Cost Benefit —
An interesting healthcare story got buried by the astonishing Supreme Court decision on Obamacare. Yesterday, the Food and Drug Administration (FDA) approved a new weight loss drug, lorcaserin (brand name Belviq).
Lorcaserin is a replacement for fenfluramine, the appetite suppressant that caused heart valve problems, particularly when used in conjunction with phentermine. The fen-phen combo because a widely popular drug in the 90s because it boasted a 15%-20% weight loss for users. But once the truth about fenfluramine’s cardiovascular damage came to light, the FDA removed it from the market, leaving phentermine in place.
Although still available, phentermine is also deadly when abused, as found in the overdose death of actor Bubba Smith of Police Academy fame.
By acting on a separate seratonin agonist than fenfluramine, lorcaserin seems to have reduced the risk of heart valve damage, but the FDA still rejected the drug in 2010 because of other concerns (PDF):
Panelists were also concerned about the development of mammary tumors in rats exposed to the drug at doses close to therapeutic doses in humans and said that this issue needed to be studied further.
As a result, the FDA panel concluded that “the potential risks of the serotoninergic drug lorcaserin outweighed its potential benefits as a long-term treatment for weight loss.”
Since raising their initial concerns, Arena (the company behind lorcaserin) has provided additional evidence on the tumors that helped it gain final approval:
The FDA staff said Arena submitted more data that showed malignant tumors in rats increased only at very high doses of lorcaserin, with rats getting at least 24 times more of the drug than the recommended dose for people.
The FDA staff said the safety margin for malignant tumors was “reassuring,” but pointed out that lower doses of the drug were still linked to benign tumors in rats.
Arena has argued the findings of rat tumors did not apply to people because they resulted from high doses or biological mechanisms specific only to rodents. No increase in cancer cases was seen in people. [emphasis mine]
So, high doses of loraserin produced malignant tumors, while lower doses produced benign tumors, and the fact that they had no increases in cancer during their two-year study was enough for the FDA to say, “Seems legit.”
But setting aside the potential for an obesity/cancer swap, how effective is lorcaserin in producing weight loss, bearing in mind the most optimistic statistics for the average overweight and obese dieter.
In September 2006, Arena launched a clinical trial called the Behavioral Modification and Lorcaserin for Overweight and Obesity Management, or BLOOM. During a two-year randomized controlled trial, 3,182 overweight and obese patients were divided into either the lorcaserin (10 mg twice a day) or placebo group. Although the study was initially just one year long, those who remained after one year became eligible to participate in the two-year study.
Patients attended counseling sessions and were encouraged to exercise moderately for 30 minutes a day and to reduce caloric intake to 600 calories below their estimated daily energy requirements. At 600 calories a day, or 4,200 calories per week, patients could expect to lose 62 pounds after one year based on the 3,500-calories-a-pound rule.
At one year, just 55% of the lorcaserin group remained compared to 45% of the placebo group. Of those who continued with the trial, 73% completed the second year. As noted in coverage of the initial FDA rejection, this trial was hardly representative of the population:
The long list of exclusion criteria included a diagnosis of diabetes, recent episode of major depression or anxiety, and treatment with a serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor within the previous 1-2 years.
Since I take Paxil (a serotonin reuptake inhibitor), I would not be represented by this trial. But, you know, best case scenario and all that.
So, how’d they do? Well, the average lorcaserin patient weighed 221 pounds at the beginning of the study and by one year, 66% of the lorcaserin patients who remained had lost an average of 18 pounds, or 5% of their starting weight. Compare this to the 7 pounds in the placebo group.
In the main study, the authors don’t specify the exact two year weight loss maintained and, instead, ay, “In year 2, patients who continued to take lorcaserin were significantly better able to maintain their year 1 weight loss than those who were switched to placebo, demonstrating a weight-maintenance benefit of long-term lorcaserin use.”
But in a supplementary index (PDF), we learn that those who took lorcaserin for two years had maintained a loss of 12 pounds. This gradual rebound is best illustrated by the chart below:
See those orange diamonds? Yeah, those are the patients who took lorcaserin both years returning gradually to their baseline weight. Even with pharmaceutical help, our bodies still nudge our weight back to the starting point.
The grey diamond group are a subset of patients who took lorcaserin the first year and were switched to a placebo the second. After two years, this group’s weight began to reflect the group that took the placebo both years.
The lorcaserin group also had small, but statistically significant, improvements in blood lipids, blood sugars and blood pressure. Those modest gains were all but wiped out by the second year. In fact, those who took lorcaserin experienced a 4% increase in LDL and an 11% increase in triglycerides between years 1 and 2, while fasting glucose returned to levels higher than baseline.
