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Archive for August, 2016

Primary Care Corner with Geoffrey Modest MD: USPSTF Recommendations on Lipid Screening in Adolescents

30 Aug, 16 | by EBM

By Dr. Geoffrey Modest

The USPSTF just came out with their lipid screening recommendations for children and adolescents (see JAMA 2016; 316(6): 625), giving them an “I” rating (current evidence insufficient to recommend screening). For full supporting documents of the USPSTF recommendations, see JAMA 2016; 316(6): 645). Their points:

  • They consider both dyslipidemia from genetic heterozygous familial hypercholesterolemia, FH, (1 in 200-500 people in North America and Europe), where there are really high cholesterol levels (LDL>190 mg/dl, often 2-3x that of unaffected people) and evidence of increased cardiovascular risk (though not typically until age 30: 1 in 6 men and 1 in 10 women have ischemic heart disease by age 40, 25% of women and 50% of men by age 50), as well as multifactorial dyslipidemia, MD, (may have genetic component as well as environmental, esp obesity, where the LDL is lower but >130). Several studies show that there is moderately good tracking of childhood hyperlipidemia into adulthood. But they comment that there are no long-term data that adolescent hyperlipidemia from MD leads to clinical cardiac events in adults. Or that treatment of the MD changes those hard clinical outcomes [i.e., no RCTs have been done, and it is hard to imagine that they ever will be. Would require lots of kids randomized into different treatment wings, maintaining those treatments for decades, and then being able to follow them until they were 50+ years old when more clinical events happen]
  • NHANES data suggest that 7.8% of children 8-17 yo have total cholesterol >200 mg/dl, and 7.4% of those 12-19 have LDL >130 [i.e., pretty common]
  • For those with FH there are data that short-term (<2 year) treatment leads to decreased LDL and decreases the early surrogate marker of carotid intima-media thickness [which actually seems to be a good predictor of future atherosclerotic disease, especially in kids]. There are no compelling data on the long-term benefit of statins through a randomized-controlled trial, since in those with FH it is considered unethical not to use statins. However, a retrospective analysis looked at children with FH who were put on statins for a mean of 10 years starting at age of 14, and compared them to the adults with FH not on statins (they predated the use of statins); they assessed outcomes by age 30 , finding that the adults had many more cardiovascular events at a younger age than the kids (at the age of 30, the cumulative CVD survival was about 90%, vs 100% in the kids, even though 28% of the kids were smokers. See Braamskamp MJ. Am J Coll Cardiol 2016; 67(4): 455). It was notable in this study that the youngest parent with an MI was 20 years old and died at age 23.
  • Harms of screening. Also inadequate evidence, though mostly concerns about medicalization (anxiety about diagnosis, labeling, potentially harmful therapy). Statins are well tolerated with transient adverse effects in kids (increased liver enzymes). And though cardiovascular disease is still the number one killer, there is concern about overdiagnosis (i.e., some people treated may never develop cardiovascular disease)
  • Therapy: statins are typically used, given the adult data. But no consensus on when to start in kids with FH (some say age 8-10, some age 20). No data on long-term use in kids [though there are potential issues concerning taking statins with pregnancy, which they did not mention….]
  • They do acknowledge the rationale for screening kids:
    • Atherosclerosis is a known progressive process which starts in kids, with autopsy studies showing that [my data, not in their document]:
      • Everyone has fatty streaks in their coronaries by age 15-34
      • Advanced atherosclerotic lesions are found in 2% of men and 0% of women aged 15-19, but
      • Advanced atherosclerotic lesions are found in 20% of men and 8% of women aged 30-34
      • The Bogalusa Heart Study found that in adolescents dying mostly from trauma at median age of 19.6, there was a strong correlation between the levels of cardiovascular risk factors (BMI, lipids, and BP) and the degree of atherosclerosis
    • Lipid levels in kids are associated with the extent of adult atherosclerosis
    • Familial hypercholesterolemia, FH, is associated with premature ischemic cardiovascular disease
    • Short-term treatment of patients with FH leads to substantially lower LDL levels and some evidence of improvement in atherosclerosis (see below)
    • Abnormal lipid levels in adults is strongly associated with coronary heart disease events
    • Early identification and intervention in adults can prevent such events
    • And, I would add, prevention of more advanced lesions upfront not only decreases mortality (still a significant number of patients die with their first MI, and more are chronically disabled), but also helps long-term, since statins do not reverse atherosclerosis (just stabilizes it and makes the plaques less likely to rupture), but the residual recurrent cardiac risk in those who sustain an MI (secondary prevention) even with statins remains much higher than in those on statins who are just at elevated cardiovascular risk (i.e., primary prevention)
  • Although there are some potential benefits of identifying and treating those with FH, there are no good data for those with multifactorial dyslipidemia. An Ohio universal screen program (n=6500) looked at nonfasting total cholesterol screening, finding elevated levels >200 in 8.5%. This cohort then had fasting lipids, finding 5.8% had LDL>130. The USPSTF review found that those with the highest likely yield for hyperlipidemia are kids with obesity (12.3%), overweight (8.9%), children 9-11yo (7.2%) and those 16-19 yo (7.2%) [There is an unexplained typical 10-15% decrease in cholesterol levels during puberty].


