Kris Kresser: Should you skip breakfast to lose weight?

Does Skipping Breakfast Help with Weight Loss?
on May 9, 2017 by Chris Kresser 

Is breakfast really the most important meal of the day? Researchers have been trying to answer that question for years, particularly as it relates to achieving a healthy weight. Read on to learn what the latest randomized clinical trials are telling us, and whether intermittent fasting is really an effective weight loss strategy.
While intermittent fasting has been lauded for its health benefits, including promoting cellular maintenance and protecting against aging and neurodegenerative diseases, popular wisdom maintains that skipping breakfast is bad for you. Often labeled as the most important meal of the day, breakfast is said to “boost metabolism” and reduce hunger. But is this really true? Mounting evidence suggests that eating three meals a day may not be important for weight loss.

In this article, we’ll explore the evidence for and against eating breakfast with all its nuances, including an ancestral approach, the problems with association studies, a review of the biochemistry of intermittent fasting, and relevant results from randomized controlled trials.
Did our ancestors eat breakfast?

The truth is, it’s hard to know for sure, but it’s thought that most hunter–gatherers ate intermittently depending upon food availability. (2, 3) Loren Cordain, founder of the Paleo diet, writes:
“The most consistent daily eating pattern that is beginning to emerge from the ethnographic literature in hunter–gatherers is that of a large single meal which was consumed in the late afternoon or evening. A midday meal or lunch was rarely or never consumed and a small breakfast (consisting of the remainders of the previous evening meal) was sometimes eaten. Some snacking may have occurred during daily gathering, however the bulk of the daily calories were taken in the late afternoon or evening.” (4)
It appears that the three-meals-a-day paradigm was not adopted until the Agricultural Revolution around 10,000 years ago. Frankly, the fact that we eat three times a day is somewhat arbitrary and seems to be based on when it was most convenient to eat during farm work and harvest. (5)

Most studies regarding breakfast consumption and obesity are association studies. And while there is undeniably an association between a lean body type and breakfast consumption, correlation does not imply causation, and many of these association studies have been inappropriately used to shape recommendations for weight loss.
Because “eat breakfast” is such popular health advice, people who are committed to their health are more likely to eat breakfast. They are also likely to avoid smoking, manage stress, and eat more fruits and vegetables, all things associated with a healthier weight. Breakfast eaters tend to be leaner, but this doesn’t mean that they are lean because they eat breakfast.

Luckily, in the last few years, several research groups have sought to use randomized controlled trials (RCTs) to answer the question “does eating breakfast cause weight loss?” Let’s take a closer look at the studies and what they found.
In one of the first RCTs in 1992, researchers separated 52 moderately obese adult women based on their normal breakfast habit (whether they ate or skipped breakfast regularly) and then randomly assigned half of each category to a breakfast group and half to a no-breakfast group. In their results, they reported a trend suggesting that women who had to make the most substantial changes to their initial eating habits achieved more weight loss. Essentially, habitual breakfast skippers tended to do a bit better when they had to eat breakfast, and habitual breakfast eaters tended to do better when they had to skip breakfast. (10) Unfortunately, when this result was cited by other studies and the media, it was widely misconstrued. First, the researchers only observed a trend for this interaction effect, meaning that it did not reach the level of statistical significance (p < 0.06, for those familiar with statistics). Second, the study was widely reported in the scientific literature as having shown that eating breakfast led to weight loss, even though the authors never concluded anything of the sort. Unfortunately, poor reporting of this study shaped scientific and popular opinion for several decades.
The belief that breakfast is important for weight loss prevailed, despite a few smaller studies that found that skipping breakfast had no effect or even a potential beneficial effect on weight loss.