So, here’s the long and short of it: lorcaserin does not seem to have the same heart valve risk as fenfluramine, but the weight loss with lorcaserin hovers around 5% of your starting weight after one year, but begins creeping back up after two years. We don’t know what happens after two years in terms of weight loss, but we do know that once you stop taking lorcaserin, your weight will rebound significantly. So, the only way that lorcaserin can be successful is if you take it for the rest of your life, which puts you at risk for developing tumors, benign or otherwise.
With such modest results, weight loss advocates have already suggested that lorcaserin could be combined with another drug (like phentermine) to produce even greater weight loss results, according to the New York Times:
Dr. Ed J. Hendricks, an obesity specialist in Sacramento, said that he and other doctors might try prescribing Belviq in combination with phentermine, to essentially reconstitute the once popular fen-phen combination. “Once that word gets out that it works the same way, you are going to have a huge demand,” said Dr. Hendricks, who was on the advisory committee that voted in favor of approving Belviq.
And yet, during the 2010 FDA review, the risks of combination also contributed to its initial rejection:
But several panelists pointed out that, if approved, lorcaserin might be used in combination with another weight-loss drug, phentermine, which has been associated with drug-induced valvular heart disease.
The possibility of abuse will be reviewed by the Drug Enforcement Agency over the next four to six months, which will determine its classification and control.
Regardless of the side effects, the financial effects have already arrived, as news of the approval sent Arena stocks soaring 29% to $11.39.
And the media has jumped on the bandwagon, with ABC News polishing this turd into a wonderdrug:
In clinical trials people who took Belviq were twice as likely to lose 5 percent or more of their weight than people who took a placebo. The drug was also linked to improvements in blood pressure, cholesterol and blood sugar levels.
“It’s about time that they approved a new drug,” said Dr. Judith Stern, a professor of nutrition at the University of California at Davis. “Obesity drugs should be on the fast track.”
Yeah, that’s right Judith Stern, fuck the breast cancer concerns, we need these drugs that can affect 5% weight loss on the market NOW! Surely this is the end of the obesity epidemic.
Now that lorcaserin has cleared the onerous FDA hurdle, Reuters reports that further trials are on the way:
Arena will have to conduct six follow-up studies, including a long-term study of whether Belviq increases the risk of heart attack or stroke, the FDA said.
Other studies will involve obesity in children, the company said.
Brilliant! Let’s lure some desperate parents into a clinical trial to see if lorcaserin can help their fat kids get thin without developing breast cancer. Sounds like a plan!
Across the pond, anti-obesity advocates sound more cautious and reserved than their American counterparts. At a 2010 meeting of the International Congress of Obesity, several experts expressed concern about the drug, including Dr. Arne Astrup, professor and head of the department of human nutrition at the University of Copenhagen:
Significant adverse effects “are not really justified when treating obesity,” he added. “If you treat epilepsy or heart failure, you can use drugs with some adverse effects as long as the treatment does something good for the patient.” But when treating obesity, the overall cardiometabolic outcome must show benefit in addition to weight loss, “or you must reserve the drug only for obese patients who are at high risk for serious outcomes,” he said.
A second, smaller BLOOM study, BLOOM-DM, sought to measure the effects of lorcaserin on those with type 2 diabetes. If BLOOM provided promising, if inadequate, information for approval, BLOOM-DM should have wreaked havoc on the approval process.
BLOOM-DM followed 604 patients who were already taking the diabetes medications metformin, a sulfonylurea, or both. Patients were randomized to one of three groups: 10 mg lorcaserin twice daily, 10 mg lorcaserin once daily (with a placebo at night), or the placebo group.
One particularly odd thing about the BLOOM-DM study is that the dose dependent response seen in early BLOOM trials went completely haywire on the BLOOM-DM study.
While 37% of the twice-daily group lost at least 5% of their starting weight, 45% of the once-daily group lost the same amount (compared to 16% of the placebo group). Likewise, the once-daily group had a greater reduction in HbA1C (a marker of insulin resistance), had more patients decrease oral antidiabetic medication, and had a greater incidence of hypoglycmic events.
Oddly enough, changes in cholesterol, blood pressure and other vital signs (as they saw in the original BLOOM study) were identical in all three groups.
But, most importantly, the average weight change in both the once-daily and twice-daily groups was around 12-13 pounds.
And, of course, this modest weight loss is credited with the improvements in metabolic health, rather than the concurrent changes in diet and exercise which patients undertook .
Ultimately, this drug will come to market and continue to disappoint people looking for the fen-phen miracle. Doctors will attempt to recreate fen-phen by combining lorcaserin with phentermine (lorca-phen), and we’ll probably begin to hear more about heart valve problems in another ten years. And, if we play our cards right, there could be an increase in breast cancer as well.
But the FDA has determined that the risks of the real-world application of lorcaserin are out-weighed by the 12 pound weight loss after two years, along with the negligible change in metabolic indicators. Once again, the FDA’s judgment does not disappoint the gobsmacked.