ICS alone is not adequate. Much stronger evidence supports the use of long-acting beta-2-agonists or leukotriene modifiers in this setting.6-8 The guidelines do not recommend using theophylline to treat acute asthma exacerbations; nor do they address using theophylline in children.
Read a Clinical Commentary by M. Lee Chambliss, MD, MSPH, at www.fpin.org.
1. Wilson AJ, Gibson, PG, Coughlan J. The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
2. Parameswaran K, Belda J, Rowe BH. The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
3. Evans DJ, Taylor DA, Zetterstrom O, et al. N Engl J Med 1997;337:1412-8.
4. Mitra A, Bassler D, Ducharme FM. The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
5. Yung M, South M. Arch Dis Child 1998;79:405-410.
6. Management of Chronic Asthma. Evidence Report/Technology Assessment. Number 44. AHQR Publication Number 01-E043, September 2001.
7. Global Initiative for Asthma, National Heart, Lung and Blood Institute, (U.S.)/World Health Organization. 1995 Jan (revised 1998).
8. Expert Panel Report 2:Guidelines for the diagnosis and management of asthma. National Asthma Education and Prevention Program/National Heart, Lung and Blood Institute (U.S.). 1997 Jul, (reprinted 1998 Apr, 1999 Mar).
1. Wilson AJ, Gibson, PG, Coughlan J. The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
2. Parameswaran K, Belda J, Rowe BH. The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
3. Evans DJ, Taylor DA, Zetterstrom O, et al. N Engl J Med 1997;337:1412-8.
4. Mitra A, Bassler D, Ducharme FM. The Cochrane Library, Issue 2, 2002. Oxford: Update Software.
5. Yung M, South M. Arch Dis Child 1998;79:405-410.
6. Management of Chronic Asthma. Evidence Report/Technology Assessment. Number 44. AHQR Publication Number 01-E043, September 2001.
7. Global Initiative for Asthma, National Heart, Lung and Blood Institute, (U.S.)/World Health Organization. 1995 Jan (revised 1998).
8. Expert Panel Report 2:Guidelines for the diagnosis and management of asthma. National Asthma Education and Prevention Program/National Heart, Lung and Blood Institute (U.S.). 1997 Jul, (reprinted 1998 Apr, 1999 Mar).
Evidence-based answers from the Family Physicians Inquiries Network