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Archive for March, 2017

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

30 Mar, 17 | by

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…

Primary Care Corner with Geoffrey Modest MD: Vitamin D Decreases Acute Respiratory Illness

29 Mar, 17 | by EBM

By Dr. Geoffrey Modest

A recent meta-analysis found that vitamin D supplementation, especially in those who were quite deficient, led to lower risk of acute respiratory infections (see


  • 25 eligible RCTs were found, with a total of 10,933 patients, aged 0-95. The researchers were able to access individual participant data from the studies. Outcome data was obtained for those participants experiencing at least one acute respiratory tract infection. The trials were from 14 countries on 4 continents. All studies supplied oral vitamin D3 to those in the intervention arm. This was given as bolus doses every month to every 3 months in 7 studies, weekly doses in 3 studies, and daily doses in 12 studies. Study duration range from 7 weeks to 1.5 years.
  • Overall demographics: 50-50 male/female, 50% < 1yo/15% 1-16yo/28% 16-65yo/10% >65yo, 5% baseline 25(OH) level of <25 nmol/L, 33% >25 nmol/L, 62% not recorded


  • There was a 12% decreased risk of acute respiratory tract infections in those receiving vitamin D supplementation, adjusted OR 0.88 (0.81-0.96), p<0.001
  • The protective effect was seen in those receiving either daily or weekly vitamin D, without additional bolus doses (bolus was defined as at least 30,000 IUs), adjusted OR 0.81 (0.72-0.91), with number needed to treat =20, though there was no benefit in those receiving 1 or more bolus doses
  • In those on either daily or weekly vitamin D, there was differential benefit depending on the baseline 25-OH vitamin D level, with p=0.006 for the interaction:
    • If <25 nmol/L (equivalent to  10 ng/ml), 70% decrease, adjusted OR 0.30 (0.17-0.53)
    • ​If >25 nmol/L, 25% decrease, adjusted OR 0.75 (0.60-0.95)
  • There was no significant difference between the groups by daily dose of vitamin D (<20mg, equivalent to <800 IU; 20-50 mg, equivalent to 800-2000IU; >50 mg, equivalent to > 2000 IU), age, BMI, the presence of asthma or COPD, or having received influenza vaccination.
  • No serious adverse events in the vitamin D group, with 0.5% having hypercalcemia and 0.2% renal stones, though both events were evenly represented in the intervention and control arms.
  • The body of evidence contributing to these results was considered to be of high quality. And a review of the individual participant data from their included studies showed that the preponderance of them showed benefit from vitamin D therapy (i.e., it was not just a couple of large studies dominating the meta-analysis)
  • In differentiating acute respiratory illnesses, the significant benefit was in 11 studies for upper respiratory infections, with a 12% benefit limited to those on daily or weekly dosing [OR 0.88 (0.78-1.00), p=0.05], not in any of the other secondary outcomes they assessed (lower respiratory tract infections, use of antimicrobials, absence from school/work, serious adverse events)


  • This meta-analysis basically found that in those patients who were quite vitamin D deficient, there was a pretty remarkable benefit to either daily or weekly vitamin D therapy in preventing acute respiratory infections (70% decrease), and specifically upper respiratory infections. There was also a 25% statistically significant decrease in acute respiratory infections in those with >25 nmol/L, though this was significantly less so than in the more deficient group. Although overall there was no benefit reported in those with 25(OH) vitamin D levels in the 25-50 nmol/L, 50-75 nmol/L or >75 nmol/L groups, they did not break this down by whether they were in the daily/weekly or bolus therapy groups (i.e., it is likely that as with the above analysis, there was benefit if these subgroups were limited to those on daily/weekly therapy. It would have been useful to see if there were a cutpoint of vitamin D level below which there was benefit from daily/weekly supplementation). And it does not appear that participants were randomized by their entry 25(OH) vitamin D levels in the individual studies in the meta-analysis.
  • This very low level of vitamin D deficiency (<25 nmol/L) is quite common in my practice (though I do work in Boston, a pretty high latitude, and with many patients with darker skin pigmentation and who are older, all 3 of which predispose to low vitamin D levels), and estimates are that around 6% (20 million) US adults are markedly vitamin D deficient (i.e. <10 ng/ml)
  • These conclusions are somewhat limited because of the small numbers of many racial or ethnic subgroups in the individual studies included in the meta-analysis
  • One pretty striking conclusion (and very unexpected to me) was that there would be such a difference between those given bolus supplements vs daily/weekly vitamin D. Other studies had suggested that giving the equivalent of about 800 IU/day, whether daily, monthly, or every 6 months, didn’t matter much, at least in terms of bone health. This data suggests that there may be a difference, at least for other outcomes.
  • Though I have not sent out any blogs on vitamin D for quite some time (see here for a slew of those blogs), there are some suggestive studies showing there are vitamin D receptors are all over the body (including the immune system, and also being associated with the induction of antimicrobial peptides and other antimicrobial chemicals such as reactive oxygen intermediates), observational studies of mortality benefit as well as benefit for specific autoimmune and other diseases, and even a study finding that vitamin D supplementation improves the response of patients with TB to medications (see  doi:10.1073/pnas.1200072109/-/DCSupplemental). Several newer studies have had some mixed results: some showing higher vitamin D levels are associated with decreased multiple sclerosis, better breast cancer survival, fewer relapses from ulcerative colitis, etc.; but some showing no benefit for pain in those with knee osteoarthritis, walking distance in those with heart failure; and several with contradictory results, e.g. for falls in the elderly, asthma in kids. A recent JAMA study (see Lappe J. JAMA. 2017; 317(12):1234) of 2303 healthy postmenopausal women >55yo in rural Nebraska found that vitamin D supplementation did not lead to decreased cancer (there are several other studies finding decreased breast, colon, and prostate cancer in those with higher vitamin D levels). But, despite the headline in Physician’s First Watch on 3/29/17 that “vitamin D supplements fail to prevent cancer in 4-year trial”, this trial looked at women who had a baseline 25-OH vitamin D level of 32.8 ng/ml (much higher than what is considered an adequate vitamin D level), were given 2000 IU of vitamin D and 1500 mg of calcium daily, and achieved a quite high vitamin D level of 43.9 ng/ml. So not so surprising that there was no benefit, since they were not even close to being vitamin D deficient.  Of note the 2011 Endocrine Society suggested that the cutpoint for vitamin D deficiency should be 20 ng/ml, though there are some suggestive data that it should be higher, at 30 ng/ml, though they felt that the data were not strong enough to push for this higher cutpoint (see doi: 10.1210/jc.2011-038). And even the 30 ng/dl cutpoint is lower than the mean in the Nebraska study!!

So, my general sense is that we probably should replete vitamin D levels (either more sun, if in the right latitudes and people are able, or by vitamin supplementation) in those who are deficient, since:

  • We do have vitamin D receptors all over our bodies for a likely evolutionary reason (and humans started off in climates where there was lots of sun)
  • There are lots of observational studies showing benefit for adequate vitamin D levels (though observational studies do not confer clear conclusions of benefit)
  • We should be careful about being too reductionist (i.e., there is not one magic bullet for health, but a constellation of healthful activities in concert, and this likely includes adequate vitamin D levels, either by adequate sun exposure or by taking supplements to increase vitamin D levels when the sun exposure is inadequate),
  • There seems to be very few adverse effects of vitamin D supplementation, including in the above Nebraska study where they achieved quite high vitamin D levels
  • And, unlike almost every other medical intervention, there is minimal cost, with potentially large benefit.

