I wanted to share the results of a long read through Google Scholar that I took. Hi r/loseit!
About me
Like 3 years ago I went on Keto and it was awesome, helping me go down from like 215 pounds to 170. I could do like five consecutive pull-ups for the first time without much effort beyond mixing up Keto Chow shakes each evening! (I love those things.) Co-workers commented on how great I looked! Cool.
Fast forward past a year of pretty easy maintenance, whereupon my doctor puts me on Zoloft, and I gained like twenty pounds back before ditching that for Bupropion, a much friendlier antidepressant that didn’t make me constantly ravenous. But try though I might, I had trouble getting back down to 170 with Keto-- I'm still hovering around 190.
This probably had something to do with the fact that I was living alone when I first lost the weight, and am now living with my fiancee and a number of roommates. Which makes sticking to Keto… substantially more difficult. “Hello I have prepared a delicious fruit pie”, a roommate will say, and I’ll unhinge my jaw and swallow it whole (like a python) thereby breaking ketosis. Which is a bummer.
I also have a couple of other roommates who themselves were having trouble losing weight, as was my fiancee even though she’s way more wonderful and industrious and conscientious than I am. And that inspired me to take a long, interest-fueled trip through Google Scholar, since it turns out that the efficacy of different methods of weight loss is super commonly-studied, and ours is a beautiful age where any internet asshole can search through unlimited carefully-indexed studies looking for incredibly specific nuggets of information. And I am just such an asshole.
DISCLAIMER
So, about me! I’m just a programmer, with no particular expertise in this or any other area. That means I am deeply unqualified to offer any kind of medical advice; my only qualification for doing anything is that I spent a bunch of time skimming online journal articles. So if you get inspired to try anything I talk about in this post, ask your doctor about it before you give it a shot or else you’ll die slowly, painfully, as your poor choices consume you from the inside out. And you will cry out "why did you betray me, UntrustworthyBastard" and I'll shrug and gesture at my username.
On to the studies! Let’s start out with
Non-pharmacological weight loss methods
"Non-pharmacological weight loss methods" are diet and exercise. This has been studied a lot, and these studies vary pretty dramatically in their results for reasons I'm not totally clear on. Probably they have a lot to do with how well the participants are made to adhere to the prescribed diet/exercise regimens.
Which is actually a core limitation of these studies! Most of these studies are intent-to-treat, which means they all include each participant in the study results even if the participants don’t follow the diet or do anything differently. Another way of phrasing this is that these studies measure the long-term efficacy of getting a bunch of people who want to lose weight into a room, and then telling them to go on a calorie deficit/keto diet/whatever (with accompanying pamphlets and sometimes logistical support, like buying them food), and then periodically hassling them afterward for the duration of the study.
Looked at in this light, it’s frankly impressive they were able to tease out any effect sizes at all. I would have liked a review article that broke the participants down into percentiles of weight loss-- that would give us a better idea of the range of outcomes realistically achievable-- but couldn’t find any meta-analyses that did this. Such is life.
Diet + Exercise
Weight-Loss Outcomes: A Systematic Review and Meta-Analysis of Weight-Loss Clinical Trials with a Minimum 1-Year Follow-Up - ScienceDirect
> A mean weight loss of 5 to 8.5 kg (5% to 9%) was observed during the first 6 months from interventions involving a reduced-energy diet and/or weight-loss medications with weight plateaus at approximately 6 months. In studies extending to 48 months, a mean 3 to 6 kg (3% to 6%) of weight loss was maintained with none of the groups experiencing weight regain to baseline. In contrast, advice-only and exercise-alone groups experienced minimal weight loss at any time point.
Systematic review of long-term weight loss studies in obese adults: clinical significance and applicability to clinical practice | International Journal of Obesity (nature.com)
> Dietary/lifestyle therapy provides <5 kg weight loss after 2–4 y, pharmacologic therapy provides 5–10 kg weight loss after 1–2 y, and surgical therapy provides 25–75 kg weight loss after 2–4 y.
This seems basically consistent with the previous study where over the long term diet and exercise-based interventions, for the most part, lead to 5-10 lbs of maintained weight loss.
Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials | British Journal of Nutrition | Cambridge Core
> [L]arge randomised clinical trials with long-term dietary interventions aiming weight loss showed that individuals under intensive lifestyle interventions lose about 4·8 kg( 2 , 38 ). Hence, the further reduction of 0·9 kg in the individuals assigned to a [very low carbohydrate ketogenic diet] would represent almost 20 % of the awaited weight loss achieved with long-term dietary interventions.