In 2013, Cornell researchers performed a randomized crossover study in 24 undergraduate students and found that skipping a meal did not result in energy compensation at later meals and that it might even be an effective means to reduce energy intake in some people. (11)

In 2015, researchers in the UK performed a similar study with a week-long intervention in 37 participants and concluded that “there is little evidence from this study for a metabolic-based mechanism to explain lower BMIs in breakfast eaters.” (12) However, these studies were both relatively short-term compared to the 1992 study and didn’t receive as much attention.
In 2014, as part of the Bath Breakfast Project in the UK, 33 obese adults were randomly assigned to a breakfast group or no-breakfast group for six weeks. (13) The breakfast group ate slightly more calories but was also a bit more physically active. The no-breakfast group ate fewer calories over the entire day but was also slightly less active and had slightly more variable glucose levels in the afternoon and evening at the end of the trial. Body mass and fat mass did not differ between the two treatments, and neither did indexes of cardiovascular health. Contrary to the popular notion that breakfast “boosts metabolism,” resting metabolic rate did not differ between the groups. Breakfast also did not provide any significant suppression of energy intake later in the day. It seemed like the evidence was mounting against popular belief.
Finally, in the largest long-term, multisite clinical trial to date, researchers attempted to settle the debate once and for all. They randomized 309 obese adult participants to a breakfast group or no-breakfast group for 16 weeks. They reported in the American Journal of Clinical Nutrition:
“A recommendation to eat or skip breakfast for weight loss was effective at changing self-reported breakfast eating habits, but contrary to widely espoused views this had no discernable effect on weight loss in free-living adults who were attempting to lose weight.” (14)
Over 92 percent of subjects complied with the recommendation they were given, but it had no impact on weight loss. They also separated individuals based on their baseline breakfast habit and found no interaction between initial breakfast habit and success of the intervention. This is directly contrary to the near-significant interaction found by Schlundt and colleagues in 1992 and was a much larger study.

But wait, does a bowl of cereal and toast with jam have the same effect as an egg omelette, greens, and a sweet potato? Food quality matters more than food quantity, right? Yep. When “breakfast” is lumped into one big category, there’s not conclusive evidence for or against it, (15) as we saw in the previous section. But researchers have looked at different types of breakfast and weight loss as well, with some intriguing results.
In 2015, a study in China found that obese teenagers ate less at lunchtime if they had an egg breakfast compared to a bread breakfast. The egg breakfast was reported to increase levels of satiety hormones, keeping them full for longer. The egg breakfast group also had significantly more weight loss. (16) Sounds pretty good to me! Unfortunately, there wasn’t a “no-breakfast” group in this study, so it’s hard to know how the egg breakfast would have compared to intermittent fasting.
Researchers in Missouri performed a randomized trial in 2015 with three different groups. They randomly assigned 57 breakfast-skipping teens to a cereal-based breakfast (13g protein), an “egg-and-beef rich” breakfast (35g protein), or to continue skipping breakfast. They found that the egg-and-beef breakfast led to voluntary reductions in daily food intake and reduced reported daily hunger. It also prevented fat mass gains over the 12-week study. (17)
The truth is, most of the studies above (that found no effect of breakfast) were likely based on a typical high-carbohydrate breakfast, a la the Standard American Diet. It would be very interesting to see the metabolic response to breakfast omission in a group of healthy individuals eating a nutrient-dense, evolutionarily appropriate diet.

What about fasting in relation to exercise for weight loss? In the fed and fasted states, we preferentially oxidize (“burn”) different substrates to produce energy. Could exercising in one state or the other provide benefits for weight loss? In 2012, researchers in London performed a crossover study, monitoring food intake and energy expenditure in 49 participants during one week with breakfast and one week skipping breakfast. They found that total energy intake, energy expenditure, and activity levels did not differ between conditions. (18)
A study in Japan in 2014 used a randomized crossover design with eight male subjects, all of whom were habitual breakfast eaters. The subjects were instructed to eat or skip breakfast, and the researchers measured their energy expenditure during the day. Interestingly, they found that breakfast skipping did not affect energy expenditure, fat oxidation, or the thermic effect of food if you looked at the entire 24-hour period (similar to the previous study), but it did change the rhythm over the course of the day.