Primary Care Corner with Geoffrey Modest MD: opiates and benzos assoc with inc mortality

28 Mar, 17 | by EBM

By Dr. Geoffrey Modest

Another observational study, this one using data-mining of large patient databases, found that concurrent use of prescription opiates and benzodiazepines was associated with increased ER visits and hospital admissions for opiate overdoses (see


  • 315,428 privately insured patients aged 18-64, continuously enrolled in a health plan with medical and drug benefits from 2001 till 2013
  • About 40% men, comorbid conditions included: heart failure, peripheral vascular disease, hypertension, COPD, diabetes, CKD, cerebrovascular disease, dementia, MI, liver disease, alcohol “abuse” (??not clear how defined), drug “abuse” (also not defined), psychosis, and depression
  • The principle search was for patients on opiates who had at least one day of overlapping prescriptions for a benzo


  • 9% of opiate users also had a benzo in 2001, increasing to 17% in 2013
  • The increase was largest in those on intermittent opiates
  • Compared to those who did not use benzos, risk of ER visit or hospital admission for opioid overdose was:
    • 14x as often for all opiate users, adjusted OR 2.14 (2.05-2.24, p<0.001)
      • 42x as often for intermittent opiate users, adjusted OR 1.42 (1.33-1.51, p<0.001)
      • ​1.81x as often for chronic opiate users, adjusted OR 1.81 (1.67-1.96, p<0.001)
    • Assuming a causal link between the combo of meds and ER visits/hospitalizations for opioid overdose, eliminating this combo (i.e. not taking benzos) would decrease these services by 15%


  • This is yet another study linking opiates and benzos to overdoses. Other studies done in several different countries have confirmed this, overall finding that around 30% of fatal “opioid” overdoses involve the concommitant use of benzos.
  • There are clear limitations in this study, most of them articulated by the researchers, including that as a retrospective study there could be hidden biases (they controlled only for the ones they assessed), the study only looked at patients continuously enrolled in their health plans (though sensitivity analyses found not much difference if looking at those enrolled for at least 2 years), they did not include patients who died from an overdose, they do not have information on the doses of meds or how those changed over the time period, and they only looked at prescription drugs (i.e. not heroin use or prescription meds bought on the street). They also did a sensitivity analysis requiring both medications overlap for at least 25% of the days of opiate prescriptions, also finding similar results.
  • I would add to this list: it is important to note that the likelihood of hidden biases is increased given that the patients on concurrent opioids and benzos had a higher incidence of every medical condition (14 of them) they tried to control for. Perhaps very significantly in this sicker population, they did not have information on potential differences in the severity of any of these medical conditions in those on benzos vs not (not all diabetes is the same…). And there are some very important conditions that they did not include: for example, they did not look at patients with anxiety disorders, including panic, for which these patients might well be on benzos appropriately for therapy, and these underlying psych conditions themselves have considerable mortality associated with them. Or, bipolar disorders with predominant mania, perhaps misdiagnosed as anxiety and also treated with benzos, yet bipolar disorder itself also has significant attendant mortality. And I should note that of these 14 conditions, the one with the most profound difference between the non-benzo and benzo groups was “depression”, noted in 4.4% in the nonbenzo group and 17% in the benzo group. And, as mentioned, there is no differentiating by severity of depression or comorbid other psych issues (i.e. those on benzos may well have had more psych issues, both quantitatively and qualitatively, which put them at higher risk of overdosing).
  • But, the bottom line to me is that there is certainly a plausible mechanism for increased overdose in those on both meds (benzos increase the respiratory depression of opiates), there is an FDA “black box” caution about simultaneous use of these meds, prior studies have found up to a 10-fold increased mortality from overdose in those on the combo, and so I think the onus is on us as prescribers to minimize the concurrent use of these medications as much as possible. That being said, I certainly do see some patients who are on opiates and do have debilitating anxiety disorders refractory to other meds/therapies, who are also on benzos. Some prescribed by me, some by psychiatrists. I do try to minimize the doses of all of their opiates/benzo. And perhaps it makes sense to try to switch the opiates in those on both classes of medications to buprenorphine, since this is associated with less respiratory depression (though as far as I know this approach has not been validated through studies. I would welcome any information from blog readers). And, it makes sense to be especially certain that these patients have naloxone at home, with someone trained in its administration.

Primary Care Corner with Geoffrey Modest MD: creatinine increases after ACE/ARB may not be so good

15 Mar, 17 | by EBM

By Dr. Geoffrey Modest

A recent article in the BMJ challenged the long-held belief that ACE inhibitor/ARB related increases in creatinine were actually renoprotective (see Schmidt M. BMJ 2017;356:j791).


  • Observational study of 122,363 patients starting treatment with ACE inhibitor (ACE-I) or ARB from 1997 to 2014
  • They assessed the rates of end-stage renal disease, myocardial infarction, heart failure, and all-cause death among patients whose creatinine increased 30% or more after starting treatment, and also assessed the effect of each 10% increase in creatinine above the patient’s baseline.


  • 2078 patients (1.7%) had a creatinine increase of 30% or more.
  • Comparing those with a creatinine increase of > 30%, vs those with < 30%:
    • 56% female vs 46%
    • Median age 68 vs 63
    • Myocardial infarction in 10.5 vs 4.5%
    • Heart failure in 19 vs 4.8%
    • Arrhythmia in 17.2 vs 6.8%
    • Peripheral arterial disease in 6 ​vs 2.5%
    • Stage 3b CKD in 6.9 vs 3.7%/stage 4 in 2.0 vs6%
    • Beta blockers in 23.7 vs 17%
    • Loop diuretics in 28.6 vs 7.2%
    • Potassium sparing diuretics in 8.8 vs 2.0%
    • NSAIDs in 34.0 vs 23.5%
    • Underweight in 2.3 vs 0.9%, healthy weight in 26.9 vs8%, overweight in 34.5 vs38.4%, and obesity 29.0 vs  33.4%
    • So, basically those with greater creatinine increases had more baseline characteristics associated with increased morbidity/mortality
  • Creatinine increases of 30% or more were associated with (adjusted for age, sex, calendar period, socioeconomic status, lifestyle factors, chronic kidney disease, diabetes, cardiovascular morbidities, and use of other antihypertensive drugs and NSAIDs):
    • 43 times the rate of end-stage renal disease, incidence rate 3.43 (2.40-4.91)
    • 46 times the rate of myocardial infarction, IR 1.46 (1.16-1.84)
    • 37 times the rate of heart failure, IR 1.37 (1.14-1.65)
    • 84 times the rate of all-cause death, IR 1.84 (1.65-2.05)
  • There was a greater increase for all outcomes as creatinine went from an increase of <10%, to 10-19%, to 20-29%, to 30-39%, and to > 40%
  • These results were consistent across calendar periods, subgroups of patients, and among those continuing to use ACE inhibitor/ARB’s
  • There were much more dramatic increases in the rate of renal failure during the 1st year after starting ACE-I/ARBs (12.2-fold increase) versus in the 2nd year (3.7-fold) versus 2nd to 5th year (1.7- fold), but then increase to 2.5-fold from 5 to 10 years. However the numbers were small and the trend was nonsignificant. However, there were similar trends for heart failure and mortality which were significant. Heart failure was initially 1.9-fold increase in the 1st year but then settled in at 1.5-fold increase.


