RAND Review

Bulging Repertoires

Treatments and Complications for the Overweight and Obese Expand with the Population

By Margaret Maglione, Lisa Shugarman, and Melony Sorbero

Margaret Maglione, Lisa Shugarman, and Melony Sorbero are public policy and health policy analysts at RAND.

The growing ranks of overweight and obese individuals in industrialized countries are expanding the market for some types of medical treatments while complicating the administration of others. Pharmaceutical companies and surgeons are offering multiple new treatment options for people who are overweight or obese. Meanwhile, some oncologists are questioning whether they should increase the doses of chemotherapy for overweight or obese women who suffer from breast cancer.

We have studied the effects of three kinds of medical treatments for the overweight and obese. We summarize our findings as follows:

For overweight or obese individuals, prescription diet drugs promote moderate weight loss when prescribed with diet recommendations. The drugs produce varying minor short-term side effects, such as insomnia and gastrointestinal upset.
For people who are morbidly obese, bariatric surgery results in greater weight loss than does a combination of prescription medications, diet, and exercise. For those who are less severely overweight, the benefits of bariatric surgery are inconclusive. About 10 to 20 percent of those who undergo bariatric surgery experience complications. Although most complications are minor, some can be serious. The overall death rate from such surgeries is less than 1 percent.
Overweight and obese women who receive chemotherapy for breast cancer are often undertreated. Some doctors apparently either base the chemotherapeutic doses for these women on their ideal weight or cap the doses at a threshold because of unfounded concerns about the potential for toxic side effects if the doses are increased to account for body weight. The poorer prognosis for survival among obese women may therefore be the result of inadequate doses of chemotherapy.

Most of the medications promoted moderate weight loss when prescribed with diet recommendations.

Individuals are deemed overweight if their body mass index (BMI, a ratio of weight in kilograms divided by height in meters squared) rises to between 25 and 29.9. Individuals whose BMI reaches 30 or higher are considered obese, while those with a BMI of 40 or above are considered morbidly obese. For example, a person who is 5 feet 10 inches tall and weighs 209 pounds has a BMI of 30, while a person who is 5 feet 10 inches tall and weighs 280 pounds has a BMI of 40.

An estimated 30 percent of the U.S. population is obese, and many industrialized countries have seen similar prevalence rates. The health consequences of obesity are considerable. Yet weight loss of 5 to 10 per-cent of total weight could markedly reduce the risks of chronic obesity-related diseases, including heart disease, diabetes, osteoarthritis, hypertension, breast cancer, and other forms of cancer.

Modest Results from Diet Drugs

About 40 percent of Americans are trying to lose weight, accounting for the increased number and popularity of prescription weight-loss medications. To assess their effectiveness and safety, the Southern California Evidence-Based Practice Center, based at RAND, analyzed 79 published studies of clinical trials of the most popular diet drugs.

Among prescription medications approved by the U.S. Food and Drug Administration (FDA) for weight loss, all but one are appetite suppressants. The exception is orlistat, which inhibits the digestion and intestinal absorption of some dietary fats. We studied four FDA-approved weight-loss medications (sibutramine, orlistat, phentermine, and diethylpropion) and five medications not approved by the FDA specifically for weight loss but that have been tested for this purpose (topiramate, zonisamide, and the antidepressants bupropion, sertraline, and fluoxetine).

Figure 1 — Most Diet Drugs Studied Promote Modest Weight Loss When Prescribed with Diet Recommendations

SOURCE: “Meta-Analysis: Pharmacologic Treatment of Obesity,” 2005.

NOTE: Black squares show average weight change. Red bands show 95-percent confidence intervals (we are 95 percent confident that the true average weight change falls somewhere between these banded extremes).

Among these medications, the two that have been studied most are sibutramine and orlistat. We found that 12 months of treatment with either drug, compared with a placebo, promoted modest weight loss when diet recommendations accompanied the prescriptions. On average, patients using sibutramine lost 9.8 pounds more than patients in a placebo group, while those using orlistat lost 6.4 pounds more (see Figure 1). Total weight loss for orlistat users averaged 17.9 pounds.

Most of the other medications — phentermine, bupropion, topiramate, zonisamide, and probably diethylpropion and fluoxetine — also promoted moderate weight loss when prescribed with diet recommendations. However, we found no statistically significant difference between patients treated with sertraline versus those who received a placebo.

Each drug produced short-term side effects, which varied by drug. Side effects ranged from restlessness and elevated heart rate to diarrhea, flatulence, bloating, abdominal pain, and indigestion. Too few of the 79 studies included children or adolescents to allow conclusions to be drawn about the effectiveness or safety of the medications for these age groups.

Just one of the 79 studies assessed long-term outcomes. In a study of 3,000 obese patients who had taken either orlistat or a placebo for four years, weight loss was greater among those taking orlistat. Likewise, the incidence of new diabetes cases was 37 percent lower among the orlistat-treated group. This study supports the hypothesis that long-term treatment with orlistat can reduce weight and help prevent obesity-related health problems. In other studies, weight loss has also been associated with reductions in high blood pressure, blood sugar, and cholesterol levels.

Surgery Suits Some Better

The growing prevalence of obesity has fueled interest in various surgical procedures, collectively known as bariatric surgery, to induce weight loss. We examined the effectiveness and risks of bariatric surgeries by analyzing nearly 150 published studies of the most commonly performed procedures.

The most common procedure, accounting for about 65 percent of bariatric surgeries performed worldwide, is gastric bypass surgery. This operation involves stapling the upper stomach into a small pouch and creating an outlet to the downstream small intestine, thereby limiting stomach capacity, shortening intestinal length, and cutting the calories and nutrients the body can absorb.