  • When reading guidelines, it is important to remember that USPSTF overall is an independent governmental agency (so less influenced by drug companies, etc., than some of the professional society recommendations), is very focused on rigorous data (so will not make recommendations if the issue has not been studied well. They say the same thing about blood pressure screening in kids: no data that screening leads to decreased future cardiovascular events, so an “I” rating). In fact, for pretty much the same reasons (lack of clearcut studies), USPSTF does not recommend screening average risk males until age 35 and women till 45. All of these USPSTF recommendations are much less aggressive than the Am Acad of Pediatrics (screen at age 2-10 in all obese kids or if family history of dyslipidemia, etc.), NCEP (screen at age 20), Am College of Physicians, etc.
  • And, as a perspective, we all screen for phenylketonuria in newborns, with a prevalence of 1 in 10,000, but not for familial hypercholesterolemia, with 50x the prevalence (>500,000 born each year)… though I do realize the rigor of studies showing benefit is different)
  • It is pretty clear that targeted screening of those considered to be high risk is not successful: in a few pediatric epidemiologic studies, 1/2 the kids would be missed by relying on parental information/ family history of dyslipidemia or premature cardiovascular disease (e.g., see Ritchie SK. Pediatrics 2010; 126(2):260). And, pretty surprisingly, only about 1/4 of FH patients receive their appropriate diagnosis by middle age (see Neil HA. BMJ 2000; 3212:148). From other organizations (e.g. Am Acad of Pediatrics), screening has been recommended as universal. Universal screening is also much easier to integrate into care than targeted screening.
  • I do definitely think that discussing diet and exercise is really important at all age groups (though adolescents may be the most resistant of them….). But I also do think, from my clinical experience, that this discussion is more effective, at least in some people, if there are personal specific markers that suggest that the individual may be at higher risk. And knowing the lipid levels of adolescents may be very helpful in changing behavior. For example, I think that knowing a person smokes helps individualize their treatment recommendations and is likely to be more effective than just telling everyone they should not smoke (of course, finding out that someone smokes is a bit less invasive than doing a blood test).
  • So, to me, the rationale to do testing wins out. One may pick up the relatively unusual cases of familial hypercholesterolemia, and it seems pretty intuitive that they need meds as supported by our understanding of their physiology and supplemented by some limited data. But one will mostly pick up the pretty common multifactorial hyperlipidemia, and I personally would pursue these patients aggressively with diet and exercise, based on logic but without definitive studies to prove it. I.e., I would use the found high lipid levels to talk with the patient (motivational interviewing) about diet and exercise and suggest much more aggressive follow-up than on their non-dyslipidemic peers. I would not start meds in this group, but if they were able to improve their lifestyle, would track their lipids and give them feedback. And, it turns out that most adolescents do not have optimal lifestyles (see next study)


Not so surprisingly to those in clinical practice with kids/adolescents, there are very impressive data that adolescents have pretty bad lifestyles in terms of cardiovascular health. A recent AHA scientific statement (see DOI: 10.1161/CIR.0000000000000441) noted:

  • 91% had poor diets, 9% intermediate diets: specifically, overconsumption of sodium, sugar, solid fats, refinded carbohydrates; under consumption of fruits, vegetables, whole grains, dairy, dietary fiber
  • Only 10% of boys and 5% of girls aged 16-19 years old had the recommended 60 minutes of moderate-to-vigorous exercise per day (including muscle-strengthening and bone-loading activities at least 3 days/week. [By the way, my untested hypothesis is that kids can use their cellphones, which seem to be pretty ubiquitous even in poorer communities, to track their “numbers of steps” they take each day, in order both to quantify an important aspect of exercise and give direct feedback to them]
  • 27% of12-19 year olds are obese (BMI>95th percentile)
  • This document does promote “early identification and control of dyslipidemia, including heterozygous familial hypercholesterolemia, throughout youth and into adulthood can reduce clinical cardiovascular disease risk beginning in young adult life”. Also it is typical that total cholesterol decreases 10-15% around puberty, independent of diet (suggesting that we should check lipids when kids are 9-11 yo, before these pubertal changes). Non-HDL is more predictive than any single lipid marker. NHANES data suggest that 26-35% of adolescents have “intermediate or poor” levels of total cholesterol overall (worst in Mexican-Americans, best in non-Hispanic whites)
  • Blood pressure. Use sex/height-specific percentile charts. 9-12% have intermediate or poor BP status
  • Fasting glucose <100 mg/dL. Part of the AHA’s Strategic Impact Goal Through 2020 and Beyond, though they note that this metric is not currently used in pediatric practice, misses the boat in obese children since hyperinsulinemia is the first sign of metabolic derangement, and does not adhere to the Am Diabetes Assn definitions (which are the same as for adults). By the fasting blood glucose <100 metric, 20-38% of 12-19 year olds have intermediate or poor levels in the NHANES study.
  • Smoking (twice as common in adolescents exposed to second-hand smoke: reinforcing the need to get parents/caregivers not to smoke, at least in the house). NHANES data suggest that about 1/3 of 12-19 year olds have tried cigarettes within the prior 30 days.