When people skipped breakfast, energy expenditure was lower during the morning but higher during the evening and sleep than those who ate breakfast. Breakfast skipping increased fat oxidation and reduced carbohydrate oxidation in the morning relative to breakfast eating and increased carbohydrate oxidation during the evening. (19)
Following up on this study, a crossover study in Korea in 2015 tracked 10 obese male college students. For one week, they ate before their morning workout. The second week, they ate breakfast after their morning workout. Their results? The fasted workout caused the men to burn more body fat, but it also increased levels of the stress hormone cortisol after exercise relative to the fed workout. (20)

While burning body fat is beneficial to weight loss, large rises in cortisol are not. It should be noted that these participants were not adapted to fasted exercise and that “fat-adapted” people might have a smaller cortisol response to fasting.
What do these studies tell us? Well first, the thermic effect of food in the morning, a common argument for why we should eat breakfast and “boost our metabolism,” is a myth. Over the total course of a day, total energy expenditure does not change. They also suggest that morning fasting might be a great time for a fat-burning workout, as long as it’s not too stressful on your body.

When you eat, the hormone insulin is released from your pancreas to the bloodstream and shuttles glucose (carbohydrate) into muscles and other tissues, where it is used for energy production. Excess glucose is converted to fat and stored in the adipose tissue. When you fast, the hormones glucagon and cortisol stimulate the release of these fatty acids from adipose tissue into the bloodstream. The fatty acids are taken up by the muscles and other tissues and broken down (oxidized) to produce cellular energy. In this concerted manner, the body switches from utilizing carbohydrates to fats as its primary fuel and ensures a constant source of energy to the body.
This is all good and rosy, as long as the body can actually make this metabolic switch. In the scientific literature, this is called “metabolic flexibility,” (21) though you may be familiar with it as “fat-adapted.” People who are “fat-adapted” are more accurately “metabolically flexible,” meaning that they can easily switch from oxidizing carbohydrates in the fed state to oxidizing fat in the fasted state, and vice versa.

On the other hand, people who are said to be “carb-adapted” are “metabolically inflexible,” meaning that they are constantly burning carbohydrates and have trouble switching to fat oxidation. These people still release fatty acids from adipose tissue to the bloodstream but have lost the capacity to oxidize fatty acids in the muscle and other tissues. The accumulation of lipids due to reduced fatty acid oxidation has been hypothesized to cause insulin resistance, (21) and a low ratio of fat to carbohydrate oxidation has been identified to be a good predictor of weight gain. (22)
The phenomenon of metabolic inflexibility may explain some of the results of breakfast studies. Most of the participants in these studies were individuals eating an evolutionarily inappropriate Standard American Diet with large amounts of refined carbohydrates three times a day. If, all of a sudden, you instruct these “carb-adapted” people to skip breakfast, you’re asking for a blood glucose crash and insatiable hunger by lunchtime. In reality, most people who want to try intermittent fasting transition do so gradually by slowly increasing the time between meals, allowing the body to adapt and restore metabolic flexibility.
This may explain why prior breakfast habits have an effect in some studies. Researchers at the University of Colorado studying 18 overweight women found that the adverse effects of skipping breakfast were restricted to habitual breakfast eaters. While habitual breakfast eaters who skipped breakfast had increased blood lipids, insulin, and free fatty acid responses at lunchtime, habitual breakfast skippers who skipped breakfast had none of these effects. The authors concluded that meal skipping may have enhanced effects in habitual breakfast eaters due to entrainment of metabolic regulatory systems. (23)
So, skipping breakfast might not cause weight loss in the short term, but if over the long term it allows your body to “reset” and restore metabolic flexibility and insulin sensitivity, you may ultimately see some weight loss benefit. This is especially true if you’re also improving the overall quality of your diet. A low-fat diet reduces your body’s ability to release fatty acids from adipose tissue and oxidize them in the muscle, (24) while a high-fat diet increases the ability to use fat for energy in muscle and thus improves metabolic flexibility. (25, 26)
Summing it up: should you fast, or break-fast?
If you’re overwhelmed by this quantity of research, you’re not alone. Researchers have been struggling to find consensus on this topic for decades. If you glazed over some of it, here are the major takeaways from this article:
Hunter–gatherers probably only ate one large meal later in the day.
You cannot trust association studies. Correlation does not equal causation!
When all breakfast is lumped together, skipping or eating breakfast has no apparent effect on weight loss.
If you separate out different types of breakfasts, a protein-rich, fiber-rich breakfast seems to confer the most benefits.
Eat before or after exercising depending on your health status and goals. Skipping breakfast will optimize fat metabolism during your morning workout, but it may also spike your cortisol levels.
Most of the individuals in these studies were “carb-adapted” individuals eating a Standard American Diet. It would be interesting to see how the results might differ in “fat-adapted,” metabolically flexible individuals eating a nutrient-dense Paleo diet.
And that’s it!

