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Primary Care Corner with Geoffrey Modest MD: physical activity energy expenditure, a new paradigm

12 Apr, 17 | by gmodest

by  Dr Geoffrey Modest

​​The Scientific American magazine just had an article which made the point that in cross-cultural studies, human beings expend the same number of calories whether they are doing intense exercise or sitting around (see ). These anthropologists studied several human populations, though this report was largely on the Hadza people who lived in the dry savanna wilderness of northern Tanzania. In particular they found that Hazda men who spent days hunting and tracking game, ate and burned 2600 cal a day. Hadza women, who also did a lot of physical work, ate and burned 1900 cal a day. This is pretty much the same as adults in the US or Europe, and was independent of body size, fat percentage, or age. Similarly, research has shown that rural Nigerian women and African-American women in Chicago have similar energy expenditure, despite large differences in activity level. And, a large collaborative effort on non-human primates found that captive primates living in labs or zoos expended the same number of calories as those in the wild.

They posit that there might be differences in calories spent on different activities, and those who are sedentary may spend more energy on other things. For example exercise reduces inflammation, so sedentary individuals may have to spend more energy reducing inflammation. In addition women who exercise a lot may have decreased estrogen levels and fewer ovulatory cycles (ie, less energy spent there), perhaps to compensate for their increased exercise-related energy expenditure. Other studies have found that those who do long-term exercise have reduced basal metabolic rates [and, my addition, have slower heart rates, which may itself be associated with longer life], expending less energy in this manner

A more scientific study published by the author of the above article looked at total energy expenditure over a range of physical activity, finding that there was a positive relationship between total energy expenditure and physical activity but only at the lower ranges of physical activity. Energy expenditure plateaued at the upper ranges of physical activity (see Pontzer H. Current Biology 2016: 26, 410.)


— 332 adults age 25 to 45, 55% female, from 5 populations across Africa North America (Ghana, South Africa, Seychelles, Jamaica, and the US)

— total energy expenditure was measured using doubly labeled water, considered the most accurate measurement (where each subject would ingest radioactively labeled water and assess urinary excretion of the isotopes)

— physical activity was measured by wearable accelerometers, measured in counts/minute


–there was a small increase in the total energy expenditure from a baseline of about 600 kcal/d with 0 counts/min (cpm) on the accelerometer to about 800 kcal/min as this increased to 230 cpm, with no significant further increase up to >700 cpm


— these articles are consistent with the repeated finding that exercise by itself does not lead to weight loss, though is an important factor in maintaining weight loss in those on a diet; these data undercut an Additive model (where total energy expenditure is a simple linear function of physical activity and that this determines variations in total energy expenditure) to more of a Constrained total energy expenditure model (where the body adapts to changes in physical activity to maintain total energy expenditure within a narrow range). And perhaps there is an evolutionary aspect as to why those who exercise have to conserve energy in other ways, such as lowering basal metabolic rate, decreasing population (and the decrease in estrogen/ovulatory cycles in women also decreases energy expenditure on growth, perhaps with the added issue that those who exercise lots to get food may need to have fewer mouths to feed to survive),  etc.

— But, of course, even if exercise does not lead to weight loss, it is important to maintain the perspective that physical activity has a multitude of important healthy benefits, both mentally and physically, and I believe we as clinicians should be encouraging it regularly with our patients. Increasingly, we are learning of the benefits of exercise even where physicians initially felt it was potentially harmful, including in patients with severe heart failure for example. (and in the old days, clinicians prescribed prolonged strict bedrest post-MI, or back pain…)

— A recent meta-analysis for example found that lower levels of exercise was associated with excess mortality (see ), and, as opposed to other studies, this one looked at total physical activity and not just leisure-time activity:

— a review of articles from 1981 to 2016, prospective international cohort studies examining association between total physical activity and least one of the 5 diseases studied: 35 for breast cancer, 19 for colon cancer, 55 for diabetes, 43 for ischemic heart disease, and 26 for ischemic stroke, yielding 174 identified articles.

— Higher levels of physical activity are associated with low risk for all of these outcomes, at 3000-4000 metabolic equivalent minutes per week, or METs/wk.

— overall, comparing those with < 600 METs/wk to those with > 8000 METs/wk was associated with:

— 14% decreased risk of breast cancer

— 12% decreased risk of colon cancer

— 28% decreased risk for diabetes

— 25% decrease risk for ischemic heart disease

— 26% decreased risk for stroke

–but for all of these, the major risk reductions occurred at lower levels of activity, with diminishing returns after 3000-4000 MET minutes/wk.

–and, another recent study (see Ekelund U. Lancet 2016; 388: 1302–10) did a meta-analysis of 13 studies with over 1 million individuals followed for 2 to 18 years, assessing sitting time, TV time and physical activity. They found that, as compared to those in the most-active quartile (35.5 MET-h/week):

— those performing < 16 MET-h/week had a 12% higher mortality rate

— those with the lowest quartile of physical activity (<2.5 MET-h/week and sitting > 8 h/ day) had mortality rates 59% higher

— And, subgroup analysis revealed that it was the exercise level determined risk, independent of the sitting time (comparing <4 h/d and up to >8 h/d of sitting time).

— However, watching TV for >5 hours per day was associated with increased mortality regardless of physical activity, with noticeable increases in the group watching 3-5 hours TV/d.

–of course, these are observational studies, though large and consistent in their conclusions. but those doing less exercise may be very different from those doing more (poorer health, different social determinants of health, etc)

So, what does all of this mean? A few points:

–exercise is really important in maintaining a healthy life (as above, but also as shown in smaller randomized controlled trials: see here ​ for an array of blogs)

–the first studies suggest that there is a conservation of total energy expenditure, largely independent of how much exercise is done. This is likely evolutionarily determined. And perhaps the energy expenditure on exercise is in part diverting energy away from what would be unnecessary bodily functions needed for the sedentary (eg decreasing inflammation, which exercise itself helps). But this finding of conservation of energy expenditure may help explain in part why increasing exercise is not associated by itself with weight loss.

–and it is interesting in the last study how TV watching seems to be a particularly bad sedentary activity, much worse than just sitting time (which would include such things as sitting at work, which might involve more thought, fidgeting, other activities than the more typically passive “vegging out” in front of the tube).

Primary Care Corner with Geoffrey Modest MD: Insulin pumps in type 1 dm, not the best solution

11 Apr, 17 | by gmodest

by Dr Geoffrey Modest

A recent trial looked at the effectiveness of insulin pump treatment versus multiple daily injections in patients with type I diabetes (see doi: 10.1136/bmj.j1285). Prior studies have suggested that pumps work better, but it may have been that those patients on pumps had received more intensive training and education than those on multiple daily injections. So, this study looked at patients given similar education, finding that the benefits of education/training outweighed the advantage of using the continuous subcutaneous insulin infusion (the pump) over multiple daily injections.



— 317 adult participants in the UK from multiple sites ​with type I diabetes were randomized to insulin pump therapy versus multiple daily injections

— Both received structured education: 267 attended one week DAFNE skills training courses (Dose Adjustment for Normal Eating), with a further visit at 6 weeks. This training stresses flexible dose adjustments according to eating, physical activity, and blood glucose level, and was slightly different for those on multiple daily injections vs pumps, to emphasize the specific use and problems with each.