  • One major concern is that only about 10% of patients receive the recommended monitoring of serum creatinine soon after starting ACE-I/ARBs and only 20% of those with an increase of >30% discontinue the drugs as is recommended.
  • It has been widely held that larger increases of creatinine after taking these medications (up to 30%) were in fact renoprotective, supported theoretically/mechanistically that by decreasing intra-glomerular pressures, we were sparing the fragile glomeruli frombarotrauma. These data were not terribly rigorous. For example, there was a small study (Apperloo AJ. Kidney Intl 1997; 51(3): 793), which did find that in 40 nondiabetic patients with impaired renal function prior to therapy, those with a greater GFR decline after ACE-I had more stable renal function, and this decline was completely reversible after stopping ACE-I therapy at 4 years.) And this study has been cited in subsequent reviews as clear evidence that the higher the creatinine increase (up to 30%) the better…
  • The benefits of the study are its huge size, its real-world outcomes data and the fact that it represented the general UK population in terms of age/sex/ethnicity, the fact that they only looked at patients who had at least one year of being continuously in the registry before they were started on an ACE-I/ARB, and that they had long-term follow-up until the 1st diagnosis of end-stage renal disease, myocardial infarction, heart failure, and all-cause mortality.
  • However, the negatives of the study are that the patients who had more significant creatinine increases were clearly sicker and had more inherent likelihood of getting these clinical endpoints. Specifically, these patients were older, had more underlying chronic kidney and heart disease, and had more drugs that were potentially nephrotoxic. In particular the use of potassium sparing diuretics suggests the possibility that these patients had more severe hypertension or heart failure requiring these drugs (and the study did not stratify the degree of these conditions at baseline). The increased use of NSAIDs might signal that these patients had more pain, were less ambulatory, perhaps more overweight (though the BMI of those with more a bump in creatinine was actually lower, the specific individuals who went on to renal failure may well have been those with a higher BMI and on NSAIDs, but these data not available), and were less able to have a healthy lifestyle, which has repeatedly been associated with increased morbidity/mortality. And, though they did mathematically model to compensate for the array of potential adverse biases, there was such a divergence in the baseline characteristics of the 2 groups (>30% versus <30% creatinine increase) that I do not trust this mathematical manipulation to compensate for the real potential biases between the groups. (In addition, they did not comment on the underlying clinical conditions of the patients comparing those with <10% increase in creatinine vs those with >30%, but only for those <30% vs >30%)
  • It was also notable that pretty much all of these outcomes were much more dramatic in the 1st year after starting ACE-I/ARBs, suggesting that we should be doing increased surveillance particularly in that 1st
  • There are some perhaps relevant prior studies which suggest that increased creatinine is associated with cardiovascular disease, found in patients with mild to moderate renal dysfunction. However, these were patients with intrinsic renal disease as opposed to medication-induced increases of creatinine. So, not sure this is directly applicable to ACE-I/ARB-induced creatinine increases, but the above results are consistent with this.
  • We also did not know the levels of proteinuria of these patients, so there could be an important unaccounted for bias here. The studies suggesting the renoprotective effect of ACE-I/ARBs in diabetics found renal protection in those with proteinuria, even at low levels of albuminuria.

There have been other studies showing that patients with very significant proteinuria, especially those with greater than 1 g of albumin per day, do have renal protection by ACE inhibitors (see GISEN group. Lancet 1997; 349: 1857, which found that in 352 nondiabetic patients with proteinuria of 3 g of more than 24 hours, ramipril led to significant decreases in proteinuria as well as the rate of GFR decline, and a subsequent study of 186 patients with 1 to 3 g of proteinuria also had renal protection, but to a lesser degree, see Ruggenenti P. Lancet 1999; 354: 359.)

So, this article does give some pause. Perhaps our model of renoprotection is not so accurate. It is notable that the new JNC 8 guidelines do not recommend using ACE-I/ARBs as the primary treatment for hypertension in diabetic patients. Also the new American Diabetes Association guidelines (blog to come out soon) comment that those with diabetes should be treated with ACE-I, ARBs, thiazides, or dihydropyridine calcium channel blockers (no preference, except they recommend ACE-I/ARBs in those with albumin to creatinine ratio is greater than 300 mg/g, level A recommendation, or in those with 30 to 300 mg/g, level B recommendation). So, what is the bottom line here? I am really not sure, pending other studies (and the best being an RCT). But this study does bring up the thinness of the prior assertions that those with ACE-I/ARB induced creatinine increases do better, and also reinforces the importance of checking creatinine (and lytes) after starting these meds, and stopping them if >30% increase. Otherwise, I am hesitant to change current practice.

Primary Care Corner with Geoffrey Modest MD: Diabetic Neuropathy Guidelines

14 Mar, 17 | by EBM

By Dr. Geoffrey Modest

The American Diabetes Association just came out with their position paper on diabetic neuropathy (see DOI: 10.2337/dc16-2042). I will limit my points to type 2 diabetes, though type 1 is covered in this paper

Summary of points:

