Cochrane for Clinicians

Putting Evidence into Practice

Does Pioglitazone Benefit Patients with Type 2 Diabetes?

TARA SCOTT, MD, Sutter Medical Center of Santa Rosa Family Medicine Residency, Santa Rosa, California

The Cochrane Abstract is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Dr. Scott presents a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a critique of the review. The practice recommendations in this activity are available at http://www.cochrane.org/reviews/ en/ab006060.html.

Clinical Scenario

A 42-year-old woman with type 2 diabetes has not achieved glycemic control with lifestyle modifications after three months.

Clinical Question

Should pioglitazone (Actos) be used, alone or in combination with other oral antihyperglycemic medications, in patients with type 2 diabetes?

Evidence-Based Answer

Pioglitazone produces a reduction in A1C levels similar to that produced by other drugs. One trial found that although pioglitazone, used as an adjunct to other antihyperglycemic medications, may lead to a statistically significant reduction in morbidity and mortality in patients with established macrovascular disease, it also increases the likelihood of hospitalization for heart failure. There is no evidence on the effectiveness of pioglitazone monotherapy for reducing morbidity and mortality. Patients taking pioglitazone, alone or in combination, are more likely to experience edema, weight gain, or congestive heart failure compared with patients taking other antihyperglycemic medications.1

Practice Pointers

Oral treatment options for type 2 diabetes include medications from several drug classes, each with a unique mechanism for reducing blood glucose levels. Pioglitazone, a thiazolidinedione, lowers blood glucose levels by increasing cellular glucose uptake and hepatic sensitivity to insulin. The U.S. Food and Drug Administration has approved pioglitazone for use alone or in combination with other oral medications or insulin. This Cochrane review found that pioglitazone, alone or in combination, lowered A1C levels by 0.8 percent compared with 0.3 percent in the placebo group, and increased high-density lipoprotein levels by 19 percent compared with 10 percent in the placebo group.

Although there is clear evidence that pioglitazone modestly improves clinical surrogates of disease, only one of the 22 studies included in this review investigated the effect of pioglitazone on patient-oriented outcomes such as death, myocardial infarction, and stroke. The large study included more than 6,200 patients with type 2 diabetes and established macrovascular disease.2 Patients taking pioglitazone in combination with other oral antihyperglycemic medications had a statistically significant lower risk of the combined end point of all-cause mortality, nonfatal myocardial infarction, or stroke when compared with placebo (11.6 versus 13.6 percent; number needed to treat [NNT] = 49). Patients taking combination pioglitazone also had a higher risk of hospitalization for heart failure (number needed to harm = 62). This study did not include patients taking pioglitazone monotherapy, and the scientific rigor of the interpretation of the results has been called into question.

In contrast, metformin (Glucophage) monotherapy has been shown to improve patient-oriented outcomes such as all-cause mortality, diabetes-related mortality, and myocardial infarction in overweight patients compared with all other classes of oral medications and insulin.3,4 Pioglitazone costs more than metformin ($326 versus $33 per month)5,6 and significantly increases the risk of edema compared with other oral hypoglycemic medications.

To help patients with type 2 diabetes reach an A1C level of less than 7 percent, the American Diabetes Association (ADA) recommends oral medications that decrease insulin resistance and suppress hepatic glucose production over medications that increase insulin secretion.7 The ADA recommends metformin or thiazolidinediones, alone or in combination, over sulfonylureas as first-line treatments; however, this is not entirely an evidence-based recommendation.7 Because of recent concerns about the cardiovascular risks of the thiazolidinedione rosiglitazone (Avandia), it is likely that the ADA will revisit this recommendation in the near future.8

Address correspondence to Tara Scott, MD, at doctarascott@mac.com. Reprints are not available from the author.

Author disclosure: Nothing to disclose.

REFERENCES

1. Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH. Pioglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev 2006;(4):CD006060.

2. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, for the PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279-89.

3. Sauer WH, Cappola AR, Berlin JA, Kimmel SE. Insulin sensitizing pharmacotherapy for prevention of myocardial
infarction in patients with diabetes mellitus. Am J Cardiol 2006;97:651-4.

4. Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev 2005;(3):CD002966.

5. Pioglitazone. Accessed August 2, 2007, at: http://www.drugstore.com/pharmacy/drugindex/rxsearch.asp?search=pioglitazone.

6. Metformin. Accessed August 2, 2007, at: http://www.drugstore.com/pharmacy/drugindex/rxsearch.asp?search=metformin.

7. Chitre MM, Burke S. Treatment algorithms and the pharmacological management of type 2 diabetes. Diabetes Spectrum 2006;19:249-55.

8. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes [Published correction appears in N Engl J Med 2007;357:100]. N Engl J Med 2007;356:2457-71.

Cochrane Briefs

Opioid Analgesia During Evaluation of Acute Abdominal Pain

Clinical Question

Does providing early opioid analgesia during evaluation of acute abdominal pain improve patient comfort or outcomes?

Evidence-Based Answer

Providing early opioid analgesia to patients presenting with acute abdominal pain does not affect or delay management decisions, but it lessens pain intensity as rated by the patient.