— Mean age 41, 60% male, 91% white, BMI 27, mean duration of diabetes 18 years, 55% with macrovascular complications/43% retinopathy/7% neuropathy/19% nephropathy, 12% with at least one episode of severe hypoglycemia in the past year, mean hemoglobin A1c 9.1 with a range 5.7 to 16.7 and only 9% had a hemoglobin A1c < 7.5%

— Main outcome: changes in hemoglobin A1c at 2 years. Secondary outcomes included body weight, insulin dose, and episodes of moderate or severe hypoglycemia. They also looked at quality-of-life and treatment satisfaction



— Mean change in hemoglobin A1c at 2 years:

–decreased 0.85% with pump treatment

–decreased 0.42% with multiple daily injections

— with adjustment for missing values etc, the A1c difference was 0.24% between the therapies, which is neither clinically nor statistically significant (0.5% being considered clinically significant)

— on a per protocol analysis, the mean difference favoring pump treatment was 0.36%, which did have a p=0.02, still not clinically significant.

— But at 24 months, combining both treatment groups, there was a hemoglobin A1c decrease of 0.54%. In those with an A1c initially >7.5%, the A1c decrease was 0.64%. These decreases, presumably attributable to the education and training prior to beginning each of the drug regimens, were clinically significant.

— secondary outcomes:

— hypoglycemia: 49 episodes in 25 patients over 24 months, did not differ between groups. The incidence of severe hypoglycemia decreased by about half for both groups as compared to baseline.

— No statistically significant difference in body weight, but there was a slight increase in HDL cholesterol and decrease in total cholesterol in both groups without a difference. Insulin dose decreased in both treatments, a little greater in those on the pumps (0.07 IU/kg). No difference in the odds of proteinuria.

— Diabetic ketoacidosis: this was greater in the pump group compared to the multiple daily injections group (17 versus 5 episodes), most related to infections, and 18% by technical failures in those using pumps

— psychosocial questionnaires: no difference between groups in generic quality-of-life status instrument. Improvement in both groups in the overall diabetes-specific quality-of-life questionnaire, though this was greater in the pump group though not always reaching statistical significance. Pump users showed greater improvement in treatment satisfaction as well as more dietary freedom and less daily hassle at both 12 months in 24 months

— other findings: those on pumps had twice the number of contacts with diabetes professionals, especially during the 1st year. There also were more face-to-face contacts and of longer duration in the 2nd year of the study.



— Pumps are used less frequently in the UK, an estimated 6% of type I diabetics use pumps there versus 40% in the US (which may be related to differences in the medical cultures between the 2 countries, with us going more quickly/easily to high tech fixes).

— Pumps are clearly more expensive than multiple daily injections: the pumps cost £2500 in the UK plus an additional £1500 for consumables (cannulas, reservoirs, batteries). And this does not include the increased number of office visits noted above.


— As per the authors, “These results do not support a policy of using insulin pumps in  those with poor glycemic control until the effects of training on participants level of engagement in intensive self-management have been determined”.  I personally support a strong effort to encourage a healthier lifestyle for both type 1 and type 2 diabetics (and pretty much everyone else), for its myriad of positive health effects.  However, diabetes raises particular challenges, since dosing of insulin in particular is so dependent on consistency in diet/exercise as well as on other events that change insulin effectiveness (eg infections, which increase insulin resistance). There may certainly be some advantages of the pump in some patients, with the potential for having more variations in life (different foods, even a small piece of cake on a birthday; doing less exercise some days when not feeling well or the weather is bad; UTIs, etc) and more flexible dosing to compensate. But this study in type 1 diabetics does point out the primacy of structured education to improve glucose control, and then considering technological fixes in some cases on an individual basis. And I think the lessons are more broadly applicable to type 2’s and beyond…​

Primary Care Corner with Geoffrey Modest MD: ?Thyroid meds for subclinical hypothyroidism in older adults

10 Apr, 17 | by gmodest

​by Dr Geoffrey Modest

A randomized controlled trial assessed the effect of levothyroxine therapy in older adults with subclinical hypothyroidism, finding no clear benefit (see DOI: 10.1056/NEJMoa1603825 )


— 737 adults at least 65-years-old who had persistent subclinical hypothyroidism were randomized to levothyroxine starting at a dose of 50 µg a day, or 25 µg if their body weight were <50 kg or had coronary heart disease, with subsequent dose adjustment to achieve a TSH between 0.4 and 4.6, versus placebo.

— Subclinical hypothyroidism was defined as TSH of 4.60-19.99, with a free thyroxine level that was within the normal reference range.

— Mean age 74, 54% women, 98% white, 97% in non-sheltered community housing, 50% with hypertension/15% diabetes/14% ischemic heart disease/13% osteoporosis/9% smokers, mean baselineTSH level was 6.4

— Primary outcomes were changes in the Hypothyroid Symptoms score and in the Tiredness score on the thyroid related quality-of-life questionnaire, at one year (range of each score was 0-100, with higher scores indicating more symptoms, and the minimum clinically important difference being 9 points for each scale). Baseline Hypothyroid Symptom score was 17, Tiredness score was 26

— Secondary outcomes included changes in generic health-related quality-of-life, comprehensive thyroid related quality-of-life, hand grip strength, executive cognitive function (as assessed with the letter-digit coding test which indicates the speed of processing according to the number of correct responses in matching 9 letters with 9 digits in 90 seconds), blood pressure, weight, BMI, waist circumference, activities of daily living, instrumental activities of daily living, fatal/nonfatal cardiovascular events.


— Mean TSH level decreased from 6.4 to 5.5 in the placebo group as compared to 3.6 in the levothyroxine group, with median dose of 50 µg of levothyroxine. This was achieved within 6-8 weeks after starting the medication.

— There was no difference in the mean change at one year in the Hypothyroid Symptom score (0.2 for each group).

— There was no significant difference in the change in the Tiredness score (3.2 in those on levothyroxine, 3.8 in those on placebo)

— There was no benefit in any of the secondary outcome measures

— There were extended outcomes assessed for about half the patients, at a median of 24.2 months, also finding no difference in the primary or secondary outcomes

— Adverse events: no difference



— Subclinical hypothyroidism is an important issue for a few reasons:

— It is very common, between 8 and 18% of adults > 65yo

— Thyroid hormone acts throughout the body with receptors pretty much everywhere, affecting cognition, skeletal muscle function, vascular tree and heart, skeletal muscle, bone, etc, etc

— There are epidemiologic data suggesting that patients with subclinical hypothyroidism are at increased risk of coronary heart disease and perhaps heart failure. Data on total mortality are mixed.

— To me, there is a fundamental contradiction in the term “subclinical hypothyroidism”, since the normal limits of free T4 level reflects the bell-shaped curve of the community lab values, whereas TSH reflects the individual person’s response to their own circulating hormone levels. And patients may not be asymptomatic (ie “subclinical”). Subclinical hypothyroidism therefore, I think, just reflects a low level of hypothyroidism, such that depression of T4 levels still remains within the community norm, but still could have effects on that individual’s body.

— Other studies have found that treating subclinical hypothyroidism has shown improvements in the Tiredness score. These studies have been small and somewhat underpowered, and often with younger patients.