So, this all reinforces the approach of lipid screening in adolescents, despite the lack of clinical outcome data. To me, the reasons to screen younger people are not just to pick up the extreme cases of familial hypercholesterolemia (which typically requires meds) but to use the results as a concrete means to educate adolescents/families about the need for lifestyle changes, with a focus on diet, exercise and obesity, for anyone with hyperlipidemia.




A Response to: USPSTF Does Not Back Lipid Screening in Adolecents

See the response below, sent around with Holly’s permission. Her study (hyperlink below) in 3 sets of adolescents/young adults aged 17-21 and their parents (including some with familial hypercholesterolemia, obesity, and generally healthy) posited different cholesterol screening scenarios, finding that in each of these 3 groups, both the adolescents and the parents saw worse cholesterol results as signifying poorer health, with several commenting about the need to change their lifestyles. This provides support for universal cholesterol screening and using the results to try to influence behavior.  Even in adolescents.



Awesome summary Geoff about an issue near and dear to my heart (pun intended!).

I am interested in whether knowing about heart health/heart disease risk changes teens behavior.  Probably not but certainly gives us something to anchor our counseling on as you note.  You might find this qualitative study we did asking teens about their hypothetical response to lipid screening interesting –

Thanks as always for such an awesome blog!!!

Holly Gooding, MD, MSc

Division of Adolescent/Young Adult Medicine, Boston Children’s Hospital

Division of General Internal Medicine, Brigham and Women’s Hospital

Harvard Medical School, Boston, MA


Primary Care Corner with Geoffrey Modest MD: PPI Harms and Benefits

29 Aug, 16 | by EBM

By Dr. Geoffrey Modest

There was a useful editorial detailing the indications for long-term proton-pump inhibitor use (see Laine L. Am J Gastroenterol 2016; 111:913). As many of you know from prior blogs, I have been very concerned that many patients are on long-term PPIs because: they work; when patients are doing better on them, we can move on to address other issues; changing them involves somewhat detailed/time-consuming discussions with patients (detracting from focusing on the other issues); changing them may not work, so we might be back to square-one; when patients see GI specialists, they are uniformly put on PPIs (at least in my experience); and, despite GI specialty recommendations to step-down therapy from PPIs to H2-blockers or antacids, studies show that this rarely happens. This review focuses on the indications for long-term PPIs, with little attention to the harms, but my guess is that most patients on long-term PPIs do not qualify for them even by these recommended indications: there are some studies finding that 70-80% of hospitalized patients put on PPIs do not have an appropriate indication. Details of the editorial:

  • The caveat: most of the studies were intervention studies with retrospective observational analysis (i.e., they were not set up as large studies comparing different therapies, and following the patients for many years to assess long-term effectiveness or adverse events)
  • GERD: for GERD symptoms, most patients do well with on-demand therapy.  In general, advice is given for long-term PPIs if erosive esophagitis, and there are studies suggesting that there is a higher risk of recurrent erosion when patients are put on placebo, H2-blockers, or intermittent PPIs. BUT, there are no data that show that recurrent esophageal erosions are harmful or that not using daily PPIs leads to Barrrett’s, and the risk of strictures is really low. Of note, many patients do use PPIs intermittently for symptoms, no matter what clinicians suggest, and most do fine, and there are observational data finding benefit of intermittent 2-4 week courses of daily therapy if twice-weekly heartburn recurs. But, I certainly do have patients who continue with their daily PPIs even if not necessary… the FDA guidelines suggest 4-8 weeks of PPIs for GERD. The editorialists in this review suggest that patients taking PPIs for GERD stop therapy 2 weeks after symptom resolution, and use H2-blockers or antacids as needed for infrequent symptoms, and if necessary, intermittent PPI courses of 2-4 weeks when symptoms recur >= 2x/week. [Given that it is often hard to do step-down therapy for GERD symptoms, I usually start with H2-blockers, step up to PPIs if necessary, and then try to step-down. In patients with mild symptoms, antacids often work just fine]
  • Barrett’s: basically, observational studies suggest PPIs may decrease neoplastic progression of Barrett’s, but the Am College of Gastroenterology and Am Gastroenterological Assn guidelines are more cautious: stating that long-term PPIs should be “considered” or discussed carefully with patients. And absolute risk of Barrett’s progression to adenocarcinoma is low (0.1%/yr). No FDA approval for this indication. The editorialists prefer using daily PPIs only if necessary to control GERD symptoms.
  • NSAIDs (my other nemesis, in terms of overuse and a plethora of adverse effects: GI, cardiovasc, renal, etc): PPIs (or misoprostol) do seem to decrease GI bleeding in those at high risk of bleeding (>65yo, high-dose NSAIDs, prior ulcers, or concurrent steroids/anti-thrombotics), and is supported in RCTs. These editorialists feel this is a clear indication for PPIs, though FDA approval is for durations up to 3-6 months. [My approach overall is to avoid long-term or high-dose NSAIDs, preferring topical treatments such as local injections, capsaicin, lidocaine gel, diclofenac gel, or oral acetaminophen. And I do have very few patients who take NSAIDs other than very intermittently]
  • Aspirin/anti-platelet agents: guidelines recommend PPIs in those at increased risk of bleeding (history of ulcers, concomitant anti-thrombotics, age>60 plus steroid therapy). Endoscopic ulcerations and recurrent ulcer bleeding have been documented in RCTs. No FDA recommendation [I do have lots of patients on low dose aspirin for cardiovascular and colorectal cancer prevention. There are some studies suggesting that low dose enteric-coated aspirin is erratically absorbed, and that the non-enteric coated aspirin has no greater incidence of gastric ulcers, so that is the one I use routinely. And with really minimal GI distress. So I do not prescribe any gastric protection routinely]
  • Dyspepsia: PPI therapy if <55yo with uninvestigated dyspepsia who are H pylori negative, or if H pylori prevalence is <10%. RCTs suggest PPIs are more effective than H2-blockers or antacids, with NNT=5. No clear guidelines on this. I did look up the Am Gastro Assn guidelines and there were no clear therapies suggested (see ). The editorialists suggest intermittent PPIs if effective to control symptoms [again, I have had considerable luck with H2-blockers or antacids, so I do try them first]