Practice Pointers

The differential diagnosis of acute abdominal pain includes many causes that may require urgent surgical treatment or hospitalization such as appendicitis, cholecystitis, bowel obstruction, kidney stones, perforated peptic ulcer, pancreatitis, diverticulitis, pelvic abscesses, and ectopic pregnancy. Most acute abdominal pain is visceral pain, which is characterized by generalized aching, pressure, or sharp pain. Visceral pain generally responds best to intraspinal local anesthetic or nonsteroidal anti-inflammatory drugs or opioids administered via any route.1 It is common practice to withhold opioid analgesia in patients with acute abdominal pain. This practice is based on the theory that opioids might mask symptoms, causing inaccurate or delayed diagnostic and treatment decisions.

To evaluate the accuracy of this theory, the authors of this Cochrane review searched for randomized controlled trials comparing opioid analgesia with no analgesia in adults with abdominal pain. Six trials, including 699 total patients, were identified. Most of the trials compared 5 to 15 mg of morphine (Duramorph) with an equivalent amount of saline. There were no significant differences between groups in changes in the physical examination, errors in treatment decisions, inaccurate diagnoses, nausea and vomiting, or length of hospitalization. The two studies that reported patient comfort found significant improvement with opioids. There was not enough information to determine if opioid use causes a delay in the decision to operate, affects costs, or affects morbidity. There was also insufficient evidence to suggest an optimal treatment regimen.

CLARISSA KRIPKE, MD

Source: Manterola C, Astudillo P, Losada H, Pineda V, Sanhueza A, Vial M. Analgesia in patients with acute abdominal pain. Cochrane Database Syst Rev 2007;(3):CD005660.

REFERENCE

1. Institute for Clinical Systems Improvement (ICSI). Health care guideline: assessment and management of acute pain. March 2006. Accessed August 2, 2007, at: http://www.icsi.org.

Repeat Cesarean Delivery vs. Planned Induction of Labor

Clinical Question

Should women who have had a previous low-transverse cesarean delivery and who require induction of labor be offered a trial of labor?

Evidence-Based Answer

There are no randomized controlled trials (RCTs) of labor induction in women with a low-transverse uterine scar. Observational studies indicate that there is a small increased risk of uterine rupture and adverse fetal outcomes, especially in women induced with prostaglandins. Although induction in these patients is common practice in other countries, based on these data, the American College of Obstetricians and Gynecologists (ACOG) recommends that patients be discouraged from induction of labor after a single previous low-transverse cesarean delivery.

Practice Pointers

Based on retrospective cohort studies, most women with one previous low-transverse cesarean delivery are candidates for vaginal birth and should be counseled and offered a trial of labor.1,2 In a retrospective, population-based review (including more than 20,000 total women), the overall rate of uterine rupture after a previous low-transverse cesarean delivery was 4.5 per 1,000; the rate was 1.6 per 1,000 with repeat cesarean delivery and no labor, 5.2 per 1,000 with spontaneous labor, 7.7 per 1,000 with nonprostaglandin induction, and 24.5 per 1,000 with prostaglandin induction.3

Another study showed that using oxytocin (Pitocin) to augment labor in women with a previous low-transverse cesearan delivery increases the risk of uterine rupture compared with spontaneous labor (8.7 versus 3.6 per 1,000); using oxytocin alone to induce labor increases the risk to 10.7 per 1,000. In women undergoing a trial of labor, the overall uterine rupture-related perinatal death was 0.11 per 1,000. The rate of perinatal hypoxic brain injury was 0.46 per 1,000 trials of labor compared with zero in women who had a repeat cesarean delivery.4

In Australia, New Zealand, and Canada, it is common practice to offer a trial of labor to women with a previous low-transverse cesarean delivery who require induction. Most physicians prefer oxytocin induction rather than cervical ripening with prostaglandins.

The authors of this Cochrane review found no RCTs to help further determine the safety of labor induction after previous cesarean delivery. In particular, it is not clear if prostaglandin use causes adverse outcomes in women attempting vaginal birth or if having an unfavorable cervix is simply a marker for complications.

The ACOG recommends that women who have had one previous low-transverse cesarean delivery be counseled and offered a trial of labor. However, because of limited and inconsistent evidence showing an increased risk of uterine rupture, the ACOG recommends that women who require cervical ripening or induction be discouraged from attempting a vaginal delivery. If a woman attempts a vaginal delivery after a previous low-transverse cesarean delivery, the ACOG recommends that her labor be managed in a hospital with immediate access to emergency obstetric care.

Because data are limited, the individual patient and her physician should make the ultimate decision. Vaginal birth after cesarean delivery should not be attempted in a woman with a classic uterine incision or history of transfundal surgery.2

CLARISSA KRIPKE, MD

Source: Dodd JM, Crowther CA. Elective repeat caesarean section versus induction of labour for women with a previous caesarean birth. Cochrane Database Syst Rev 2006;(4):CD004906.

REFERENCES

1. Dodd JM, Crowther CA, Huertas E, Guise JM, Horey D. Planned elective repeat caesarean section versus planned vaginal birth for women with a previous caesarean birth. Cochrane Database Syst Rev 2004;(4):CD004224.

2. American College of Obstetricians and Gynecologists. Vaginal birth after previous cesarean. ACOG Practice Bulletin No. 54. Obstet Gynecol 2004;104:203-12.

3. Lydon-Rochelle M, Holt VL, Easterling TR, Martin DP. Risk of uterine rupture during labor among women with a prior cesarean delivery. N Engl J Med 2001;345:3-8.

4. Landon MB, Hauth JC, Leveno KJ, Spong CY, Leindecker S, Varner MW, et al., for the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Maternal and perinatal outcomes associated with a trial of labor after prior cesarean delivery. N Engl J Med 2004;351:2581-9.

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). See CME Quiz on page 939.

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

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