— About half of the patients with subclinical hypothyroidism will progress to overt hypothyroidism with a low serum thyroxine level over 10 to 20 years, with an annual progression rate of 2 to 4%. However some also have spontaneous recovery, less likely in those that are anti-TPO antibody positive

— Some limitations of the study which limit its generalizability:

​– The study tested a pretty uniform demographic (white people with stable housing and not a lot of medical comorbidities)

— The median achieved TSH level was 3.6, and some people believe that a more reasonable target is between 0.4 and 2.5 (i.e., it is possible that there would have been a measurable effect if they had achieved the lower and perhaps optimal TSH concentration)

— Very few people had TSH levels > 10, with a mean only slightly above the normal range, meaning that most of the patients had really mild hypothyroidism, which has a lower likelihood of progressing further or being symptomatic

— Hypothyroid symptom levels at trial entry were also quite low to begin with

— The trial was underpowered to detect an effect on cardiovascular events or mortality

— They did not measure thyroid antibody levels (which do predict to some extent which patients are more likely to progress to hypothyroidism)

— They did not find any difference in the speed of information processing, which has been found to be slowed in persons with subclinical hypothyroidism. However they did not assess other measures of cognitive function, though these are typically pretty blunt instruments (MMSE, MOCA, etc) and might not pick up very subtle though potentially important changes for the person and family/supports. But treating the subclinical hypothyroidism might still make a real difference for the individual, especially in the long-term (and a 65 year old in otherwise good health has a 20ish year life expectancy)

So, what is one to do with older patients who have subclinical hypothyroidism? The answer is not entirely clear, and this study really only adds the finding that short-term treatment of essentially asymptomatic patients with minimal laboratory abnormalities suggesting hypothyroidism does not seem to be effective. And I am particularly concerned about the potential links with atherosclerosis and cognitive decline. ​My sense is that it does seem reasonable to treat people with higher TSH levels (e.g.>10) since they have a higher likelihood of progressing to overt hypothyroidism. In those with lower TSH levels, it might be reasonable to check anti-TPO levels and treat those patients. It also might be reasonable to treat those who are more symptomatic than in this trial. But, overall, if one elects not to treat, it does make sense to follow these patients closely to see if they progress to more thyroid dysfunction. But one concern I have is that the usual symptoms of hypothyroidism, on the one hand, are pretty nonspecific, and, on the other hand, in many cases reveal themselves so slowly over time that patients may accommodate to them and not even notice them (though their treatment might still positively affect their quality-of-life).


for review and critique of thyroid screeninng guidelines, see here

Primary Care Corner with Geoffrey Modest MD: Home-based CBT for low back pain

6 Apr, 17 | by gmodest

​by Dr Geoffrey Modest


As mentioned in a recent blog (see here ), the effectiveness of medications for chronic pain is somewhat limited, and more studies have been coming out about nonpharmacologic therapy, either as solo or adjunctive therapy. Cognitive behavioral therapy (CBT) has been shown to benefit patients with chronic low back pain (see blog referenced below), but patient access to such therapy may be limited. In this light, a new trial showed that home-based, telephonic therapy may be as good as in-person CBT (see doi:10.1001/jamainternmed.2017.0223).


— Details:

— a single center VA study enrolled 125 patients with chronic back pain, allocated equally to interactive voice response-based CBT (IVR-CBT) versus standard CBT

— this was a non-inferiority study, with primary outcome being change from baseline to 3 months in patient-reported Numeric Rating Scale (NRS) of pain, a scale from 0 to 10. Secondary outcomes included pain-related interference in daily activities; and emotional functioning, sleep quality, and quality of life at 3, 6, and 9 months. These were assessed by the West Haven-Yale Multidimensional Pain Inventory, and the Morris Disability Questionnaire.

— 97 men and 28 women, 65% white/26% black, mean age 60, 20% full-time employed/14% part-time/15% unemployed/29% retired, 18% disabled, 26% with history of substance abuse, mean duration of back pain was 11 years, 55% with nonspecific cause/43% with radiculopathy or spinal stenosis, 12% with opioid prescriptions at baseline, average NRS pain rating was 5.58,

— All patients received a manual specific to their intervention (CBT versus IVR-CBT), to be followed over 10 weeks. The manual included an introductory module about the rationale for CBT, 8 pain-coping skill modules, and a relapse prevention module. All patients received IVR, consisting of 11 weeks of daily telephone calls to the patient to assess pain, sleep, step count, and pain-coping skill practice; if patients were engaged in a progressive walking program; and if they continue to receive care from their primary care clinician. All patients in both groups received these calls.

— In-person CBT involved weekly 30 to 40 minute treatment sessions, where the therapist reviewed the IVR reports and provided feedback during the sessions

— IVR-CBT involved receiving therapist reviews of the IVR reports in a 2 to 5 minute personalized feedback session


— Results:

— 82% completed at least 3 treatment sessions, though the IVR-CBT group attended 2.3 more sessions than in-person CBT (8.9 versus 6.6)

— NRS score: IVR-CBT decreased 0.77 points, versus a decrease of 0.84 with CBT, signifying noninferiority. Both groups had statistically significant reductions in average pain intensity at 3 and 6 months post-baseline but not after 9 months. These improvements were considered clinically meaningful changes, though of modest effect size.

— Statistically significant improvements in physical functioning, sleep quality, and physical activity of life at 3 months occurred in both treatment groups, with no difference between the groups.

— Post-treatment, 33% of those with standard CBT reported clinically meaningful improvement in pain intensity of at least 30% compared with 19% in those receiving IVR-CBT, not statistically significant.

— Adverse events: 46 participants, mostly related to increased pain from exercise, no difference between groups


— Commentary:

— IVR-CBT seems to offer a more accessible and lower cost treatment option for patients with chronic low back pain, which may well apply to other types of chronic pain (there are data supporting CBT benefit for back pain, osteoarthritis, and fibromyalgia). CBT involves helping patients reconceptualize pain as influenced not only by biological but by psychological, behavioral, and social factors. Patients learn cognitive (e.g. reframing catastrophic thoughts) and behavioral (e.g. relaxation techniques) coping skills through this process, as elaborated in the article.

— It is notable that patients were more engaged with the IVR-CBT-based therapy, attending significantly more sessions, than with standard CBT therapy. This suggests not just the acceptability of this IVR-CBT therapy, but likely also the decrease in burden/increase in accessibility and appeal of this treatment.

— There are several limitations to the study, including the fact that it was carried out in only one VA Hospital and with a small number of patients. Also, there was no nonintervention/placebo arm. However, this last concern may be less significant given that the average duration of pain was 11 years, suggesting that patients actually act as their own control.

— Also, it would be really interesting to know how those with a history of substance use disorder (26% in this article) or those on prescription opioids (12%) would do with IVR-CBT. The numbers of patients in this study was probably too small to get meaningful insight into this.


So, this may well be a viable and accessible alternative or adjunct for chronic pain management, and may really help patients who are functionally impaired by the pain, adding to the increasing numbers of nonpharmacologic therapies for this common and difficult problem. It also adds to the impetus for us to offer these types of therapies instead of just jumping to prescribe medications.

see​ which reviews a few articles: the main one on tai chi for knee arthritis, another on mindfulness-based stress reduction for chronic pain, and another on CBT for back pain




Primary Care Corner with Geoffrey Modest MD: One-time flex sig?