If anything is clear from this consortium of research, it is the need for individualized nutrition. I’ve written several articles and spoken on my podcast previously about why intermittent fasting (IF) may not work for everyone. If IF works for some people (they lose weight) and is detrimental to others (they gain weight), and these people are all lumped together, we’ll see a net zero change in weight.
So how do you know if intermittent fasting is right for you? Try an n=1 experiment: eat or skip breakfast for a period of time, and notice how it affects your weight, mood, productivity, gut function, and other factors. Transition slowly if necessary, by eating your first meal of the day later and later each morning. There are some predictors of success with fasting, but only you can really know if IF works well for you.

Better quality of life reported for young type one diabetics with lower HbA1c levels

nutritional scale

Better quality of life reported for young type one diabetics with lower HbA1c levels

Summarised from Independent Diabetes Trust Newsletter Sept 17

An international study of almost 6,000 young people showed that lower HbA1c levels were associated with a higher quality of life scores between the study age range of 8 to 25 years.
Those who reported the lowest quality of life scores were aged 19 to 25 and females had lower scores than the males across every age range.
The study showed that advanced ways to measure food intake, more frequent blood sugar testing, and taking exercise for 30 minutes a day, were all associated with higher satisfaction scores.
The researchers concluded that if young people have trouble controlling their diabetes, they should focus on the three factors that they can potentially control to make life easier.
Measure your food accurately
Test your blood sugar frequently
Exercise for at least 30 minutes a day

(Diabetes Care May 26 2017)

BMJ: Diabetic ketoacidosis is the biggest threat to type ones



Adapted from BMJ Minerva 23 Sept 17 and BMJ Learning Module Clinical Pointers in Diabetic Emergencies Oct 17

Type ones under the age of 30 have a mortality rate three times that of their non- diabetic friends.
This rather shocking statistic was discovered by Welsh paediatricians who have been tracking their children with diabetes since 1995. Furthermore the death rate has not gone down over all this time despite improvements in monitoring and therapy. Ketoacidosis is the leading cause of death. Although microvascular and to a lesser extent macrovascular complications can occur, they do not affect mortality rates in this age group.
Out of a hundred or so type one adult diabetics approximately 3 or 4 will develop diabetic ketoacidosis each year. Currently 3-5% will die. Not all deaths will occur in hospital because not everyone is identified as having ketoacidosis prior to death. Recognition by relatives, friends, police and medical professionals would be an important factor to improve transfer to hospital.
Ketoacidosis is also be the presenting sign of diabetes in 6% of the total number of ketoacidosis patients. It may have been precipitated by a viral infection and can be confused by a variety of illnesses such as gastroenteritis, flu and alcohol intoxication and withdrawal.
Assuming a person can be recognised as ill and needing hospital assessment, recognition of DKA is improved by always checking a blood glucose in an acutely ill person in the A and E department.
If levels of glucose are high, and the characteristic symptoms are present eg dehydrated looking, tired, nausea, vomiting, abdominal discomfort and breathing rapidly, then the diagnosis can be further explored by checking the blood electrolytes.
The immediate treatment is re-hydration with a litre of normal saline and the administration of intravenous or subcutaneous insulin usually 0.1 u of insulin per kilogram body weight. As the potassium level can be affected, particularly a tendency to go too low after treatment has started to work, this needs monitored every hour or two. The problem is that irregularities of the heart beat can occur if the potassium level is not adjusted correctly.
It can be seen that management of DKA in the established case is tricky and time consuming. Therefore it is wise to seek medical advice while you or the one you are concerned about, is still relatively well and can for instance still tolerate oral fluids and give a coherent history.
Early recognition and treatment is the key to a good outcome in DKA.