  • This editorial reviews the accepted recommendations for using PPIs, along with some of the available data. I think it is useful because so many of the patients we see in the community are on long-term PPIs for non-recommended indications.
  • And, there are substantial data in the literature on the potential adverse effects of PPIs, including the potential for gastric atrophy (a potentially premalignant lesion) especially in those with concurrent H Pylori infections, decreased mineral absorption (iron, calcium, magnesium), decreased vitamin B12, decreased bone mineral density and increased fractures, hypomagnesemia, increased enteric infections (C. difficile, C jejuni), increased pneumonia, and increased cardiovascular events. There have been more recent associations with chronic kidney disease and dementia (see blogs below).
  • And, in case you are interested, not so surprisinglyPPIs adversely affect the microbiome (after all, the acidity of the stomach probably does have some evolutionary protective effect on preventing enteric infections (and maybe much much more). see doi:10.1136/gutjnl-2015-310376 .
  • Of course, there are some patients who really do need PPIs for symptom relief/quality-of-life, but these can often be used intermittently.
  • So, I initially prescribe PPIs only in patients who have really severe presenting symptoms of GI distress (though I will often get a stool for H Pylori antigen prior to starting the PPIs). And in those already on PPIs I personally have had good success in switching people to H2-blockers, or even just intermittent antacids, though some do seem to need an occasional PPI, rarely daily long-term PPIs.

Prior blog on Barrett’s:

Relevant prior blogs on adverse effects of PPIs:

Primary Care Corner with Geoffrey Modest MD: Statin Use Lowers Cirrhosis Risk in Hep B

26 Aug, 16 | by EBM

By Dr. Geoffrey Modest

A new study looked at a large number of patients with chronic hepatitis B (CHB) who were on a statin, finding improved hep B outcomes (see Huang Y. Am J Gasstroenterol 2016). This blog follows a recent one I sent out: see , which reviewed a recent study showing statin benefit in those with hepatitis c, also comments on the benefit of statins in NAFLD, and mentions that the data on hep B is more mixed. Details of the current study from Taiwan, where 15-20% of the population has CHB, half of which is by perinatal transmission:

  • Population-based cohort study in Taiwan, with 298,761 patients with chronic hepatitis B (but without concomitant hep C, biliary cirrhosis, or alcoholic liver disease) and 6,543 on statins
  • Mean age 50, 53% male, 5 year follow-up on cirrhosis and same for decompensated cirrhosis, more comorbidities in the non-statin group (including more cardiovascular and pulmonary diseases)
  • Compared on 1:1 ratio with non-statin taking patients, with propensity scoring (to mathematically attempt to eliminate confounders). Also controlled for “inception point” of when statins started, to make sure that the comparisons between patients happened at the same approx time (to decrease likelihood that they were treated differently because of treatment changes over time)