So tl;dr: Non-calorie-restricted ketogenic diets work marginally better than low-fat calorie-restricted diets on average, but not by much-- Keto loses you like 12 pounds, and low-fat diets lose you like 10 pounds.
This is a larger effect size than we saw in earlier studies, which could be explainable by the study length cutoff here was 1 year whereas the earlier, more pessimistic study required like four years of followup to be included in the meta-analysis (leaving more time for weight regain).
What about exercise?
Exercise
Isolated Aerobic Exercise and Weight Loss: A Systematic Review and Meta-Analysis of Randomized Controlled Trials - ScienceDirect
> Moderate-intensity aerobic exercise programs of 6-12 months induce a modest reduction in weight and waist circumference in overweight and obese populations. Our results show that isolated aerobic exercise is not an effective weight loss therapy in these patients. Isolated aerobic exercise provides modest benefits to blood pressure and lipid levels and may still be an effective weight loss therapy in conjunction with diets.
This, you’ll notice, pretty much aligns with the r/loseit conventional wisdom on the topic: Exercise alone tends not to do it unless you're Michael Phelps, who my fiancée tells me eats multiple tubs of ice cream each day.
So far, so depressing-- everyone here knows that if you have the industriousness and conscientiousness to stay on a consistent calorie deficit, you’ll lose weight. It's just empirically this doesn't happen to the degree most of us would want. Though don’t forget the study limitations! Intent-to-treat is a harsh mistress, and the use of averages in these study results conceals a lot of individual variation in patient response to these diets.
Anyway, on to other, more exotic (but not that exotic) methods of weight loss!
FDA-approved pharmacological interventions
Drugs!
This’ll be a pretty short list; the FDA has a very high bar for safety and efficacy for weight loss drugs, and as such has approved only 9 (?) drugs in this class for current usage, several of which are on-patent and thereby only affordable to the twelve riches members of the Saudi royal family. The FDA's conservative about approving these, since the history of weight loss medications includes shit like Fen-Phen (can kill you) and DNP (can make you go blind and then kill you; though at least this one was obvious enough that it was banned by the FDA at around the same time the FDA got the authority to ban things.)
So the FDA makes really fucking sure these days that there's nothing waiting in the weeds before approving stuff for weight loss. Oftentimes this assurance comes from jamming together drugs with a long history of safe use for other conditions (see the discussion of Contrave below), which seems sensible enough.
As for whether you’d like to take drugs for weight loss, your call-- I know a lot of people on r/loseit take pride in losing weight the natural way, and more power to them. That said, the following is the opinion of the notoriously risk-averse FDA:
> The U.S. Food and Drug Administration (FDA) recommends pharmacotherapy for weight loss when lifestyle interventions (diet, exercise and behavioural therapy) have failed and the body mass index (BMI) is °30kg/m2 with no concomitant obesity-related risk factors, or if the BMI is °27 kg/m2 and the patient has at least one obesity-related risk factor.
I'm aware that this does not align with the r/loseit conventional wisdom, which mostly has it that drugs are a dangerous crutch unsuitable for long-term use (and, by implication, short-term use). Which isn't always true! Lots of drugs you can basically stay on forever (such as bupropion, a popular antidepressant). The unknown risks of doing so ultimately must be weighed against the known risks inherent to obesity, which are substantial; in that way, it's a similar cost-benefit analysis as taking drugs for any other chronic condition. I myself will probably be on acid reflux medication until the day I die, and it's super worth it.
On that cheery note: to the drugs!
Orlistat (Xenical)
> weight loss achieved was about 3% [of total body mass] greater for subjects taking orlistat than for those taking placebo.
> produces significant gastrointestinal side effects (oily faecal spotting, flatus with discharge, faecal urgency, oily stools, increased defecation, faecal incontinence, abdominal pain) in 15-30% of the patients under treatment, that tend to disappear with time if the patient adheres to a low fat diet.
Gross.
This one’s notable because almost all of the other weight loss drugs on the market do so via the mechanism of reducing appetite; this one’s an exception, in that it instead stops your body from absorbing some of the fat you eat whereupon it comes out the other side.
Let’s move on.