Is there a new “magic bullet” for type two diabetes?

SLGT-2 Inhibitors Gaining Traction as a Class in Preventing Cardiovascular Consequences
April 15th, 2017 Diabetes in Control

Chest pain

Are we experiencing the next “magic bullet” in type 2 diabetes?
Cardiovascular mortality has long been established as the primary cause of death in patients with type 2 diabetes (T2D).

Cardiovascular effects of oral antidiabetic medications came to the forefront in 2007 with the landmark article in the New England Journal of Medicine, written by Dr. Steven Nissen.  In this publication, Dr. Nissen showed a strong association between use of rosiglitazone and increased incidence of cardiovascular complications and deaths.  In the years following, the FDA placed strong restrictions on the prescribing of rosiglitazone, sharply decreasing the market for Avandia.  Subsequent studies showed no correlation between the use of thiazolidinediones and adverse cardiovascular events, causing the FDA to reverse its stance on Avandia.  This class of agents was of particular interest because it was among the first of the oral agents that did not display the hypoglycemia seen with the sulfonylureas.  More importantly, this event caused the FDA to re-examine its approval process, and enforce that cardiovascular studies be done in all new drug presentation trials.
Until recently, there were no groundbreaking studies that suggested any class of oral hypoglycemic could significantly reduce CV risks associated with diabetes.  In January 2016, the European Heart Journal reported the results of EMPA-REG OUTCOME, a randomized placebo-controlled trial with over 7,000 subjects looked at empagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, which works by reducing glucose reabsorption at the renal tubule, thereby increasing glucose excretion. While a known effect is the reduction of hyperglycemia in T2D, there is also an increase in diuresis, weight loss, and reduction in blood pressure without associated tachycardia.  EMPA-REG OUTCOME showed that patients who received empagliflozin demonstrated significant declines in heart failure hospitalizations and cardiovascular deaths, without a rise in adverse effects, regardless of baseline heart failure state.  Based on these findings, Eli Lilly, the manufacturer of the Jardiance® brand of empagliflozin, saw a significant increase in their stock value, as their product was given preference over other available SGLT-2 inhibitors.
Earlier this month, the American College of Cardiology held the ACC.17, where the results of the CVD-REAL study were released .  CVD-REAL was a meta-analysis looking at over 364,000 patients from 6 different countries (United States, United Kingdom, Germany, Norway, Sweden, and Denmark), with T2D. Subjects were receiving either a SGLT-2 inhibitor or another glucose-lowering drug (oGLD) with even distribution across both arms in all six countries.  Of the patients studied, 3% had baseline heart failure, 13% had baseline cardiovascular disease, and 27% had baseline microvascular disease. The primary endpoint was hospitalization for heart failure, which showed a reduction strongly favoring the SGLT-2 inhibitors (hazard ratio [HR] 0.61; p < 0.001).  The secondary endpoints of all-cause mortality also favored the SGLT-2 inhibitors (HR, 0.49; p<0.001), as did heart failure hospitalizations and all-cause deaths in total (HR, 0.54; p<0.001).
Of important significance is the lack of population heterogeneity across the different countries, which suggests that the positive effects seen can be associated with the entire class of SGLT-2 inhibitors (which include dapagliflozin [Farxiga®] and canagliflozin [Invokana®]), and not just empagliflozin.