  • Diabetic neuropathy is a diagnosis of exclusion: diabetic patients may well have non-diabetic causes of neuropathy that should be pursued.
  • 50% of diabetic neuropathies are asymptomatic. It is important to assess for them, for example, to decrease the likelihood of significant foot trauma, improve symptoms and quality of life, and decrease sequelae
  • Prevention of neuropathy:
    • Data are largely for distal symmetric polyneuropathy (DSPN) and for cardiovascular autonomic neuropathy (CAN).
    • Best evidence is for those with type I diabetes where it is important to optimize glucose control as early as possible: 78% relative risk reduction with enhanced diabetes control
    • Risk reduction seems to be less in glucose control with type 2 diabetes, perhaps in part reflecting the different pathophysiology and comorbidities: type 2 diabetes tends to be associated more with overweight, polypharmacy, older age; but also many patients with type 2 diabetes have been prediabetic or diabetic for many years prior to diagnosis. In fact 10-15% of newly diagnosed diabetes already have evidence of DSPN.
  • Distal symmetric polyneuropathy (DSPN)
    • Most common (75% of all neuropathies). Defined clinically by symptoms or signs. Electrophysiologic testing or neurology referral are rarely needed.
    • 50% of people have DSPN after 10 years of disease, and is associated with levels of glycemia, height (perhaps as a proxy of nerve length), smoking, blood pressure, weight, and lipids
    • Those with predominantly small-fiber neuropathy present with pain, burning or tingling feeling, sometimes with a shooting sensation. There may also be hyperalgesia. And this may be found in 10 to 30% of patients just with impaired glucose tolerance. Those with large fiber involvement have numbness, tingling without pain, and loss of protective sensation
    • DSPN is associated with foot ulceration/amputation risk (important to assess regularly and refer to podiatry early), Charcot neuro-arthropathy, unsteadiness and falls (should assess gait/balance, though minimal data to support), and quality of life (DSPN can really affect quality of life, and is associated with depression, anxiety, medication nonadherence)
    • Patient should be assessed annually, those with type I diabetes should be assessed starting 5 years after the diagnosis. Consider assessing those with glucose intolerance as well. Assessment should include temperature or pinprick sensation (small fiber function), vibration sense with a 128 Hz tuning fork, proprioception, ankle reflexes, and 10-g monofilament (large fiber function), and the 10 g monofilament also helps assess risk for ulceration and amputation
    • Important to rule out the myriad of other causes of neuropathy, including vitamin B12 (see blog which notes the overall increased incidence of B12 deficiency in diabetics) as well as infections (HIV, hepatitis B, Lyme), thyroid disease, paraproteinemia, alcohol or medications, heavy metal poisoning/work-related exposures, etc.
    • Symptom management: consider pregabalin or duloxetine as the initial​ approach. Though gabapentin may also be used (they do comment that pregabalin has a more linear, dose-proportional absorption and more rapid onset of action). They also note that tricylcic antidepressants (TCAs) are effective but beware of adverse effects. There seems to be some efficacy for the selective norepinephrine/serotonin reuptake inhibitor venlafaxine (dose 150-225 mg/d), mechanistically similar to duloxetine. Opioids should be avoided, given the risks of addiction, as either first- or second-line agents. However, tapentadolextended release, which has analgesic effects both through the m-receptor and noraderenaline reuptake inhibition, is FDA-approved, though there are systematic reviews/ meta-analyses which challenge its effectiveness. And some patients do seem to respond to adding low doses of these opioids in combo with the above agents).
  • Autonomic Neuropathies
    • Cardiovascular autonomic neuropathy (CAN)
      • May be present prior to a formal diagnosis of diabetes, ​is found in up to 60% of patients after 15 years, and is an independent risk factor for cardiovascular mortality (2+ fold increased risk, controlling for other risk factors), arrhythmia, silent ischemia, any major cardiovascular event, and myocardial dysfunction.
      • May be asymptomatic early and detected only by decreased heart rate variability with deep breathing, esp with EKG monitoring (see which discusses ways to measure CAN), but can include symptoms of light-headedness, weakness, palpitations, fainting/syncope. Exam may show resting tachycardia, or orthostatic hypotension without compensatory increase in pulse.
      • Symptom management:
        • Optimize glucose control (to prevent or delay CAN, though this is most evident in type 1 diabetes, but some benefit in studies with type 2), reinforcing lifestyle interventions both in prediabetics and diabetics prior to developing CAN. For those with orthostatic hypotension, can use both nonpharmacologic treatments (exercise, assuring adequate fluid intake/volume repletion) and meds (fludrocortisone, midodrine)
      • Gastrointestinal neuropathies can be anywhere in GI tract, from esophageal dysmotility to gastroparesis to lower GI symptomsof diarrhea, constipation, incontinence
        • Gastroparesis
          • ​May be present in 1% of type 2 diabetics, from a community-based study (higher in type 1 diabetes). Can affect glucose variability and unexplained hypoglycemia because of changes in food absorption. [my experience suggests that gastroparesis may well be more common than this]
          • ​Consider checking for symptoms in those with other microvascular complications  (“C” recommendation), exclude other causes (g. opiates, GLP-1 agonists (grade “C” recommendation”) [and, I would add, considering decreasing dose of metformin, esp since 500mg once a day or even 250mg seems to add substantial clinical benefit], and can do gastric emptying studies to document (grade “B” recommendation”) [I would also add that gastroparesis is usually evident by history, and that it is probably useful just to try the nonpharmacologic and even pharmacologic therapies empirically]
          • Treatment includes eating multiple small meals/d, decreasing dietary fat (which also causes gastroparesis), decreasing other drugs than those mentioned above which can make it worse (g. anticholinergics, pramlintide and ? DPP-4 inhibitors), and one can prescribe metoclopramide, the only FDA-approved agent, though it is associated with extrapyramidal symptoms, acute dystonic reactions, akathisia, tardive dyskinesia, acute dystonic reactions) and is recommended to use for only 5 days (which is problematic for such a chronic condition, and I have patients on this agent for much longer, with frequent assessments by me for the above adverse reactions)
        • Urogenital neuropathies includes bladder and sexual dysfunction, the latter including erectile dysfunction (3x more common in diabetics, may involve combo of autonomic neuropathy, vascular disease, and I would add psych issues, such as depression, stress, etc.) and/or retrograde ejaculation in men and sexual dysfunction in women (decreased sexual desire, increased pain with intercourse, decreased sexual arousal, inadequate lubrication).
          • Bladder dysfunction should be assessed in those with recurrent urinary tract infections, pyelonephritis, incontinence, palpable bladder
          • Recommendations: consider screening men with other forms of neuropathy for ED (grade C) and women with other forms of neuropathy for lower urinary tract symptoms and sexual dysfunction (grade E)
        • ​Sudomotor dysfunction includes dry skin, anhidrosis, or heat intolerance, and occasionally gustatory sweating (food consumption, and occasionally just the smell of food, leading to sweating of head and neck area)
        • Other neuropathies:
          • Mononeuropathies: especially of median, ulnar, radial and common peroneal nerves. cranial neuropathies are rare but include cranial nerves III, IV, VI, VII and usually resolve spontaneously over months
          • Diabetic radiculoplexus neuropathy (also called diabetic amyotrophy): unilateral thigh pain, weight loss, followed by motor weakness. self-limited (though I have a type 1 diabetic patient with this in one of his shoulders)


  • They do promote pregabalinand duloxetine as their primary go-to’s. I personally do not use them till much later in the pyramid of meds, partly because they are relatively new agents (and the older ones have stood the test of time), partly because there are mechanistically similar drugs available (gabapentin and venlafaxine), partly because these are non-generic and quite expensive, and partly (e., a lot) because they require prior approvals from many insurers.​
  • In the vast majority of cases, I have prescribed tricyclic antidepressants with great success. Although amitriptyline is the one used the most overall, it has the most adverse effects. I prescribe either desipramine or nortriptyline, which work as well and with many fewer adverse effects (desipramine has the fewest, but nortriptyline is helpful to take at night if the patient has trouble sleeping). The usually effective doses are desipramine 25-50mg (occasionally 75), or nortriptyline 10-50mg. Not sure why, but the 2012 ADA guidelines (see Diabetes Care 35:2451–2458, 2012) found that there was no significant difference between amitriptyline, duloxetine and pregabalin, though the current guidelines seems to have booted TCAs off the top tier (they are generic with long history of use and knowledge of long-term adverse effects, both plusses, which does raise the question to me of adverse drug-company induced bias….)
  • Gabapentin is used a lot for neuropathy, though the studies have been mixed (and the drug company has been taken to task for withholding large, unpublished negative studies).  And in my limited experience, is associated with many adverse effects and requires a very slow titration up.