  • Those on statins had:
    • 57% lower risk of developing cirrhosis [RR=0.43 (0.34-0.52, p<0.001)]: in 30,000 person-years of follow-up, 173 of those on statins developed cirrhosis (incidence rate 0.561/100 person-years), vs 400 not on statins (1.338/100 person-years)
    • 53% lower risk of developing decompensated cirrhosis [RR=0.47 (0.34-0.64, p<0.001)]: in 30,000 person-years of follow-up, 59 on those of statins developed decompensated cirrhosis (incidence rate 0.190/100 person-years), vs 126 not on statins (0.411/100 person-years)
    • Adjusted for age, gender, comorbidity index (which includes MI, CHF, PVD, rheumatic disease, chronic pulmonary disease, dementia, renal disease, cancers, HIV), hypertension, diabetes, hyperlipidemia, hepatocellullar carcinoma, obesity, NAFLD, aspirin use, diabetes medication, CHB treatment, non-statin lipid meds, and triglyceride meds: those on statins had
      • 49% lower risk  of developing cirrhosis [RR=0.51 (0.41-0.63, p<0.001)]
      • 47% lower risk of developing decompensated cirrhosis [RR=0.53 (0.43-0.66, p<0.001)]
    • In looking at the length of time taking statins, there was a dose response for the adjusted hazard ratios:
      • Cirrhosis
        • 15% lower if statin use 28-90 days (nonsignificant)
        • 53% lower if 91-365 days (p<0.001)
        • 80% lower if >365 days (p<0.001)
      • Decompensated cirrhosis
        • 7% lower if statin use 28-90 days (nonsignificant)
        • 39% lower if 91-365 days (borderline significant  at p=0.053)
        • 77% lower if >365 days (p=0.001)
      • The Kaplan-Meyer curves for both of the above showed widening curves over 12 years, with the major divergence in the first 6 years of follow-up
    • Also, overall mortality over 12 years of follow-up was lower in those on statins (13% vs 17%, with p<0.001)


  • The reason I bring up this article is that I still hear clinicians who feel that it is dangerous to prescribe statins in those with underlying chronic liver disease. As mentioned in the prior blog noted above, there are some reassuring data for NAFLD and Hep C. This huge trial, I think, pretty clearly adds Hep B to the mix. Although these are mostly retrospective/observational studies, and therefore not rock-solid RCTs, they pretty much show that statins at least are not harmful to an already-inflamed liver, and may well be beneficial. Of course, with observational studies, there always is the issue of unequal treatment in the different groups (were those on statins perceived to be less sick with their CHB and therefore getting more aggressive cardiovascular treatment??), but the use of propensity-matched scoring for lots of potential confounders and making sure that people were compared during the same time-frame (to minimize differences in overall treatment during differing time periods) do strengthen the conclusions.
  • There is reasonable biologic plausibility: studies have shown that simvastatin lowers portal pressure in patients with cirrhosis, and improves portal hypertension and sinusoidal endothelial dysfunction in rats (presumably by increasing nitric oxide and decreasing hepatic vascular resistance). And reduction in portal pressure correlates with protection from complications from cirrhosis. Also statins seem to inhibit fibrosis through several mechanisms (e.g. decreasing procollagen I and a-smooth muscle actin, connective tissue growth factor, etc.) and may directly decrease hepatitis B viral replication
  • The dose-response curve (the longer on statins, the more protective) also strengthens the likely conclusion that statins are protective against disease progression
  • And statins may be particularly useful in those with chronic inflammatory conditions such as hepatitis, since these patients are more predisposed to cardiovascular disease
  • So, it seems to me, that for the major international causes of chronic liver disease (hep B, hep C, NAFLD), we should not hold off using statins for fear of increasing the liver problems. That being said, I do check and follow liver function tests a bit more closely, though I have never found any problems in these patient groups.

Primary Care Corner with Geoffrey Modest MD: Neighborhood Deprivation and Diabetes Risk

24 Aug, 16 | by EBM

By Dr. Geoffrey Modest

There have been many studies finding that poverty or living in poorer neighborhoods is associated with increased morbidity or mortality. However, it is hard to dissociate the array of potential risk factors associated with poverty to validate a true association (for example, do those with more morbidities overall tend to move to poorer neighborhoods since their income tends to be lower, etc. (“social drift”) – so that the association is really with the burden of increased morbidities?). In this light, a quasi-experimental situation existed in Sweden finding that those refugees assigned to poorer neighborhoods had more diabetes (See White JS. Lancet Diabetes Endocrinol 2016; 4: 517).


  • 61,386 refugees aged 25-50, who arrived in Sweden from 1987-91, were assigned to one of 4833 different neighborhoods in a quasi-random fashion (90% of all refugees were randomly assigned. Those reuniting with family members or those with financial resources to support themselves were not randomly assigned). The goal of Sweden’s policy was to distribute the refugee workforce more evenly throughout the country. All refugees received Swedish language and training courses and social welfare support for about 18 months. There was no restriction on the refugees’ subsequent mobility within Sweden.
  • 85% were 25-34 yo, 74% married/cohabitating, 30% with 2 children, 45% from the Middle East/northern Africa or Iran/19% Eastern Europe/14% Latin America
  • The neighborhoods were classified as high deprivation, moderate deprivation, or low deprivation based on the different levels of poverty and unemployment, schooling, and social welfare participation.
  • 45% of refugees were assigned to a moderate-deprivation and 47% to high-deprivation neighborhoods, though only 8% to a low-deprivation one.
  • They excluded any with diagnoses of diabetes within the first 5 years after arrival in Sweden, as a means to filter out those with incipient diabetes.
  • Primary outcome was the diagnosis of type 2 diabetes between 2002-2011