5 Apr, 17 | by gmodest

by Dr Geoffrey Modest
An observational study in the UK initially reported that a single flexible sigmoidoscopy screening significantly reduced subsequent colorectal cancer incidence as well as colorectal cancer mortality after 11 years of follow-up. They now found similar results after 17 years of follow-up (see S0140-6736(17)30396-3).
— multicenter randomized trial done from 1994-1999, randomized 170,432 men and women aged 55 to 64 to sigmoidoscopy (n= 57,098, of whom 40,621 were screened) vs control (n=112,936).
— mean age 60, 51% women.
— At screening in the intervention group: 18 were referred to surgery directly, 2131 (5%) were referred for a colonoscopy for high risk polyps, and 38,825 (95%) were discharged with low risk polyps or no polyps at all
— primary outcomes were: incidence and mortality of colorectal cancer
—  after 17.1 years of follow-up
   — colorectal cancer was diagnosed in 1230 individuals in the intervention group and 3253 in the control group: distal colorectal cancer was diagnosed in 529 in the interventions group (126 at the time of screening) and 1987 in the control group. Proximal colon cancers were diagnosed in 612 in the intervention group and 1255 in the control group.
   — 353 individuals in the intervention group and 996 in the control group died from colorectal cancer
— intention to treat analyses:
    — colorectal cancer incidence was reduced by 26%, HR 0.74 (0.70-0.80), p<0.0001
    — colorectal cancer mortality was reduced by 30%, HR 0.70 (0.62-0.79), p<0.0001
        — mortality related to distal colorectal cancer deaths was reduced by 46%, HR 0.54 (0.45-0.65), p<0.0001
  — per protocol analyses (ie, those who actually had a sigmoidoscopy in the intervention group):
    — colorectal cancer incidence was reduced by 35%, HR 0.65 (0.59-0.71)
    — colorectal cancer mortality was reduced by 41%, HR 0.59 (0.49 0.70)
        –mortality related to distal colorectal cancer deaths was reduced by 66%, HR 0.34 (0.26-0.46)
— sigmoidoscopy screening had no effect on all-cause mortality or on mortality from proximal colonic lesions (above the reach of the sigmoidoscope)
— the estimated number needed to screen (NNS) to prevent a single colorectal cancer diagnosis over 17 years was 98; it was 191 after the 11 year assessment
— the estimated NNS to prevent a certified death from colorectal cancer over 17 years was 220; it was 489 after 11 years
— no difference in the efficacy of sigmoidoscopic screening between men and women in terms of distal cancer, though the overall effect was less in women [women have been found to have more proximal colon cancers in several studies, including this one, one in the US and one in Norway]. The NNS for women was 165, much higher than men likely because of lower incidence of colorectal cancer in the control group in women than men and the fact that women had more proximal cancers. Also, there was no outcome difference between those 55-59yo versus 60-64yo at the time of the screening
— the 11 year data from the study showed that colorectal cancer incidence was reduced by 33%, distal colorectal cancer incidence by 50%, and colorectal cancer mortality by 43% (similar to above)
–A review of the graphs in the 17-year follow-up article shows that at about 4-5 years post-screening, the curves for colon cancer incidence cross (the intervention group picked up more cancers prior to the 5 year mark, the control group having much more afterwards, with curves then diverging). The incidence of proximal cancer was the same throughout the study. Colorectal cancer mortality diverged after about 5 years, with essentially parallel curves for the last 4 years. This latter finding suggests that follow-up after the 17 year mark would likely continue to show benefit  from a single screen (the annual incidence rate ratio reductions were 74% between years 6 and 10 and 69% between years 11 and 16 post initial screen).
— for reasons that escape me, several studies have found that excision of colonoscopy-discovered right colonic lesions (i.e. beyond the reach of the sigmoidoscopy) do not affect mortality (eg see Baxter NN. Ann Intern Med  2009; 150:1). This finding, in and of itself, adds further support to sigmoidoscopy screening, which is significantly less invasive and has significantly fewer adverse consequences than colonoscopy.
— a pooled analysis of 3 other trials also found extended benefit for flexible sigmoidoscopy screening, though these trials did not find benefit in women >60 years old. The current study authors argue that the screening should be done in people younger than 60 years old anyway, where women seem to have equal benefit.
so, pretty powerful article. The current recommendations have not changed (though are more aggressive in the US than Canada or the UK: (eg see here ). But this article suggests a few things:
–though we may offer patients the recommended screening intervals (as per the recommendations), it is reassuring that the likelihood of cancer or mortality is significantly less even after a single negative sigmoidoscopy (and I have seen a few articles in the past suggesting that colonoscopy screening may also be effective for more than 10 years. eg Nishihara R. N Engl J Med 2013;369:1095, which found protection up to 15 years after a negative colonoscopy)
–it also raises the issue of the natural history of colon cancer, with most of us learning it was on average about 10 years to develop cancer in apparently normal cells (supporting the screening intervals of the recommendations). It seems that people with visually normal exams at screening are at much lower risk of development of cancer for many more years than those with adenomas or early cancers (ie, those with lesions of some sort have a different colonic substrate and are therefore more genetically or environmentally or both predisposed to cancer even after resection than those with apparently normal colons, so it is erroneous to apply the same  finding of metamorphosis to cancer from them to normal individuals.)
–and it even raises tangentially a bigger issue about cancer: smokers with disturbed lungs, such as with COPD, seem to be at higher risk of lung cancer than those with radiographically normal lungs even with the same smoking history, or women with nonmalignant breast changes on biopsy are more predisposed to breast cancer,
–and perhaps even calculations of deleterious effects of radiation exposure is much worse in those with underlying abnormal tissues (which raises yet another issue: doing more mammograms in women with abnormal noncancerous breast tissue, or in smokers for lung cancer screening, might be much more risky than in women or smokers with normal tissue. So, the recommendations to increase radiologic screening in both cases may actually cause more harm in those with abnormal baseline tissues than the current models suggest. though i digress……
See here  , which reviews a population-based study in Norway, similarly finding that a one time flexible sigmoidoscopy decreased deaths from colorectal cancer by 27%, with 10.9 years of follow-up.

Primary Care Corner with Geoffrey Modest MD: Review of diabetes care guidelines 2017