So, a pretty useful compilation of diabetic neuropathies, along with reasonable approaches (though there are no medications which actually treat the neuropathies, only ameliorate the symptoms). My own approach is that anyone with any mono or polyneuropathy should be checked for diabetes (for example, they limit the cranial nerve neuropathies to the facial and extraocular movement nerves, though I have seen a couple of diabetic patients with anosmia.) Also, they do not comment that it is not so uncommon in diabetics to have radiculopathies typically on the trunk which simulating zoster clinically and respond to the above meds.

See for a meta-analysis of the meds used for DSPN, finding that SNRIs, capsaicin, tricyclics and anticonvulsants work for short-term pain control (seemed that SNRIs and TCAs were best). Opiates were last by a fair margin.

Primary Care Corner with Geoffrey Modest MD: Syncope Guidelines

13 Mar, 17 | by EBM

By Dr. Geoffrey Modest

Finally a guideline on syncope management (See​ ​, or 10.1016/j.jacc.2017.03.003), these from the Am Heart Assn/Am College of Cardiology. Many of us, I think, have been relying on suggestions from such sources as UpToDate, which are not rigorously evaluated and validated by at least a semi-independent association (the American Heart Association, though does have intrinsic potential biases for more cardiologic workup and investigation than a truly independent organization such as the National Institutes of Health in the US or National Institute for Health and Care Excellence NICE in the UK, does take the issue of upfront conflicts of interest more seriously than most other specialty groups, in this case with neither the chair nor vice-chair with any stated conflicts of interest, as well as 8 of the 15 committee members without stated conflicts).


  • Syncope is a common condition: estimates of prevalence as high as 41%, recurrent syncope in 13.5%. Mayo Clinic report of 19% prevalence in selected community residents over 45 years old (mean age of 62, more often in females, 22% vs 15%). Trimodal age distribution: first episode age 20, 60, or 80 yo. Different etiologies by age: older people more often associated with cardiac causes/meds/comorbidities: esp aortic stenosis, renal dysfunction, AV or left bundle-branch blocks, and meds associated with orthostatic hypotension. Also syncope in 12-15% of those with heart failure. younger people: more likely noncardiac
  • Initial evaluation:
    • History
      • Focus on prognosis, diagnosis, reversible or amelioratable factors, comorbidities, medication use, and patient/family needs
      • Prognostic factors depend on separating neural from cardiac causes (the latter being worse), assessing prodromal symptoms (e.g. the most common cause of syncope being vasovagal, a reflex syncope that has typical features of upright posture, exposure to emotional stress, pain; associated with diaphorsesis, warmth, nausea, pallor), family history, meds and comorbidities
    • PE
      • Especially orthostatic blood pressure and pulse changes, murmurs/gallops/rubs, basic neuro exam for focal abnormalities that would lead to a more detailed exam
    • ECG
      • Especially bradyarrhythmias with sinus pauses or high-grade conduction block; ventricular tachyarrhythmias. Or arrhythmogenic substrate (WPW, Brugada, long-QT syndrome, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy ARVC)
    • Then risk assessment
      • Stratify by cause of syncope/reversibility of underlying condition (vasovagal has better prognosis than heart failure with preserved ejection fraction, which is better than advanced cardiomyopathy, which is better than acute aortic dissection)
      • Data not really available on stratifying by high vs intermediate vs low-risk groups. There are some data on short and long-term risk factors (30 days after ER visit or 12 months later, showing the usual culprits
        • Short-term: male, older than 60 yo, no prodrome, prior palpitations, exertional syncope, history of structural heart disease, heart failure, cerebrovasc disease, fam history of sudden cardiac death, persistent bleeding, positive troponins
        • Long-term: many of same, but added diabetes, high CHADS-2 score, cancer, low GFR
        • And there are some studies suggesting “risk scores”, but they have different definitions of syncope, outcomes, etc., so not so practical, but typically include some of the above: age cutoff (45 or 65), abnormal ECG, prodrome, exertional, signs of volume depletion, etc.
      • Further testing: costly and often ineffective as a general rule and should be guided by the above initial exam. in particular, if the initial exam is not reasonably definitive:
        • Targeted blood testing:
          • CBC and lytes have low yield when done routinely, and should be guided by history/physical (moderate recommendation, nonrandomized trials)
          • Brain natriuretic peptide and troponins, uncertain evidence, though they do comment that BNP “is elevated in patients whose subsequent cause for syncope is determined to be cardiac”
        • If eval suggestive of cardiovascular abnormalities, consider further cardiac workup (not recommended as routine)
          • Transthoracic echo, if structural heart disease suspected, esp valvular disease, HCM, LV dysfunction (moderate recommendation, nonrandomized trials)
          • CT/MRI: MRI if suspect infiltrative disease such as sarcoid, or if suspect ARVC; CT esp if suspect pulmonary embolism (weak recommendation, nonrandomized trials)
          • Stress testing: esp if syncope during exertion (moderate recommendation​, limited design)
          • Cardiac monitoring: if suspected arrhythmia, choice dependent on likely timing of next syncope (Holter if likely in next 24-72 hours, others if longer). (moderate recommendation​, limited design). BUT they do push some for implantable cardiac monitors, which has the highest yield for those with no answer from noninvasive testing (moderate recommendation, with RCTs)
          • In-hospital monitoring: good to do telemetry
          • Electrophysiological studies: recommendations based on older studies. Can be useful in those with syncope from suspected arrhythmia, mostly useful in those with structural heart disease (yield of 50% vs 10%). (Moderate recommendation, nonrandomized trials)
          • Tilt-table testing: though they give this a moderate recommendation with RCTs to support, they do note that the utility is highest in patients with suspected recurrent vasovagal syncope, BUT there is overall only “moderate sensitivity, specificity, and reproducibility,” with “the presence of false-positives in controls”, and the diagnosis can typically be made through structured history taking as well and long-term cardiac monitoring.
        • If eval suggestive of neurogenic orthostatic hypotension, also not to be done routinely. Can be associated with multiple system atrophy, Parkinson’s, Lewy Body dementia, or peripheral autonomic dysfunction from diabetes, amyloidosis, immune-mediated neuropathies, hereditary sensory or autonomic neuropathies, inflammatory neuropathies. Less commonly with B12 deficiency, neurotoxins, porphyria, HIV or other infections
          • EEG during tilt-testing: patients can have both epileptic convulsions as well as pseudosyncope, which can be sorted out by doing tilt-testing with EEG monitoring (moderate recommendation​, limited design)
          • Head MRI and CT: no benefit in absence of focal neuro deficits or head injury
          • Carotid artery imaging: no benefit without focal neuro deficits
          • Plain EEG: no benefit unless symptoms suggestive of a seizure
        • Then treatment decision
          • There is a large section on guideline-based therapies for arrhythmias and structuralcardiac disorders, which i will not review here
          • Vasovagal syncope: patient education on diagnosis and triggers, lying down when symptoms begin (if sufficiently long prodrome), and in recurrent syncope:
            • Midodrine if no history of hypertension, heart failure or urinary retention. Studies suggest 43% reduction in symptoms. (moderate recommendation, RCTs)
            • Orthostatic training: e.g. repetitive tilt-table tests, or daily standing against a wall in the house for prolonged time periods (weak recommendation, RCTs)
            • Fludrocortisone, esp if inadequate response to fluids and salt (weak recommendation, nonrandomized trials)
            • Other approaches with weak recommendations include: b-blockers in those >42 years old (poor performance in younger patients), encouraging increased salt and fluid intake, decreasing meds that cause hypotension, SSRIs