  • Cumulative diabetes incidence was 5.8% in low-deprivation, 7.2% in moderate-deprivation, and 7.9% in high-deprivation neighborhoods, with background diabetes prevalence in Sweden being 4-6%
    • In adjusted models, being assigned to high- vs low-deprivation neighborhoods was associated with a 22% increased risk of diabetes [OR 1.22 (1.07-1.38), p=0.001], and moderate- vs low-deprivation neighborhoods having a 15% increased incidence.
    • Diabetes risk accumulated over time: 5 years of additional exposure to high-deprivation vs low-deprivation neighborhoods was associated with a 9% increased diabetes risk


  • So, this study does account for some of the expected different circumstances which could account for some of the preselection bias of differences in morbidity/mortality in people living in communities of differing deprivation levels (e.g., social drift).
  • The resulting diabetes incidence differences are therefore likely related to neighborhood-specific differences, such as that those living in poorer neighborhoods tend to eat cheaper and less healthy foods that predominate there, have fewer psychosocial supports, and have less access to safe exercise venues.
  • However, this was not a true randomized trial, especially because those refugees with higher incomes may have opted out of this process and there was a significantly lower % assigned to the low-deprivation areas. So, that does limit the generalizability of the conclusions somewhat (though the numbers of people involved and the differences they found in diabetes incidence were quite impressive)
  • There is an important social context here: though there were significant differences in the low vs high deprivation neighborhoods in Sweden, overall these differences are much more profound in the US, where both the basic differences between neighborhoods is more striking (higher income inequality) and the available social resources in the poorer communities are considerably less (Sweden is known for its strong public safety net).

For more blogs on the relationship between socio-economic status (SES) and morbidity/mortality, see: reviewed a different Swedish study finding that those with diabetes who had lower socio-economic status had higher rates of all-cause, cardiovascular, diabetes-related mortality.

And an array of blogs in the grouping which look at BMI, height and the attendant SES; life expectancy and income; income disparities and life expectancy; etc.

Primary Care Corner with Geoffrey Modest MD: Insulin vs GLP-1 agonists for patients failing oral med treatment

18 Aug, 16 | by EBM

By Dr. Geoffrey Modest

As many of you know based on my prior blogs, I have largely switched from using insulin to prescribing a GLP-1 agonist as my second line treatment for diabetes, after metformin (though I still use the short-acting sulfonylurea glipizide after metformin in patients who decline injection therapy, then try to use a GLP-1 agonist as the next step). A recent blog (see ) looked at using liraglutide vs placebo in older diabetic patients at high risk of cardiovascular events, finding that the GLP-1 agonist lowered A1c by 0.4 percentage points (the other meds were increased in the placebo wing to narrow the A1c gap), was associated with more weight loss, and had a 15% mortality benefit as well as a 22% decrease in major cardiovascular events, with benefit evident within 12-18 months. A recent retrospective review of the UK Health Improvement Network (10.5 million patients in 532 general practices) found benefit of adding a GLP-1 agonists over insulin (see doi:10.1136/heartjnl-2015-309164).


  • 2003 patients were treated with either insulin or a GLP-1 agonist after failure of metformin/sulfonylurea dual-therapy (419 patients on MET+SU+insulin, and 1584 on MET+SU+GLP-1 agonist), with 5 years of follow-up
  • Mean age 53, 50% male, no difference in socio-economic status by Townsend deprivation index, but significant differences comparing insulin vs GLP1 groups in mean A1c of 9.9 vs 9.4, BMI 30 vs 40, BP 133/80 vs 136/83, aspirin in 14 vs 20%, BP meds in 37 vs 51%


  • Overall rates of Major Adverse Cardiovascular Events (MACE, including mortality, and nonfatal MI or stroke), using propensity-scoring to mathematically adjust for baseline differences in the groups:
    • MET+SU+insulin: 231, for rate of 44.5/1000 person-years
    • MET+SU+GLP-1 agonist: 11, for rate of 7.7/1000 person-years
  • So, a 73% reduction in the GLP-1 group [HR 0.27 (0.14-0.53), p<0.0001)]
    • No difference in A1c levels
    • Insulin was associated with a significant increase in weight (+1.78 kg vs -3.93 kg)
    • There was a similar MACE outcome in those with BMI>30: 84 vs 11 MACE with a 69% MACE reduction; and in those with BMI>35: 30 vs 7 events, with a similar 69% MACE reduction.
    • In subgroup analysis of the individual MACE events, only mortality was statistically significantly different, with a 79% decrease in the GLP-1 agonist group.