4 Apr, 17 | by gmodest

By Dr. Geoffrey Modest
The annual update of the American Diabetes Assn Standards of Medical Care in Diabetes had a few changes over last year’s (​see Diabetes Care, Janurary 2017; 40, suppl 1). I will highlight those changes (see the text for the overall recommendations).
promoting health and reducing disparities in populations (a major update): 
–they acknowledge (finally) that psychosocial care is important in the overall care of diabetics, including self-management, mental health, communication, and life-stage considerations. 
–specific recommendations to look at the patients’ social context (including assessing food insecurity, housing stability and financial barriers) and make use of local community resources and support for self-management​
classification and diagnosis of diabetes
–having a baby ≥ 9 pounds was bumped from the list as an independent risk factor for development of prediabetes or Type II diabetes. and for women with gestational diabetes, they extended the earlier time to check postpartum from 6-12 weeks to 4-12 weeks with oral glucose challenge test
comprehensive medical evaluation and assessment of comorbidities (a new section):,
–recommends a patient-centered communication style using active listening; eliciting patients preferences and beliefs; and assessing literacy, numeracy, and potential barriers to care (but not mentioning motivational interviewing.  perhaps next year???). 
–they also recommend “considering” screening for anxiety in patients who exhibit anxiety or worries, “consider” annual screening for depression as well as at the diagnosis of diabetic complications, consider screening for eating disorders (esp if hyperglycemia and weight loss are unexplained), annual diabetes screening for patients on atypical antipsychotics
lifestyle management:This section was renamed to focus on the importance of lifestyle management. There are few changes this year:
— nutrition therapy was updated to those on flexible insulin therapy to include counting fat (in particular increasing mono-unsaturated fats which may improve glucose metabolism and lower heart disease risk) and protein (protein seems to increase insulin response without increasing plasma glucose concentrations), as well as counting carbohydrates, to reflect the effect of these dietary factors on insulin dosing and blood glucose levels. They also suggest eating foods rich in long-chain omega-3 fatty acids, though the beneficial role of dietary supplements is not supported by the evidence.
— they recommend that prolong sitting be interrupted every 30 minutes with short bouts of physical activity, such as briefly standing, walking, or performing other light physical activities..
— they also added a recommendation stressing the importance of balance and flexibility training in older people
— they highlight the importance of the psychosocial issues: they should be integrated with a collaborative, patient-centered approach and provided to all people with diabetes, with the goal of optimizing health outcomes and health-related quality of life.
— Consider screening for cognitive impairment and depression in those >65 yo
Prevention or delay of type II diabetes
— more emphasis on screening for prediabetes using an assessment tool or informal assessment of risk factors. Patient should receive intensive behavioral lifestyle interventions
— metformin should be considered as preventive therapy in those with prediabetes especially if the BMI is >35,if they are <60 years old, or in women with prior gestational diabetes and/or those with rising A1c despite lifestyle intervention.
— There is also a recommendation that vitamin B12 levels be measured periodically, given the newer data linking metformin use to vitamin B12 deficiency
Glycemic targets
— they redefined clinically significant hypoglycemia as a glucose <54 mg/dl (3.0 mmol/L)
— no significant changes in the overall A1c goals, noting that a reasonable goal for many nonpregnant adults is <7%. Consider <6.5% for selected individuals (e.g. those with short duration diabetes, diabetes that is treated with lifestyle or metformin only, long life expectancy, no significant cardiovascular disease) who can achieve it without significant hypoglycemia or other adverse effects. And less stringent goals such as <8% may be appropriate for those with a history of severe hypoglycemia, limited life expectancy, advanced microvascular microvascular complications, extensive comorbid conditions
obesity management
— for overweight and obese patients with type 2 diabetes who are ready to lose weight, there should be a combination of diet, physical activity, and behavioral therapy to achieve >5% weight loss. Such an intervention should be high intensity (16 sessions in 6 months), focusing on a 500-750 kcal/d energy deficit. It’s okay to use very low-calorie diets (<800 kcal per day) in carefully selected patients, monitored closely, for a three-month intervention only
— weight loss medications may be effective as an adjunct in those with a BMI >27
— metabolic surgery (a.k.a. bariatric surgery) “should be recommended” in patients with a BMI >40 (BMI >37.5 in Asian Americans), and in adults with BMI 35-40 (32.5-37.4 in Asian Americans) when hyperglycemia is inadequately controlled. There needs to be long-term lifestyle support and routine monitoring of micronutrient and nutritional status after surgery.
Pharmacologic approaches
— consider empagliflozin or liraglutide in patients with established cardiovascular disease to reduce mortality risk
— they comment on the noninferiority of basal insulin plus glucagon-like peptide 1 (GLP-1)  receptor agonist as compared to basal insulin plus rapid acting insulin
— they modified their therapy pyramid to include the costs, especially since the cost of insulin has gone up so dramatically (mean AWP of > $300 per vial). However, they continue suggesting that after metformin monotherapy, one could choose any of the following agents without specific preference: sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, or basal insulin.
Cardiovascular disease and risk management
— for patients without albuminurea, can use any of 4 classes of antihypertensives: ACE inhibitors, angiotensin receptor blockers, thiazide-like diuretics, or dihydropyridine calcium channel blockers. The general target blood pressure is <140/90 mmHg (as with JNC8), though lower target such as 130/80 may be appropriate for those at high cardiovascular risk and this can be achieved without undue treatment burden
— lipid management: they do focus on lifestyle modification. For patients <40 years old with additional atherosclerotic risk factors, consider using moderate or high intensity statin along with lifestyle changes. In those 40-75 years old without additional atherosclerotic risk factors, consider using moderate or high intensity statin, high intensity statin if they have additional atherosclerotic risk factors. And consider using a moderate intensity statin in those >75 years old, and high intensity statin if additional risk factors. Also should consider adding ezetimibe to moderate intensity statin in those with acute coronary syndrome and LDL >50 and those who cannot tolerate a statin.
— Consider aspirin therapy for primary prevention in those with diabetes, including most women and men > 50 years old with at least one additional cardiovascular risk factor but who are not at increased risk of bleeding.
— they changed the target for pregnant women with diabetes and chronic hypertension, suggesting a blood pressure goal of 120-160/80-105 mmHg. They also highlight the increased risk of retinopathy in women with pre-existing diabetes who are planning pregnancy or are pregnant
Microvascular complications
— not much change overall. They do state that if there is no evidence of retinopathy and the glycemia is well-controlled, ophthalmologic exams can be done every 2 years. They do reinforce that retinal photography is an acceptable screening tool but is not a substitute for comprehensive eye exam. For neuropathy, see recent blog specifically on those recommendations.
–personally, I have always felt that diabetes management is probably the most difficult of “medical” diseases, in part because of the complex array of psychosocial issues at all stages of diabetes (and beginning in pre-diabetes), and in part because of the necessity yet complexity of working with patients to make major, consistent changes in lifestyle (diet, weight control, exercise, etc), more difficult in a society which does not prioritize or even clearly articulate these generally healthful patterns in a meaningful way: witness how difficult it was to deal with trans fats, where the data against them have been compelling for decades; the push-back, specifically from the perspective from industry have been shown to be minimal/insignficant; and many in public health have gone against the tide/status quo over years to remove trans fats formally from the diet, still with incomplete success.
–it is pretty remarkable to me that the psychosocial issues have taken so long to bubble up to the being recognized and emphasized, along with suggestions for action. the suggestions are still pretty reserved: i personally feel that we should always have been looking at patient education as a 2-way street (and the backbone of treatment), incorporating patients values and understanding, and providing motivation for lifestyle changes mainly by involving the patient in the discussion as the main driver (vs lecturing them on diet and exercise). and given the diverse perceptions on what diabetes is and the potentially devastating effects of its complications, i personally would do more than just “consider” screening for depression and anxiety…
— as per many of my blogs, I remain quite impressed with the GLP-1 receptor agonists, which can be given as a simple once a week injection, and I regularly prescribe them now as my 2nd medication after metformin. They do not cause hypoglycemia, usually are very well-tolerated, help with weight loss, and I have seen quite dramatic effects. Last week I saw 2 patients on long-standing metformin and insulin, and when a GLP-1 agonist was added, their A1c in both cases went from about 9.5 to 6.5, in one case with the patient stopping their insulin. And they have the benefit of likely decreasing cardiovascular events (eg, see​ ). A recent report on empagliflozin found benefit for those with established cardiovascular disease, though I have concerns about the quality and conclusions of that study (see )
— these recommendations still do not deal with my concerns about using A1c as the target of therapy, which the FDA has allowed since the mid-1990s. Some medications that lower A1c pretty well have significant serious adverse reactions (the most obvious example being rosiglitazone and its attendant increase in cardiovascular disease), whereas others lower cardiovascular risk (such as the GLP-1 agonists), and others seem to be pretty neutral (although a lot of these are newer agents and we don’t really know their long-term adverse consequences). So, I do disagree with the approach of ADA that all of the second-tier drugs, after metformin, are equal options.
see here for many blogs on diabetes
see here for recent blog on B12 deficiency in diabetes
see for blog on ADA recommendations for neuropathy sent out a few days ago but not yet posted

Primary Care with Geoffrey Modest MD: Diabetic peripheral neuropathy, and more drug company shenanigans

4 Apr, 17 | by gmodest

By Dr Geoffrey Modest

There was a recent systematic review in the journal Neurology on pharmacotherapy for diabetic peripheral neuropathy pain and its effect on quality of life (see doi. org/ 10. 1212/ WNL. 0000000000003882). This appeared right after the recent guidelines from the American Diabetes Association (see link below), but had several eye-opening differences.