  • Though CBC and lytes do have a low yield, I personally will continue to do them regularly, since they are cheap/easy and may unexpectedly lead to an important intervention by finding an unexpected anemia or hypokalemia, etc.
  • I would reinforce the importance of manually checking baseline and orthostatic blood pressure. See (See more studies on orthostatic hypotension, including the finding that initial hypotension on standing is in fact much more common than standard orthostatic hypotension after a couple minutes)
  • In terms of vasovagal syncope, which is so common: if the patient has baseline lowish blood pressure which decreases on standing, I do recommend fluids and salt (with limited effect though), and there was a recent article not included in the guidelines above which did show benefit of fludrocortisone (see, which I have used on several patients, sometimes with midodrine, to good effect.​
  • As noted, the guidelines do go through lots of details on the treatment of the cardiac conditions associated with syncope, and can be referenced in the paper itself.​

So, overall I think this is a very useful guideline, which appropriately minimizes routine testing beyond the history, physical and EKG (though, as mentioned, I do usually check a CBC and lytes even in otherwise asymptomatic patients).

Primary Care Corner with Geoffrey Modest MD: Probiotics in c diff

9 Mar, 17 | by EBM

By Dr. Geoffrey Modest

A recent systematic review with a meta-analysis looked at 19 published studies on the efficacy of probiotics in preventing C. difficile infections (CDI) in inpatients put on antibiotics, finding benefit if given close to the 1st dose of antibiotics (see 10.1053/j.gastro.2017.02.003).


  • 6261 subjects were involved in these 19 studies
  • The studies were done in the USA, UK, Turkey, Canada, Norway, China, Italy, and Germany. Several different probiotic formulations were used, most with Lactobacillus species. The daily dose of probiotics varied dramatically from 4 to 900 colony forming units, most started the probiotics within the 1st 2 days of beginning the antibiotics, duration of probiotics varied from 14 days to 14 days after completion of the antibiotic course, and the age varied from those greater than 18 up to age 80 (weighted average 68 years). Commonly excluded groups were those who were pregnant, immunocompromised, required intensive care, had pre-existing GI disorders. The hospitals’ baseline incidence of CDI range from 1.5 to 7.4%
  • Overall 4 probiotic species were studied: Lactobacillus, Saccharomyces, Bifidobacterium, and Streptococcus.


  • The overall incidence of CDI in the probiotic cohort was 1.6% (54/3277); in the control group it was 3.9% (115/2984), with p<0.001.
  • The pooled relative risk of CDI was decreased 58% with probiotics, RR 0.42 (0.30-.57)
  • The number needed to treat was 43 patients to prevent one case of CDI
  • Meta-regression analysis showed that there was a significant decline in probiotic efficacy for each day in delay of starting probiotics after the 1st dose of antibiotic, with an 18% decrease for every day the probiotics were delayed (p=0.04)
    • Probiotics given within the 1st 2 days of starting antibiotics had a 68% risk reduction of CDI, RR 0.32 (0.22-0.48) than starting later, where there was a 30% reduction, RR 0.70 (0.40-1.23)
  • No adverse events attributable to probiotics (in general adverse events tended to be less in the probiotic group)
  • Overall quality of the evidence was high. The magnitude of efficacy was the same when analysis was limited only to the high qualities trials


  • CDI incidence has increased dramatically in the past 10 years, more than doubling and costing $4.8 billion, with attendant morbidity and mortality (more than 29,000 deaths in 2011). The standard treatment has approximately 20% treatment failure and around half of the patients have recurrence, especially those who are older.
  • Certain probiotics seem to colonize the gut well, despite concurrent use of antibiotics: specifically Lactobacillus and Bifidobacterium.
  • To me it is difficult to assess with certainty their conclusions about timing, given the inconsistency of the approach to treatment (huge variability in types and doses of probiotics), as well as the fact that the vast majority of studies treated early, within the first 2 days or so. However, it does make intuitive sense that if we are to protect the gut with probiotics, that should be done early, especially before there is a large overgrowth of C. difficile
  • The best guess of the authors, though not definitive, was at the most efficacious probiotics were: Lactobacillus, and Lactobacillus in combination with either Streptococcus or both Streptococcus and Bifidobacterium
  • A review of the individual studies found that they all found benefit from the probiotics, though for some of the individual studies these did not reach statistical significance.
  • A cost-benefit analysis done in the UK suggested that using a Lactobacillus probiotic in hospitalized patients over 65 on antibiotics would lead to a cost savings of over $500 per patient. Another study in Canada also suggested cost savings.
  • So, though current guidelines, for example from the American College of Gastroenterology, do not recommend the use of probiotics for the primary prevention of CDI, this meta-analysis is pretty convincing that they work with no evident adverse effects. And, I would think, should be strongly considered in outpatients put on broad-spectrum antibiotics (e.g. Ciprofloxacin).

Prior blogs: is a blog on the efficacy of probiotics in irritable bowel syndrome has a slew of blogs on the microbiome has many blogs C. diff

and, has many on antimicrobial resistance

Primary Care Corner with Geoffrey Modest MD: Penicillin Allergy???

8 Mar, 17 | by EBM

By Dr. Geoffrey Modest

A large concern in treating patients with infections is the very high prevalence of “penicillin allergy”, leading to the use of broad-spectrum antibiotics as well as 2nd or 3rd line medications, which are usually more toxic, along with their attendant effects on antimicrobial resistance as well as secondary infections such as C. difficile­­­­. A recent article looked at 2 methodologies to determine the safety of using beta-lactams in these “penicillin allergic” patients (see 10.1016/j.jaci.2017.02.005).