The investigators in CVD-REAL have come forth and stated that their findings do indeed line up with those from EMPA-REG OUTCOME.  The significance of this is there now exists an open market for SGLT-2 inhibitors, and that these once very costly medications may experience considerable cost reduction across the class, giving patients more affordable options.
As David Kliff, publisher of Diabetic Investor, recently stated, Dr. Nissen has received plenty of negative feedback from the community for his claims against rosiglitazone.  However, because of his initial findings and subsequent correction, the FDA has re-established its approach to the approval process for treatments of type 2 diabetes to include necessary studies of cardiovascular outcomes, much to the benefit of our patients, and that’s certainly a good thing.
Practice Pearls:
The significance of the fall and rise of rosiglitazone has had a tremendous impact on how type 2 diabetes treatments are evaluated.
EMPA-REG OUTCOME has demonstrated considerable positive effects on cardiovascular outcomes in T2D patients receiving empagliflozin, an SGLT-2 inhibitor.
The recent CVD-REAL study has strengthened the notion that all SGLT-2 inhibitors significantly reduce hospitalizations due to heart failure, as well as displaying a decline in cardiovascular deaths in the T2D population.
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457-71.
FDA website. FDA significantly restricts access to the diabetes drug Avandia. Press release, September 23, 2010. NewsEvents/Newsroom/PressAnnouncements/ ucm226975.htm Accessed March 24, 2017.  
FDA website. FDA panel votes narrowly to modify Avandia restrictions, June 6, 2013.
American College of Cardiology Website. CVD-REAL Study: Lower Rates of Hospitalization For HF in New Users of SGLT-2 Inhibitors, March 19, 2017.

Mark T. Lawrence, RPh,PharmD Candidate, University of Colorado-Denver, School of Pharmacy NTPD

BMJ: Continuous glucose monitoring in pregnant women halves adverse birth effects

Freestyle libre

Adapted from the BMJ article by Susan Mayor 23 Sept 17

A study has shown beneficial effects in type one pregnant patients. One in two babies born to such women have complications such as prematurity, stillbirth, congenital anomalies, and being too big. These are due to high blood sugar levels in the womb and there has been no reduction in these in the last 40 years.
Denise Feig, the author of the study, based at the University of Toronto, says, “Keeping blood sugar levels in the normal range during pregnancy for women with type one diabetes is crucial to reduce risks for the mother and child. As insulin sensitivity varies through the pregnancy adjusting insulin accurately is complex. Since our results have come through we think that continuous blood sugar monitoring should be available to all type one women.”
In the international study 325 women who were planning a pregnancy or pregnant took part. Two thirds were randomised to get the monitors and the rest had standard treatment. Large newborns were halved and so was neonatal intensive care admissions and hypoglycaemia. Women had a small but significant reduction in HbA1c. They had more time in the normal blood sugar range and hypoglycaemia was not increased.
The extra cost of the monitors could be offset to some extent by the reduced cost of medical care after the birth.

Lifestyle changes add up to a longer life

Adapted from an article by James Hamilton in the Herald 14th October 2017

If you want to improve your life expectancy you can do the sums and see just how much extra time you can have according to Scottish researcher Dr Peter Joshi.
Obesity levels are now three times more than in the 1980s. At that time six percent of men and eight percent of women were affected. This has spurred an Edinburgh team to look into the genes affecting longevity in families and the lifestyle factors that affect life span in individuals. The old nature/ nurture debate again. Overall 600,000 people were tested and their family histories explored.
When it comes to longevity the balance comes down much more to lifestyle than your genes.
Educate yourself: add a year to every year educating yourself beyond school. That’s really like going to university for free. You get the time back at the other end!

Get slim: add a year for every surplus stone you lose. Diabetes complications is the main factor in causing the reduced life expectancy.
Stop smoking or don’t start: add seven years to your life if you don’t smoke those 20 cigarettes a day.
Praise the parents: some people have a gene that improves their immune function giving an extra six months life expectancy.
Blame the parents: Addiction to drugs and alcohol are somewhat genetically based.
Blame the parents (again): A gene that affects cholesterol reduces lifespan by about eight months.

The full report is the journal Nature Communications.