— the researchers updated a 2014 systematic review of 57 studies (see  Griebeler ML. Ann Intern Med 2014; 161:639, and prior blog on this  here) with 24 additional published studies and 25 unpublished studies. All trials were published between 1990 and 2015. The number of participants range from 20 to 804. They referenced the website clinical on March 9, 2016 to get data on unpublished studies.


Results, from placebo-controlled RCTs (those with moderate or large effect are highlighted):

— for anticonvulsants:

   — pregabalin, 16 RCTs, small effect, with low strength of evidence (SOE)

   — gabapentin, 5 RCTs, not effective, low SOE

— serotonin-norepinephrine reuptake inhibitors/antidepressants:

   — duloxetine, 7 RCTs, large effect, moderate SOE

   — venlafaxine, 2 RCTs, large effect, moderate SOE

   — tricyclic antidepressants, 4 RCTs, moderate effect, low SOE

— opioids

   — typical opioids (eg, oxycodone), 4 RCTs, not effective, low SOE

   — atypical opioids (tramadol, tapentadol), 5 RCTs, moderate effect, low SOE

— topical agents

   — capsaicin cream 0.075%, 5 RCTs, not effective, low SOE

— other agents

   — dextromethorphan, 3 RCTs, not effective, low SOE

   — mexiletine, 5 RCTs, not effective, low SOE

   — botulinum toxin, 2 RCTs, moderate to large effect, low SOE

–there were not enough data to evaluate the effect of these medications on quality-of-life.

–adverse effects: varied by agent. Dropout rates in the studies varied from 2.5% to 70% for oral agents, very low for topicals



— Unfortunately, few of the studies extended beyond 3 months (mean follow-up was 8.8 weeks with a maximum of 22 weeks), limiting their clinical utility some.

— The presumptive difference between the typical and atypical opioids as above is that the atypical ones have activity as norepinephrine reuptake inhibitors as well as mu agonists, with moderate effectiveness (vs oxycodone, a mu agonist, which was no more effective than placebo)

— I was a little surprised that capsaicin cream had no benefit, given the initial studies. And I have had patients do pretty well, with essentially no adverse effects. But, even if this is mostly a placebo effect, it is a pretty harmless med and if it works…

— The American Diabetes Association review  gave primary billing to pregabalin and duloxetine (see here  )

— The ADA review also did find a small benefit for oxcarbazepine, with low SOE, but not for other anticonvulsants such as topiramate, valproic acid, or lamotrigine.

— So, why are the above conclusions so different from those of the American Diabetes Association?  Of the 25 additional studies in which were unpublished, 18 were actually completed. The researchers were able to include 7 of these 18 completed studies. Of note, though pregabalin seemed to be effective, with a moderate reported effect size, when the 6 additional unpublished studies were included (all with negative results), the effect size decreased to “small”. In fact an analysis which included these negative studies found that the number of patients who would need to be treated with pregabalin for one patient to achieve a 50% pain relief was 7.7, so pretty few patients seem to benefit from pregabalin (Finnerup NB. Lancet Neurol 2015; 14:162)

–I suspect that the reason that gabapentin was considered ineffective but pregabalin not is mostly related to the serendipity of the studies done. Their anticipated physiologic effect is essentially the same, though gabapentin may be more slowly and erratically absorbed. In both cases there have been published studies suggesting positive efficacy of the medications, but on digging a tad under the surface, there are several large unpublished studies for each finding no benefit.  My guess is that they really do have similar and probably low levels of effectiveness. As with most drugs, some patients may benefit more than others. Is this from genetic differences in receptors or other drug mechanism?  Or maybe placebos work better in some people when they have mild to moderate adverse effects, and these meds both certainly do…(I have never seen anything written on this, but I suspect that meds with more systemic adverse effects may have more placebo effect as well, since some patients may internalize that meds with adverse effects must be stronger meds???…).The recent negative study of pregabalin in sciatica does also raise the question of its overall utility (see here  ). So, I’m not convinced that we should use pregabalin (only available as an expensive brand-name drug) over gabapentin (widely available generic), if we decide to use one of these types of drugs.

— One important finding in the current Neurology review was that venlafaxine, available as an inexpensive generic, was found to have a large effect size, with moderate SOE. This was also found for tricyclic antidepressants, though with moderate effect size. I am a bit hesitant to endorse venlafaxine as the single best agent (largest effect size of meds, somewhat larger than duloxetine which has no generic), since there were only 2 studies published on it. But I will add it to my short list of initial meds to try, along with tricyclics.

–so, bottom line here: the American Diabetes Association’s top 2 drugs, pregabalin and duloxetine, have both been knocked down by this more extensive Neurology review….. and, I think all systematic reviews should include looking at to find potentially pivotal negative studies which have not been published.


But, I think there are a few pervasive generic issues that this systematic review brings up:

–one of the biggest issues raised by this systematic review is: what should we trust in the medical literature? Clearly meta-analyses and systematic reviews can come to different conclusions based on their study inclusion criteria (see here for some of my thoughts on this). But additionally, we have moved to a place where the majority of large-scale medical studies are industry-funded. And they have a very clear bias to publishing the most positive results and putting the most positive spin on their results. And negative results are often not reported (this was the reason the feds required new studies to be logged into when they are initially approved, a law enacted in 1997). And the finding above about pregabalin is a case in point (a similar issue prevailed in the initial gabapentin studies, where there were also large, unpublished negative studies).  So, though pregabalin was highlighted in the recent Am Diabetic Assn recommendations 2 weeks ago, when the unreported negative studies are included, it really does not look so good…

–And,  as per here  companies often do not conform to government regulation/requirements, including rarely providing post-marketing data as required by the feds (their compliance rate was on  the order of 15%!!!!!). And, and, and, this whole situation is very likely to get whole lots worse with Trump, as the FDA moves to earlier licensing of drugs and medical devices, with less rigorous attention paid to their actual clinical benefit. So, the really difficult challenge is “what should I believe in the medical literature??”  I’m not sure how to answer that. But we need to be diligent, skeptical, and even less ready to jump on the bandwagon for new meds and medical devices. (One of my real purposes in writing these blogs is to critique studies or guidelines, and to assess their real generalizability and utility in the context of primary care clinical practice. And I hope they provide some context to help assess applicability of the studies/guidelines…..)


Primary Care Corner with Geoffrey Modest MD: Treating LDL to target?? More evidence

3 Apr, 17 | by gmodest

By Dr. Geoffrey Modest


A recent Korean multicenter observational study found that patients with coronary artery disease who achieved an LDL <70 mg/dl had very significantly decreased atherosclerotic plaque progression than those with higher LDL, further supporting the concept of treating-to-target to specific LDL levels (see



–147 patients with visible plaques on coronary CT angiography (CTA) who had another CTA at least 2 years later (median 3.2 years), as well as lab values within 1 month of both the baseline and followup CTAs

–mean age 62, 57% male, BMI 25, hypertension 65%, diabetes 33%, active smoker 20%, NCEP ATPIII risk score <10 in 55%/10-20 in 32%/>20 in 13%, Framingham risk score <10 in 63%/10-20 in 29%/>20 in 9%. Of note, those who achieved an LDL<70 were sicker: 1.95 vs 1.54 cardiac risk factors, 54% vs 26% with diabetes. though overall not a high risk group.

–initially, 57% asymptomatic, 8% noncardiac chest pain, 29% atypical chest pain, 3% typical chest pain and 3% shortness of breath


–prior to initial CTA: cholesterol 183 mg/dl, HDL 48, LDL 114, TG 154, and 40% were on a statin

–prior to followup CTA: cholesterol 162, HDL 48, LDL 92, TG 122, and 73% on statin

–mean LDL initially in those who had followup LDL<70: 106 mg/dl (vs 116 mg/dl in those with LDL>70) [so, those who achieved a lower LDL started with a lower LDL]

–mean follow-up LDL in those who had  LDL<70: 57 mg/dl (vs 104 in those with LDL>70). All patients who achieved LDL<70 were on a statin.