  • Of 1000 medicine in-patients with a noted penicillin allergy in a single Boston hospital, 625 were admitted with a presumed infection: mean age 66, 60% female, 70% white/16% black, reported penicillin allergy was rash or hives in 60%/angioedema 15%, anaphylaxis 8%
  • Patients were assessed during 3 different time periods: 148 patients in a standard-of-care group (SOC), 278 in a penicillin skin testing group (ST), and 199 in a group using a computerized guideline-based management app (APP) to predict real allergy
  • ST group: excluded patients with penicillin intolerance (such as GI upset), patients taking medications that might interfere with skin testing (such as antihistamines), and also patients with multiple beta-lactam allergies, penicillin anaphylaxis in the last 5 years, or type II-IV hypersensitivity reactions to penicillin
  • APP group: the clinical support basically divided people into low risk (benign delayed maculopapular rash); medium-to high-risk (urticaria, angioedema, anaphylaxis, recent or severe delayed maculopapular rash; and those who should avoid a beta-lactam (history of Stevens-Johnson syndrome, toxic epidermal necrolysis or exfoliative dermatitis; DRESS syndrome or acute interstitial nephritis; or serum sickness-like reaction)
  • Primary outcome was the actual use of penicillin or cephalosporin during the hospitalization


  • ST group: 179 (64%) were felt to be skin test eligible, but only 43 (24%) actually receive skin testing and none of those were allergic, defined as negative skin test and tolerance of an oral amoxicillin 250 mg test dose. As compared to the SOC group,
    • Nonsignificant 30% increased odds of use of penicillin or cephalosporin overall, adjusted OR 1.3 (0.8-2.0), but a highly-significant 5.7-fold increased use in a per protocol analysis, adjusted OR 5.7 (2.6-12.5), p<0.001 [the per protocol analysis limited the analysis to those few who actually got the skin test]
    • Of the ST per protocol patients, there was increased odds of penicillin or cephalosporin prescriptions for discharge treatment, with OR 2.5 (1.04-6.2)
  • APP group: 292 unique website views (averaging 26 seconds only), 112 users (38%) completed clinical decision support. Patients in the low or moderate-to-high risk groups as above were given test doses of beta-lactam antibiotics with an initial dose of 1/10 of an IV dose or 1/4 of an oral dose. The 2nddose was administered 30 minutes later, comprising the remainder of the therapeutic dose. Nurses assessed patients every 30 minutes for the duration of the challenge. As compared to the SOC group,
    • Significant 80% increased odds of use of penicillin or cephalosporin, adjusted OR 1.8 (1.1-2.9), p=0.03


  • Penicillin allergy is remarkably common, up to 15% of all inpatients are recorded as having a penicillin allergy, and 5-25% of inpatients who are treated for infections. Three quarters of patients with an alleged penicillin allergy would otherwise use a beta-lactam antibiotic in other studies, but in the SOC group only half of them received one.
  • Not using a beta-lactam antibiotic when that would otherwise be indicated leads to more treatment failures, adverse events, and antibiotic resistant organisms such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus.
  • There were few patients who actually had skin testing, mostly because of difficulty in coordinating the testing for those felt to be eligible, which the authors note would have been different if they hired an on-site clinician for that purpose (some patients also refused skin testing).
  • Another concern about skin testing is that fewer than 15% of US hospitals have the appropriate reagent on formulary. The per protocol analysis of the ST arm may be open to bias (vs the intention-to-treat analysis looking at the overall group), however the low numbers of patients getting skin testing clearly biased the results to negative.
  • However, it is quite remarkable how much effect the pretty simple computerized guideline and decision support provided. It should, however, be pointed out that this was not a clean randomized-controlled trial, so there are potential inherent biases (including the possibility that there were different sensibilities and approaches to treating infections, perhaps related to the different time periods above, or proclivities of the ID departments, ward attendings, residents, etc.)
  • These results parallel those in a prior blog regarding skin testing. See found that of 146 patients with history suggestive of IgE-mediated penicillin allergy (but excluding those with history of anaphylaxis), only one patient had a positive skin test, and the remaining 145 did fine with oral penicillin. Of note, as opposed to the prior blog, those with Type I (IgE- mediated) hypersensitivity reactions were excluded from the above study.
  • Why is “penicillin allergy” so rampant?? as a singular anecdote, 25 years ago one of my children had otitis media in the middle of the night when he was less than a year old, and as a really tired parent I decided to watch him instead of getting antibiotic treatment (he wasn’t really very sick appearing, and at that point in Europe most otitis media was not being treated with antibiotics), he remained relatively stable for the next day or 2, then developed a maculopapular rash. If he had been given a beta-lactam antibiotic, he would have been labeled as penicillin allergic perhaps for the rest of his life. I do realize that there are negatives to treating family members, however my tiredness won out….
  • So, what does this all mean? The combination of the current and prior blog strongly suggest that true penicillin allergy is really quite unusual (the number quoted is <5% of those with listed penicillin allergy). And the ability to use beta-lactams for common outpatient (and inpatient) infections is really useful, especially as we are trying so hard to protect our microbiome and decrease resistance. [And, by the way, adverse reactions, need for hospitalization, costs…]. It would be really great to have a large study looking at the computer-assisted app to see the real incidence of bad allergic reactions to beta-lactams in each of the low and moderate-to-high risk groups, with an eye to using beta-lactams, perhaps initially in a monitored setting (depending on the actual incidence of severe reactions in these cohorts in subsequent studies).

Primary Care Corner with Geoffrey Modest MD: Fructose and NASH

7 Mar, 17 | by EBM

By Dr. Geoffrey Modest

A recent study found that fructose consumption and serum uric acid were independently associated with non-alcoholic steatohepatitis (NASH) in obese kids with non-alcoholic fatty liver disease (NAFLD), (see


  • 271 obese children (by BMI) with NAFLD were studied
  • NASH was diagnosed by biopsy, with a NAFLD score of at least 5, and by the fatty liver inhibition of progression (FLIP) algorithm (another algorithm for the diagnosis of NASH)
  • Fructose intake was determined by a food frequency questionnaire
  • Hyperuricemia was defined as a serum uric acid level >5.9 mg/dl


  • NASH occurred in 37.6% of the children
  • Mean age 11.5, 38% female, BMI 27, waist circumference 87cm, AST 48/ALT 62, uric acid 5.8, LDL 100/HDL 45, BP 112/68, TNF-a Of note, there were significant differences between those with NASH and those without, but only for: waist circumference, AST/ALT, total cholesterol (but not LDL, HDL alone), triglycerides, fructose consumption, and TNF- a
  • Hyperuricemia was found in 47% of the kids with NASH, vs 29.7% without NASH (p=0.003)
  • Adjusting for multiple measured confounders:
    • Uric acid level was associated with NASH, OR 2.49 (1.87-2.83), p=0.004
    • Fructose consumption was associated with NASH, OR 1.61 (1.25-2.85), p=0.001
    • These associations with NASH were independent of each other
    • Though, fructose consumption was still independently associated with hyperuricemia, OR 2.02 (1.66-2.78), p=0.01
    • These data on NASH were confirmed by using the FLIP algorithm