Among the morbidly obese, surgery resulted in a loss of 45 to 65 pounds that was maintained up to ten years and was accompanied by significant improvements in several obesity-related conditions.

A second common method, particularly outside the United States, is adjustable gastric banding. In this operation, surgeons tie a restrictive band around the uppermost portion of the stomach and insert a small outlet to the lower stomach. The band can be adjusted for tailoring of the stomach outlet, which controls meal capacity and the rate of the stomach emptying into the intestines. This method accounts for about 24 percent of bariatric surgeries performed worldwide.

Two other surgical techniques were examined in our review. In vertical banded gastroplasty, surgeons staple a hole into the center of the stomach until it resembles a doughnut, thereby shrinking the stomach capacity and restricting food consumption. In biliopancreatic bypass, surgeons create a common channel where contents from the stomach and intestine mix, inducing weight loss primarily through malabsorption.

For morbidly obese individuals — those with an average BMI of 40 or more — bariatric surgery resulted in greater weight loss than did nonsurgical treatments, including prescription drugs and diet recommendations. Among the morbidly obese, surgery resulted in a loss of 45 to 65 pounds that was maintained up to ten years and was accompanied by significant improvements in several obesity-related conditions, such as hypertension, diabetes, elevated cholesterol, and sleep apnea.

Figure 2 — Patients Who Underwent Bariatric Surgeries Maintained Significant Weight Loss After Three Years

SOURCE: “Meta-Analysis: Surgical Treatment of Obesity,” 2005.

NOTE: Black squares show average weight loss from four types of bariatric surgeries three years following surgery. Red bands show 95-percent confidence intervals (we are 95 percent confident that the true average weight loss falls somewhere between these banded extremes).

Figure 3 — About 10 to 20 Percent of Those Who Undergo Bariatric Surgery Experience Complications, Mostly Minor

SOURCE: “Meta-Analysis: Surgical Treatment of Obesity,” 2005.

NOTE: NR = not reported.

Figure 4 — The More Severely Overweight the Women, the Greater the Frequency of Undertreatment for Breast Cancer

SOURCE: “Undertreatment of Obese Women Receiving Breast Cancer Chemotherapy,” 2005.

NOTE: Individuals whose body mass index (BMI) falls between 25 and 29.9 are considered overweight. Obesity is defined as a BMI of 30 or more. Severe obesity is defined as a BMI of 35 or more.

The data strongly support the superiority of surgical therapy also for those with BMIs between 35 and 39.9. However, this evidence cannot be considered conclusive in the absence of a study with a concurrent comparison group.

Long-term comparisons of outcomes among the surgeries are available up to only three years after surgery. At the end of this shorter time frame, patients who had undergone gastric bypass surgery lost an average of 91 pounds, compared with 77 pounds for adjustable gastric banding, 71 pounds for vertical banded gastroplasty, and 117 pounds for biliopancreatic diversion (see Figure 2).

Mortality rates from the surgeries were less than 1 percent, and we found no statistically significant difference in mortality rates among the procedures. Complications from surgery were common but mostly minor in severity, although the occurrence of complications may differ among procedures in clinically important ways (see Figure 3). Too few children and adolescents underwent the surgeries to allow us to assess the effectiveness or safety for these age groups.

Breast Cancer Undertreated

Obesity both increases the risk for breast cancer and worsens its prognosis. Both the increased risk and poorer prognosis have been attributed to physiological factors, such as higher blood levels of the hormone estrogen. However, an additional factor contributing to the poorer prognosis for obese women, in terms of cancer recurrence and overall survival, might be the delivery of inadequate doses of chemotherapy.

The dosage of most chemotherapeutic drugs is based on the patient’s body surface area (BSA), calculated from weight and height and expressed in square meters. Because concerns have been raised about the potential for toxic side effects if chemotherapeutic doses for obese women are increased to account for body weight, some doctors have apparently either based the doses for obese women on their ideal weight or capped the doses at a particular BSA, such as two square meters, even though little evidence exists to support doing so.

In partnership with clinical researchers at the University of Rochester, we used the medical files of nearly 10,000 women treated for non-metastatic breast cancer in the United States between 1990 and 2001 to assess whether obese women were in fact systematically undertreated. We found that overweight and obese women indeed received intentionally reduced doses of chemotherapy for breast cancer more often than did women of healthy weight.

During the first cycle of chemotherapy, doctors reduced the doses by 10 percent or more for fully 37 percent of severely obese women (those with BMIs of 35 or higher), 20 percent of obese women, 11 percent of overweight women, and 9 percent of women of healthy weight (see Figure 4). The average reduction in dosage across all BMI categories was 20 percent.

Increased doses for subsequent cycles of chemotherapy were uncommon. Only 3 percent of overweight and obese women who had initially received a reduced dose received an increased second dose. Just 4 percent of underweight and healthy-weight women received dose escalations.

The irony is that severely obese women, regardless of having received either full or reduced doses, suffered fewer severe side effects than did other women. There is accumulating evidence that obese patients do not experience increased toxic effects when dosed according to actual body weight. While not studied specifically in obese women, the receipt of full doses of chemotherapy is associated with improved overall and disease-free survival. There is even the possibility that using actual body weight in dosing the severely obese with breast cancer may still constitute undertreatment.

Patients treated in more recent years were less likely to receive dose reductions, but great variability remained in the frequency of dose reductions across the 901 oncology practices studied. This unwarranted variation most likely reflects persistent clinical uncertainty regarding optimal doses for overweight and obese women. As the incidence of obesity, particularly severe obesity, grows in many countries, eliminating unwarranted dose reductions will grow in importance.

RAND Review

Bulging Repertoires

Treatments and Complications for the Overweight and Obese Expand with the Population

Margaret Maglione, Lisa Shugarman, and Melony Sorbero are public policy and health policy analysts at RAND.