–univariate associations for annual plaque volume change: BMI (p=0.045), hypertension (p=0.040),follow-up LDL<70 (p=0.018)

–multivariate association: only the achieved LDL on followup CTA exam was associated with less plaque volume change (p=0.021)

–in the subgroup on statins: comparing those achieving LDL <70 (n=37) vs >70 (n=70):

–change in plaque volume: 12.7 vs 41.8 mm3, p=0.009

–annual change in plaque volume: 4.6 vs 14.5 mm3, p=0.015



–There are some limitations to this study, including its retrospective/observational design (eg, there could be missing unknown biases which influenced the aggressiveness of patient treatment), lack of information on the particular statins and doses used, and lack of data on consistency of statin use (data only for the month before the CTAs)

–However, the conclusions of this study are impressive in terms of differences in plaque progression, and add to the already pretty abundant literature finding that achieved LDL is an important target to therapy in those with coronary artery disease. And, I might add that even the 2013 AHA/ACC guidelines, which call for statin intensity determined by demographic or comorbidity criteria and not “treating-to-target” (ie, not using patient-level achieved LDL levels) do implicitly incorporate a treat-to-target approach in that they support more aggressive LDL reduction in some patients over others. But, they argued that since there were no clear RCTs stratifying patients to specific LDL goals, they should therefore not recommend using  LDL targets. This reasoning was suspect to me (as per prior blogs), since pretty much all of the other AHA recommendations were based on even​ less rigorous data​

–There are several older studies which supported treating LDL to target instead of prescribing high- vs moderate-intensity statins based on categories of risk.

–studies have shown pretty unambiguously that the achieved LDL determines the risk of cardiac events (there is a summary of the evidence in the ezetimibe blog referenced below)

–older studies using IV ultrasounds have also shown decreased plaque progression with statins. Coronary CTA, as in the above study, has been shown to be reproducible, correlates well with IVUS measurements, is noninvasive (other than radiation…)​, and supports the prior more-invasive IVUS studies

–several new studies have reinforced the utility of trying to decrease LDL to a lower target:

–IMPROVE-IT trial found that adding ezetimibe to simvastatin in 18,144 patients led to a 24% reduction in LDL levels (down to 53.7 mg/dl), associated with a 6% decrease in a composite of cardiovascular outcomes.   See here  for a critique of that study, along with more detailed arguments for targeting-to-treat LDL levels, plus an argument for adding HDL into the treatment decision model.

–FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) study, just released of 27,564 patients followed over 2.2 years (see DOI: 10.1056/NEJMoa1615664) found that adding PCSK9 inhibition, vs statin therapy alone (70% on high-intensity, 30% on moderate-intensity) led to a mean LDL of 30 mg/dl from a baseline of 92 mg/dl, and an associated 15% reduction in the combined primary endpoint (MI, stroke, hospitalization for chest pain, stent placement, death), a reduction from 11.3% to 9.8% of patients. [this was less of a reduction than the anticipated 20% reduction, which, by the way, led to a significant reduction in the value of the company in the stock market…]. In terms of secondary outcomes: 20% reduction of the combination of cardiovascular death, MI, or stroke; 27% decrease in risk of MI;  21% decrease in stroke, and 22% decrease in coronary revascularization, with clinical benefit evident within 6 months and increasing thereafter. There was no significant reduction in cardiovascular deaths or hospitalizations for unstable angina. I personally am not pushing these very expensive injectable drugs at this point (and have never prescribed them), but bring up this study as further evidence that targeting a low LDL seems to be beneficial.

–I suspect that some of the rationale for pushing the statin intensity argument, as opposed to the treat-to-target, is that if there is not a really simple guideline, many patients will not be treated at all with statins.  And I do respect that argument. The rationale for starting statins when patients are in the hospital with an atherosclerotic cardiovascular event is that otherwise they might never get the statin….

–but, there is large inter-patient variability in what the achieved LDL will be on different doses of statins, some of which depend on the initial pretreatment LDL and some on just individual variation (eg, some of my very high risk patients on atorvastatin 10mg achieve LDLs of 40 or so. Do they need more aggressive treatment? with the attendant increase in adverse reactions?)

–and, on the other hand, I certainly have several patients who did not achieve their LDL goal even with the “high-intensity” atorvastatin 40 or even 80mg, but who did when switched to rosuvastatin 40mg.

–so one consequence of not using a target LDL is that we may be undertreating some high-risk patients, even without needing to go to the newer agents. and the other is that we may be overtreating others by starting off with too high a dose of statins.

–and, i think it makes reasonable sense to target the LDL levels on a per-patient and per-statin basis (ie, not on a community scale, where the dose is determined by age, comorbidities, etc).  it’s a bit like treating hypothyroidism by the T4 level, where normal is a bell-shaped curve based on community data, vs TSH, which reflects the individual’s response to their own ambient T4 level​


–my major concern with statins really is the finding that many patients stop doing general lifestyle changes (and perhaps many clinicians do not continue to focus on them) because of the pretty dramatic lipid improvement with statins.  But the data are pretty consistent that a healthy lifestyle has a multitude of positive physical and psych effects beyond just the cardiovascular ones, and it is important to me that we continue to help motivate patients to improve their diet and exercise in particular.


–so, my sense is that there really are consistent data from an array of different types of studies suggesting that lower LDL levels lead to less accumulation of atherosclerotic plaque (as in the above study) as well as fewer atherosclerotic events (per both older statin studies as well as the newer studies with the newer agents), that titrating statin dose to the individual patient seems reasonable based on this, that we can pretty often achieve LDL levels <70 through that titration (likely to the benefit of the individual patient, especially important in secondary prevention),  but that we should be vigilant in reinforcing healthy lifestyle changes.


Primary Care with Geoffrey Modest MD: pregabalin did not help sciatica

3 Apr, 17 | by gmodest

​By Dr. Geoffrey Modest


A recent Australian RCT found no significant benefit for pregabalin in patients with acute or chronic sciatica (see Mathieson S. N Engl J Med 2017: 376: 1111).


— 207 patients were randomized to pregabalin initially at a dose of 150 mg per day, adjusted to a maximum of 600 mg per day versus placebo for 8 weeks

— sciatica was defined as radiating pain to one leg below the knee, accompanied by nerve root or spinal nerve involvement as indicated by at least one of dermatomal leg pain, muscular weakness, sensory deficits, or diminished reflex. The sciatica had to be present for a minimum of one week and a maximum of one year, and considered at least moderate in intensity or had resulted in at least moderate interference with daily activities

— mean:  55% female, 53 yo, dermatomal pain in 85%, motor deficits in 30%, neurologic deficits in 35%, sensory deficits in the 4%, pain in both legs in 8%, pain on straight leg raising in 63%, clinical level of spine causing problems S1 in 50% /L5 in 33%/L4 in 22%/S2 in 10%/more than one level in20%, PainDETECT <12 in 45% (which suggests that a neurologic component was unlikely)/13-18 in 25% (neurologic component unclear)/greater than 18 in 25% (neurologic component likely). Mean duration of leg pain was 63 days.

— the primary outcome was  leg pain intensity, measured on a 10 point scale, 0 being no pain and 10 worst pain; secondary outcome was the extent of disability, back pain intensity, and quality of life measures. Measurements were made at 8 weeks and at one year.