Phentermine+Topiramate (Qsymia)
Clinical utility of phentermine/topiramate (Qsymia™) combination for the treatment of obesity (nih.gov)
In this trial, about 8% of patients with placebo (diet + lifestyle counseling) lost >10% of their body mass; conversely, 47% of patients in the experimental group (diet + lifestyle counseling + Qsymia) lost >10% of their body mass. Note that 1% of people in the experimental group got kidney stones, so drink your water. It sounds like this is a consequence of the topiramate (at least, this appears to be a known side effect of topiramate taken alone.)
Off-label drugs for weight management (nih.gov) has a really interesting discussion of phentermine-- at the time it was approved it was under pretty serious regulatory scrutiny for its structural resemblance to meth (and thus presumed addictive potential); for this reason it was approved for short-term use only, which tends to be interpreted as up to 3 months. Post-approval studies, happily, have failed to find evidence for chemical or psychological dependence regardless of duration of use; the linked article claims:
> There was protracted opposition to re-approval from those who maintained the sympathomimetic obesity drugs that had dangerous addiction potential. No evidence of addiction had appeared during 18 years of increasingly frequent use, but the FDA re-approved them all, having silenced the opposition by announcing the drugs would be approved for short-term use only
> US physicians treating obesity [...] continued to use phentermine and the other sympathomimetic amine anorectic drugs off-label long-term. Surveys of prescribing practices among physicians treating obesity have confirmed that a majority of these physicians continue to prescribe the sympathomimetics off-label in this manner.
This is verified in a different study:
Addiction potential of phentermine prescribed during long-term treatment of obesity | International Journal of Obesity (nature.com)
> Phentermine abuse or psychological dependence (addiction) does not occur in patients treated with phentermine for obesity.
And also:
A Study of Abrupt Phentermine Cessation in Patients in a Wei... : American Journal of Therapeutics (lww.com)
> Cravings for the substance abused, the hallmark characteristic of substance dependence and withdrawal, were entirely absent in the phentermine-treated subjects. Abrupt cessation of long-term phentermine therapy does not induce amphetamine-like withdrawal. Long-term phentermine therapy does not induce phentermine cravings. Symptoms observed after abrupt phentermine cessation represent loss of therapeutic effect and are not withdrawal.
(I emphasize this part because the idea of getting addicted to something freaks me out.)
Phentermine Alone
Effects of a meal replacement system alone or in combination with phentermine on weight loss and food cravings - Moldovan - 2016 - Obesity - Wiley Online Library
> The phentermine group lost 12.1% of baseline body weight compared with 8.8% in the placebo group.
Naltrexone/bupropion (Contrave)
Contrave, a bupropion and naltrexone combination therapy for the potential treatment of obesity. - Abstract - Europe PMC
> Preliminary data demonstrated placebo-subtracted weight losses of 3 to 7% and improvements in obesity-related comorbidities and cardiovascular risk factors. The primary adverse effect leading to discontinuation of treatment was nausea.
So a bit less effective than Qsymia based on phase 3 trials, but not by much; the bright side is it’s not a stimulant if you don't like stimulants. The “off-label drugs” article above claims this is sometimes combined with Phentermine but that there is no data on how often this happens or what the results are. Which is unsatisfying.
As an aside, bupropion is just Wellbutrin, an extremely common antidepressant, and naltrexone is an anti-addiction agent they use to get people off alcohol. Naltrexone’s been on the market for 15 years, and Bupropion has been on it since like the 80s. Which makes me suspect it’s quite safe, since we’ve had decades for long-term side effects to make themselves known. Food for thought. Ask your doctor.
(Speaking of long-term effects, very early on they were concerned that Contrave might hurt long-term cardiovascular health, which luckily wasn't observed in practice. Then later they thought it might actually help cardiovascular health instead, but Orexigen fucked up the study so now we'll have to languish in ignorance forever, I guess?)
Liraglutide (Saxenda)
Apparently middling effectiveness. I’d paste some sources, but the post is getting long and this drug is like 1000 dollars a month. So maybe look into it if you shit gold. (I am, of course, joking-- shitting gold is a contraindication for Liraglutide and other GLP-1 inhibitors. Ask your doctor.)
Non-FDA-Approved Drugs
Hahahahaha you fools, do not do this
Weight Loss Surgery
I have a truly marvelous discussion of weight loss surgery that this margin is too narrow to contain.