  • This was a retrospective observational study, so has the limitations of all such studies: unable to prove causation because of differences in the groups and other potential confounders. As is evident above, the group on the GLP-1 agonists was significantly more obese, had a lower A1C but also a higher blood pressure and were more likely to be on aspirin or antihypertensive therapy. However, the overall results, with attempts to mathematically control for these differences, are in agreement with two large recent meta-analyses finding cardiovascular benefit of GLP-1 agonists, though these benefits are not consistent in all studies or meta-analyses over time.
  • I have been concerned for a while about potential adverse effects of insulin, at least at a cellular level, given its potential role as a growth factor (stimulating smooth muscle migration, proliferation and inflammation) as well as its procoagulant effects (stimulating circulating tissue factor-procoagulant activity), and it may even promote HMG CoA reductase activity (the one blocked by statins). And there are some observational/epidemiological studies suggesting increased cardiovascular events with increasing insulin levels even in nondiabetics. GLP-1 agonists, in particular, seem to me to be particularly physiologic, restoring a normal enzyme which is depressed in diabetic patients (through the “incretin effect”), which leads to food-stimulated insulin secretion without significant hypoglycemia and pretty consistently with weight loss. I consider this data as suggestive that higher insulin levels potentially could increase cardiovascular risk, do not conclusively show that relationship, but this study, as well as the liraglutide study mentioned above, do support the conclusion that GLP-1 agonists are likely more cardioprotective.
  • There has been concern about GLP1-associated pancreatitis and pancreatic cancer, though more recent large studies do not confirm these events.
  • This study reflects a large number of patients in different actual primary care practices throughout the UK.
  • So, my sense is that there are increasing data that the efficacy of GLP-1 agonists to decrease A1c levels is pretty similar to insulin, there are not the downsides of hypoglycemia or weight gain found with insulin, and there are several studies finding important cardiovascular and mortality benefits, consistent with some of the known physiologic effects of GLP-1 agonists vs insulin. And, my personal experience is that these meds are well-tolerated overall (major adverse effect being GI, or some soreness/lumps at site especially of some long-acting exenatide injections) and really do improve glucose control.

Primary Care Corner with Geoffrey Modest MD: Weight Loss and Resting Metabolic Rate

17 Aug, 16 | by EBM

By Dr. Geoffrey Modest

One of the hardest tasks for us and our patients is maintaining weight loss in those who are overweight and obese. A recent NIH study looked at this issue, finding that people who had lost a lot of weight had long-term “metabolic adaptation” leading to a significant lowering of resting metabolic rate (RMR) and much less overall energy expenditure (see doi:10.1002/oby.21538 ). This study looked at 14 of the 16 “Biggest Loser” competitors from this televised weight-loss competition.


  • Baseline: median age 35, 6 men/8 women, weight 149 kg, BMI 49.5
  • At the end of the competition (30 weeks), through an aggressive program of diet and exercise, the mean weight loss was 58.3 kg, BMI deceased to 30, and the RMR decreased 610 kcal/day below baseline (this decrease in RMR was expected, as per a multitude of prior studies).
  • The following hormone levels improved dramatically after weight loss (at 30 weeks): insulin, C-peptide, triglycerides, HDL, adiponectin, T3, leptin, and the calculated HOMA-IR (which correlates with insulin resistance)
  • This weight loss was primarily from fat mass but with relative preservation of fat-free mass [likely from the intensive exercise training]
  • After 6 years:
    • Participants regained a mean of 41.0 kg (though wide variation: 1 person did not regain weight, though 5 were within 1% of their baseline weight or above), 80% of the weight gain was from fat However, 6 years later the RMR remained 704 kcal/d below baseline (actually non-significantly worse than the RMR after the remarkable initial weight loss), and metabolic adaptation was down 499 kcal/d [I believe this is basically RMR corrected for fat-free mass, but this was never clearly stated in the study]
  • The metabolic adaptation at the end of the competition (30 weeks) correlated with the amount of weight loss, did not correlate with the ultimate weight regained, but it did improve some in those who regained the most weight (and metabolic adaptationdid not improve at all in those who maintained the weight loss, with a dose-response curve)