— 74% of patients in each group were considered to have adhered to the dosing schedule, defined as taking at least 80% of their prescribed trial regimen.

— at week 8, the mean unadjusted leg pain intensity score was 3.7 in the pregabalin group and 3.1 in placebo group, nonsignificant

— at week 52 the mean unadjusted leg pain intensity score was 3.4 in the pregabalin group and 3.0 in placebo group, nonsignificant

— no significant differences were observed with respect to any of the secondary outcomes at either week 8 or 52, including either physical or mental components of quality of life scores, global perceived effect, or extent of disability. Also there was no difference in the number of hours that the patients were absent from work over the year, the percentage of patients who used additional medications pain, or the percentage of patients who used health services.

— Post hoc analysis showed that the duration of leg pain did not modify the effect of pregabalin [though most of the patients had sciatica for less than 3 months, so were not in the chronic category.]

— 227 adverse events reported in the pregabalin group and 124 in the placebo group, with dizziness being the most common in the pregabalin group (70 events versus 19)


— I am not sure how to reconcile the baseline PainDETECT scores, which suggests that a neurologic component to the pain was most likely present in only 25% or so, with the reported 63% having pain on straight leg raising, 44% having a sensory deficit, 30% with a motor deficit and 35% with a neurologic deficit. This PainDETECT tool is a validated questionnaire which basically includes all of the regular subjective questions for radicular pain (as documented appropriately in the study above) and their intensity, and does not include the physical exam, which, as in the above study, found many patients with significant deficits and positive straight leg raising sign. But all of the patients sounded clinically like they had neuropathic pain and were likely to be treated as such (as above, all of them had: “radiating pain to one leg below the knee, accompanied by nerve root or spinal nerve involvement as indicated by at least one of dermatomal leg pain, muscular weakness, sensory deficits, or diminished reflex”). And, when the researchers did control for the PainDETECT score, they did not find that it modified the results.

— One limitation of the study was that most patients had relatively short-term symptoms of sciatica, and three quarters of patients spontaneously have resolution of symptoms within 3 months (see Ropper AH. N Engl J Med 2015; 372: 1240)

— So, my sense is that, based on this study, it seems that pregabalin had no benefit for patients who might present to us in primary care with clinical acute-to-chronic sciatica.  Which raises a very real and common clinical dilemma: what is the best way to treat such a patient???? Though this study undercuts a potential role for the medication pregabalin, are there other meds targeted for neuropathy which might work, such as tricyclics or duloxetine/venlafaxine?? Unfortunately, the data are quite meager regarding the use of nonpharmacologic interventions in those with radicular pain (see the Ropper article referenced above), including physical therapy, spinal manipulation, exercises, yoga/back strengthening exercises, etc, though there are better data supporting some of these for regular old low back pain. Since patients with sciatica do better with activity than rest, it does seem reasonable to provide analgesia to allow the patient to do more activity (though unproven). And, though not mentioned in this Ropper review, are some of the more recently described nonpharmacologic interventions used in non-neuropathic pain: see  blog here which also includes links to several other blogs supporting the utility of tai chi, mindfulness stress reduction, cognitive behavioral therapy. Bottom line: we just do not have great meds for chronic pain, these nonmedical interventions do seem to help for chronic pain, and they may be worth trying (and studying) for neuropathic pain.

— And, this dearth of information for treatment of sciatica from well-conducted studies does point to a fundamental problem in our medical research approach: we (ie drug companies, with some governmental/public support) spend huge amounts of resources to develop (really expensive) meds for rare diseases, yet some common and really disabling conditions (eg sciatica) are not investigated rigorously, especially for nonpharmacologic interventions, but also for existing meds (there is not much incentive to test an already-approved drug like pregabalin, since it is probably already being prescribed widely, so the downside of a negative study for the drug company is much greater than the upside of a positive study).



Primary Care Corner with Geoffrey Modest MD: fenofibrate,not so effective

30 Mar, 17 | by gmodest

There was extended followup of ACCORD-Lipid study for 5 years after the study ended, which confirmed the original conclusions that adding fenofibrate to simvastatin in diabetic patients did not improve cardiovascular outcomes, and that the assessment of prespecified outcomes also found that the subgroup with low HDL/high triglycerides did better with fenofibrate, but women overall did worse (see doi:10.1001/jamacardio.2016.4828 )



–4644 patients (90% of surviving participants) agreed to the 5-year followup of the ACCORD-lipid trial, after the fenofibrate vs placebo intervention was finished (all patients received simvastatin)

–this cohort was similar to the original study (these are the pre-trial baselines): 31% women, 66% white/14% black/7% Hispanic, 35% previous cardiovascular event, 4% heart failure, 14% current smoker/46% former, BMI 32, 11 year duration of diabetes, A1c=8.25%, LDL 100, HDL 42 in women/37 men, TG 188



–simvastatin treatment (20 or 40mg dose, titrated) did lead to a mean decrease of LDL to 80 mg/dl, which basically continued in the post-trial period. The TG (triglyceride) decreased to 145 in those on fenofibrate and 170 on placebo, with both achieving 161 mg/dL in the post-trial period. HDL increased during the ACCORD trial to about 41 mg/dl in both groups, and pretty much stayed the same in the post-trial period.

–primary outcome (nonfatal MI, nonfatal stroke, fatal CV event): essentially the same non-significant 7% difference as found in the trial

–secondary outcomes (individual components of the primary outcome, plus revascularization, hospitalization for heart failure, all-cause mortality): all continued to be nonsignficant

–prespecified subgroups, primary outcome in all of them were nonsignificant, other than in:

–female: 30% increase, HR 1.30 (1.01-1.68)

–male: 16% decrease, HR 0.84 (0.73-0.96)


–this trial adds to several others suggesting that fenofibrate does not have much cardiovascular benefit, including the FIELD trial. Gemfibrozil, however, either singly or in addition to statins, does confer clinical benefit in several studies. I am  unaware of any trials directly comparing different fibrates, but one meta-analysis of fibrates and CAD outcomes did find significant clinical benefit with gemfibrozil (23% decrease) vs none with fenofibrate or benzafibrate (see Lancet 2010; 375:1875)

–on secondary analyses, however, there is some consistency in finding that fenofibrate is clinically helpful in those with diabetic dyslipidemia (low HDL, high TG), which occurs in up to 35% of diabetic patients (though only 17% of the ACCORD cohort)

–the male/female difference found here is concerning, though was not found in the FIELD trial, which did have more female participants. And I am unaware of any male/female differences in trials with other fibrates.

–the above “legacy” study is important, since it does show that using fenofibrate for a pretty long trial (4.7 years) did not show any residual benefit 5 years later. Several other trials, such as the Coronary Drug Project, did show benefit on longer-term followup after the trial ended (with niacin, in the case of the CDP), confirming the utility of these legacy trials (and they might also show delayed adverse events).

–so, one concern is what agent to add when a statin does not give adequate cardioprotection, especially in diabetics with dyslipidemia and very high triglycerides? The fact that 2 trials did find some benefit for fenofibrate in this subgroup is reassuring, but not definitive since this was a subgroup analysis (though prespecified).  It does seem that gemfibrozil is a more potent fibrate, though there is the  concern of drug-drug interactions with statins: increased myopathy/ rhabdomyolysis. A recent article, however, did suggest that this consideration may be overblown (see here which looks at drug-drug interactions, suggesting that it is safe to use either atorvastatin or rosuvastatin with gemfibrozil, though perhaps best at lower doses. And that may well be the best alternative…

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