Which medicines work most effectively for diabetic neuropathy?

What treatments can improve pain and quality of life?

This comprehensive report was first published in April 2017 by Diabetes in Control and discusses what old and new medicines work for diabetic neuropathy and importantly which ones don’t.

Pharmaceutical Products and Drugs
Diabetic neuropathy is a nerve disorder that the National Institute of Diabetes and Digestive and Kidney disease estimates affects about 60 to 70% of diabetic patients in some form, with the highest rates of neuropathy occurring in patients who have had diabetes for over 25 years.

Although diabetic neuropathy can affect almost any organ in the body, the most common type of diabetic neuropathy is peripheral neuropathy. Peripheral neuropathy, which is often worse at night, results in tingling, numbness, and pain occurring in the hands, arms, fingers, legs, feet, and toes.

The best way to prevent diabetic neuropathy is keeping glucose under control and maintaining a healthy weight, but for those who experience this painful condition, finding the best relief can often be difficult and confusing.
Building upon a previously published study from 2014, a new systemic review was conducted to “systemically assess the effect of pharmacological treatments of diabetic peripheral neuropathy (DPN) on pain and quality of life” plus a search of PubMed and Cochrane Database of systemic reviews (reviews from 2011 – March 2016).
A total of 106 randomized controlled trials were used in the final systemic review, including trials analyzed by the previously published study. Only two medications, duloxetine and venlafaxine, had a moderate strength of evidence (SOE) compared to the low strength of evidence found with the remaining 12 study medications. As a class, serotonin-norepinephrine reuptake inhibitors (SNRIs) was found to be an effective treatment for diabetic neuropathy with the most commonly reported adverse effects of dizziness, nausea, and somnolence. Venlafaxine and tricyclic antidepressants were also determine to be effective at relieving pain compared to placebo using the previous analysis’ data.

Pregabalin was determined to be effective at reducing pain compared to placebo but found to have a low SOE due to the inclusion of four unpublished studies causing potential bias. Pregabalin, as well as the other anticonvulsants included, had adverse effects of dizziness, nausea, and somnolence.

Oxcarbazepine was also found to be an effective neuropathy pain reliever compared to placebo.
Atypical opioids have a dual mechanism of action, norepinephrine reuptake inhibition and mu antagonism, which aids in a class wide effective pain relief compared to placebo, and more specifically tramadol and tapentadol were found to be effective vs placebo. The most common adverse effects reported for opioids were constipation, somnolence, and nausea.

The last medication that was determined to be an effective pain reliever of diabetic neuropathy compared to placebo was botulinum toxin

Gabapentin, using five randomized controlled trials, was determined at two different doses to be ineffective at treating pain when compared to placebo. Other agents that were determined to be ineffective treatments for diabetic neuropathy were typical opioids (oxycodone), topical capsaicin 0.075%, dextromethorphan, and mexiletine.

Practice Pearls:
Pregabalin, oxcarbazepine, and tapentadol have shown to be effective vs placebo at relieving pain due to diabetic neuropathy and are also FDA approved for this indication.
Serotonin-norepinephrine reuptake inhibitors may be a good choice for relief of diabetic neuropathy pain and have the additional benefit of relieving depression that is commonly associated with diabetic neuropathy
Additional studies are needed to assess long-term pain relief effectiveness.

“Nerve Damage (Diabetic Neuropathies) | NIDDK.” National Institutes of Health. U.S. Department of Health and Human Services. Web 05 April 2017
Julie M. Waldfogel, Suzanne Amato Nesbit, Sydney M. Dy, Ritu Sharma, Allen Zhang, Lisa M. Wilson, Wendy L. Bennett, Hsin-Chieh Yeh, Yohalakshmi Chelladurai, Dorianne Feldman, Karen A. Robinson. “Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life”. Neurology, 2017; 10.1212/WNL.0000000000003882 DOI: 10.1212/WNL.0000000000003882
Mark T. Lawrence, RPh, PharmD Candidate, University of Colorado-Denver, School of Pharmacy NTPD