  • As noted in prior blogs, there seems to be a pretty consistent relationship between fructose consumption and uric acid levels, as was shown in this study. And there are data suggesting that dietary fructose can be part of the pathogenesis of NAFLD (induction of de novo lipogenesis, inflammation, insulin resistance). Studies in adults have found that hyperuricemia is associated with insulin resistance, type II diabetes and metabolic syndrome.
  • There are many dietary sources of fructose. The major ones for most people are table sugar (sucrose, a disaccharide of glucose and fructose) and high fructose corn syrup (in a surprising number of foods, as a very cheap and potent sweetener). Perhaps the “low-hanging fruit” here is sodas, consumed by very large numbers of people ( , finding that on average 26.3% of US adults consume at least one sugar-sweetened beverage daily, up to 41.4% in Mississippi, the highest of states, and that soda by itself was consumed by 24.5% of those 18-34 yo, and 47.4% in Mississippi). And a NHANES study (Welsh JA. JAMA 2010; 303(15): 1490) found that on average, 15.8% of calories came from added sugars, and that >25% of the patients got >25% of their total energy from added sugar. My experience is that it is easier to help people stop sodas and juices, substituting water, than other dietary interventions.
  • I am not sure why we focus so exclusively on BMI, since the data are pretty consistent over the decades that abdominal obesity is really the bad actor, more metabolically active and associated with inflammatory markers, diabetes/insulin resistance/metabolic syndrome and is independently associated with cardiovascular risk (BMI is not: its association is mediated by its association with other risk factors, such as blood pressure, lipids). Waist circumference is a much better, though not perfect, marker of visceral obesity than BMI. That being said, there is a pretty strong relationship (but not always) between BMI and waist circumference, especially in those with BMI >35. The most reasonable recommendations I have seen is to measure the waist circumference regularly, especially if the BMI is between 25-35. Although practically we should reinforce lifestyle changes in all patients with high BMI, independent of waist circumference, I think the patient should understand that for those with a high waist circumference, their cardiometabolic risk is even higher. See for the fuller argument

So, this study does add some important information: it confirms that both uric acid levels and fructose are associated with NASH in kids that they are associated with each other, but that they are also independent predictors (and there are several studies which show that decreasing fructose consumption, as in sodas, is associated with decreased uric acid levels. See blogs below). So, bottom line is that fructose consumption is bad and should be decreased, even if the uric acid level is just fine.

See for prior blog of fructose consumption in kids and cardiometabloic and weight improvements is one of 3 articles on NAFLD, highlighting an important role of fructose  more on the microbiome and hepatic changes with fructose

Primary Care Corner with Geoffrey Modest MD: Internet-based improvement in knee pain

6 Mar, 17 | by EBM

By Dr. Geoffrey Modest

There have been several articles recently dealing with nonpharmacologic management of chronic pain (see blogs at end). A recent Australian one looked at the effectiveness of an Internet-delivered training intervention, finding remarkable and apparently durable benefit in patients with chronic knee pain (see doi:10.7326/M16-1714).


  • 148 people over 50 years old with chronic knee pain: mean age 61, 56% female, 57% urban/43% rural, mean BMI 31, symptom duration 2-10 years in 50%/> 10 years in 27%, 57% employed/30% retired, 38% on acetaminophen combinations/23% NSAIDs/21% on topical anti-inflammatories/only one person on opiates, 50% anticipated moderate improvement by the intervention/17% anticipated large improvement, 60% used the Internet for social media daily
  • Those randomized to the intervention received 3 Internet delivered treatments
    • Educational material about exercise and physical activity, pain management, emotions, healthy eating, complementary therapies, and medications. Those in the control group also received this material
    • An interactive automated physiotherapist-prescribed home exercise in pain-coping skills training (PCST) called PainCOACH, and were asked to complete eight 35- to 45-minute modules, one per week, and practice pain-coping skills daily
    • Seven Skype sessions with a physiotherapist over 12 weeks, sessions lasted 30- 45 minutes(videoconferencing). The physiotherapist performed a brief assessment and prescribed a lower limb strengthening home exercise program to be performed 3 times a week. Exercise progression was monitored. Patients were provided with instructions, video demonstrations, and equipment such as resistive bands and ankle weights.
    • Pain was assessed using an 11 point numerical rating scale (NRS) as well as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 3 months. Primary outcomes were pain during walking using the NRS, and physical function using WOMAC.  Secondary outcomes were knee pain, quality of life, global change, arthritis self-efficacy/coping/pain catastrophizing.
    • The minimum clinically important difference (MCID) for the NRS pain score is 1.8 units, and for the WOMAC physical function subscale is 6 units.


  • The educational material was accessed by 78% of participants in the intervention group and 88% in the control group. Those in the intervention group attended a mean of 6.3 of 7 Skype physiotherapy sessions and completed 6.4 of 8 of the PainCOACH modules. 68% of the prescribed home exercise sessions and 64% of the PCST practice sessions were completed.
  • The intervention group had significantly more improvement in pain (mean difference 1.6 units) and physical function (mean difference 9.3 units) versus the control group at 3 months.
  • These improvements were sustained at 9 months, with a mean difference of 1.1 units for pain and 7.0 units for physical function.
  • In terms of secondary outcomes: there was significant difference between the groups in essentially all of the secondary outcomes
  • Adverse events from the intervention were minor, with increased knee pain being most common in both groups but more so in the active intervention group.


  • Given the problem with chronic pain meds, be they NSAIDs and their multitude of renal/ GI/cardiovascular complications, or the very significant concerns regarding using opiates for chronic pain, it is reassuring that non-pharmacologic and patient-empowering strategies can be effective.
  • And, as we all know, chronic knee pain is remarkably common: the anticipated projection is that 1/2 of US adults will develop knee osteoarthritis by age 85, but 50% of people with symptomatic knee OA are less than 65 yo.
  • It is notable that the functional differences in the intervention group were well more than what is considered minimally clinically important improvement, and this was almost reached for pain. It is also notable that these benefits were apparent at 9 months, 6 months after the intervention was over.
  • The study had the benefit of having both urban and rural patients, which is especially important for the latter group given their decreased access to face-to-face interventions.
  • One limitation of the study is that it seemed that this was a reasonably healthy cohort, given that most anticipated significant improvement by the intervention and most were only on mild analgesics [They did not define what “acetaminophen combinations” were, in either the article or supplement, but I assume these did not include opiate combinations, since they say only one person was on opiates], and participants could not have such severe knee pain that it limited their ability to exercise.
  • But, as an encouraging result, we in primary care do see lots of patients who have only mild-to-moderate pain, that meds work variably well (and have their toxicities), and it does seem that the results of this 3-month non-pharmacologic intervention is durable for at least the next 6 months.
  • And, it turns out that there currently are a slew of apps available: including Pain Coach (free, but not the same as above), some for back pain exercises, chronic pain relief, several for yoga/meditation, etc. I looked at a couple and they have some useful information, and may be a useful tool to help/empower some patients, though I did not find any as complete as in this study. Let me know if you have found any great ones.
  • So, this study reinforces and adds to the growing body of literature that suggest that a cornerstone of chronic pain therapy, this time for the knee, is non-pharmacologic (see other recent blogs below). One hopeful sign in the US is that in 2016, 87% of those older than 50 and 64% older than 65 do use the internet. I.e., if there are education-level appropriate, linguistically-diverse, culturally-sensitive materials available, they might really help people. Even those who are unable to read could benefit from these materials (perhaps with the help of a younger family member….)

For related articles, see: for a review of an article showing the benefits of tai chi, for an article on the benefits of mindfulness stress-reduction and cognitive behavioral therapy reports the CDC guidelines, stressing the use of adjuvant meds prior to starting opiates, though giving short shrift to non-pharmacologic therapies and, for a slew of other articles in the folder:​ ​list

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Latest from EBM