  • Background: from the initial studies, the physiologic phenomenon of metabolic adaptation (also called “adaptive thermogenesis”, or AT) reflects the evolutionary imperative that the body readjusts to maximize efficiency in times of starvation by lowering energy expenditure. AT has been found to be independent of changes in fat-free mass and takes weeks to develop; in earlier studies it seemed to be independent of the magnitude of weight loss after reaching the peak of a 10% weight loss threshold (see Muller MJ. Obesity 2013; 21: 218). Adaptive thermogenesis is associated with a variety of changes related to decreases in resting and total energy expenditure, including decreased sympathetic nervous system activity, T3, and leptin. There are some early suggestions from animal studies that giving exogenous leptin restores at least some of the decreased RMR
  • Many studies have shown that in the setting of starvation, the body in fact lowers its metabolism to conserve energy and weight. One perhaps interesting issue is the role of genetics (I have seen nothing to answer these questions in searching around on this). For example, is there a difference in the metabolic adaptation/changes in RMR in those who are overweight but coming from families with lots of obesity vs those where there is not an apparent genetic burden for obesity? Overall, obese individuals are more likely to have lower RMR from several studies, but are those who are lean at baseline but have a lower RMR more likely to develop obesity than those with a higher RMR? Not so clear. At least some studies suggest that eating leads to thermogenesis (i.e., it might be that even in those with low metabolic rates, eating increases their metabolic rates enough that they do not become obese; and, therefore, perhaps there is no causal effect of low metabolic rate and eventual obesity). In fact some small studies noting lower RMR in obese women found that the RMR was actually higher in obese women if one corrected for fat-free body mass (see Hoffmans M. Int J Obesity 1979;3(2):111). A bit of a bag of worms….
  • Interestingly, bariatric surgery does not create the same issue of metabolic adaptation as does starvation: with surgery there seems to be an effective reset of the body’s weight set-point within a year of bariatric surgery, for unknown reasons (see Hao Z. Obesity (Silver Spring) 2016; 24: 654)
  • There were a couple of interesting studies (both from the same group) suggesting that weight loss by a low glycemic diet causes less decrease in RMR:
    • One found thatresting energy expenditure in overweight/obese young adults decreased much less with a low glycemic index diet (96 kcal/d, or 5.9%) vs a low fat diet (176 kcal/d, or 10.6%) [Those on low GI diet also had less hunger, improved insulin resistance, triglycerides, CRP and blood pressure]. See Pereira MA. JAMA 2004; 292: 2482
    • This was confirmed in another study (see EbbelingJAMA 2012; 307: 2627), finding that isocaloric feeding led to decreases in resting energy expenditure of 205 kcal/d in a low fat diet, 166 kcal/d in a low-glycemic index diet and 138 kcal/d in a very low-carbohydrate diet. Total energy expenditure decreased 423, 297 and 97 kcal/d respectively.
  • But, the bottom line from this study: at least in the case of those with severe morbid obesity (median BMI of 50), losing weight had the anticipated decrease in energy expenditure, but even 6 years later, this lowering of RMR through metabolic adaptation did not revert to their baseline. What does that mean? For one thing, it reinforces what many patients and clinicians know: losing weight is really hard to do, and if weight is lost, it is really really hard to keep it off in the long-term. Which doesn’t mean that we all should give up. Just that this understanding is really important, and we all (including patients) should really try to avoid the blame-game (some variant of “if you really want to lose weight, you can” morphing to “if you don’t lose weight, it reflects your lack of will-power, tenacity, ability to get things accomplished….”). and, my suggestion is that, given the remarkable difficulty in losing weight, those so motivated need lots of hand-holding: seeing them frequently to discuss how they are doing and collectively deciding on adjustments, encouraging lots of exercise to help maintain the weight loss, and overall collectively setting often small goals and slowly ramping them up as the patient is capable of doing (understanding that there will be bumps along the way). My guess is that this approach works much better than: “great, you understand what you need to do to lose weight, come back in 3-6 months”.

Primary Care Corner with Geoffrey Modest MD: Zika and Neurologic Problems in Brazil

1 Aug, 16 | by EBM

By Dr. Geoffrey Modest

STAT (see has frequent updates on Zika, noting the following:

  • Puerto Rico reported the biggest weekly rise in Zika cases yet, with 1,336 new cases for the week ending June 30, including 533 pregnant women diagnosed with the virus
  • Two patients who were infected with the Zika virus have developed severe thrombocytopenia
  • Brazilian researchers have observed a sharp increase in cases of Guillain-Barré syndrome

For this last point, there was a recent release of an article in Neurology (see doi:10.1212/WNL.0000000000003024) from Brazilian neurologists who started a study group in Rio to further understand the Zika-related neurologic disorders (Guillain-Barré syndrome –GBS, meningoencephalitis, transverse myelitis), finding that in the period Dec 5, 2015 to <arch 18, 2016, there were:

  • 20 confirmed cases of GBS (there had previously been 15 case in 24 months prior to Zika: so average GBS cases increased from 0.67/month to 5.4/month)
  • 17 were associated with a viral prodrome consistent with Zika (pruritic rash, fever, arthralgias).
  • But there is an issue with associating all cases with Zika, since Zika is so prevalent there and 80% of cases are asymptomatic, making the causal link difficult especially in those without a clear prodrome
  • They have also seen Zika-related AMAN (acute motor axonal neuropathy), acute motor sensory polyneuropathy, acute inflammatory demyelinating polyradiculoneuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, and Miller Fisher variant along with encephalitis, transverse myelitis and acute disseminated encephalomyelitis following a Zika prodrome.
  • The neurological associations are not limited to Brazil’s outbreak/variant: there were cases of Zika-related GBS and AMAN in French Polynesia, which is genetically distinct from Brazil.
  • Also a couple of recent new transmissions: from an infected woman to her male sexual partner, and a possible case of a domestic worker getting infected.

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