You don't need to be signed in to read BMJ Blogs, but you can register here to receive updates about other BMJ products and services via our site.


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: 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: vitamin B12 and diabetic autonomic neuropathy

23 Feb, 17 | by EBM

By Dr. Geoffrey Modest

A recent Danish study found that vitamin B12 deficiency was associated with diabetic cardiovascular autonomic neuropathy, CAN (see Hansen CS. J Diabetes Complic. 2017; 31(1); 202)


  • 469 type II diabetic patients were screened for CAN by several measures, as well as for peripheral neuropathy.
  • Mean age 59, 60% male, diabetes duration 10 years, 5% excessive alcohol consumption, 12% smokers, BMI 32, blood pressure 132/82, 6% on vitamin B12 supplementation (though 16% in those in the highest B12 quartile), 80% on lipid-lowering drugs, 75% on metformin, 4% on PPIs alone and 10% on the combination with metformin, 40% on insulin
  • CAN was measured after a 5-minute supine resting period:
    • Heart rate variability (HRV)
    • 3 tests assessing cardiovascular autonomic reflexes:
      • Lying-to-standing test
      • Deep breathing test (E/I ratio), a measure of heart rate variation during deep breathing [which is affected by an abnormality in the parasympathetic nervous system]
      • Valsalva
    • Peripheral neuropathy was measured electronically by vibration sensation


  • B12 level varied from the lowest quartile mean of 190 to the highest quartile of 486 pmol/l
  • Serum levels of B12 were significantly lower in those on metformin or proton pump inhibitors, p <0.001.
  • Higher level of B12 were significantly associated with a lower odds ratio of CAN, p=0.04
  • A 25 pmol/l higher level of vitamin B12, adjusted for age, sex, diabetes duration, and alcohol consumption, was associated with:
    • 6% lower level of CAN diagnosis, odds ratio 0.94 (0.88-1.00, p= 0.034)
    • An increase of E/I ratio of 0.21% (p= 0.038)
    • A decrease in resting heart rate of 0.25 bpm (p= 0 .025)
  • No association between B12 levels and decreased vibration/peripheral neuropathy


  • Cardiovascular autonomic neuropathy is very common in patients with type II diabetes, ranging in prevalence from 20 to 65% and increasing with length of diabetes. CAN is also an independent predictor of cardiovascular mortality and morbidity. But CAN may well be overlooked clinically until a patient is symptomatic, typically late in its course.
  • Vitamin B12 deficiency is also quite common in diabetics, with estimates from 2-33%, potentially mediated in part by the use of metformin through a not-so-well understood mechanism. This relationship is both metformin dose-dependent and treatment duration dependent, and may be measurable in as little as 4 months after the onset of use. In addition, the frequent use of proton pump inhibitors may decrease vitamin B 12 levels. Another potential and common mechanism for B12 deficiency in older patients is the age-associated decrease in several digestive enzymes, leading to the inability to liberate B12 from foods thereby decreasing its absorption (studies have found b12 deficiency in 10-25% of elderly, typically asymptomatic).
  • This was an observational study, therefore it is difficult to attribute causation. In addition, there is no compelling evidence that correcting B12 deficiency decreases the likelihood of CAN [one Indian population-based study of healthy elderly showed that B12 supplementation in those deficient led to normalization of decreased heart rate variability (see Sucharita S. Autonoom Neurosci 2012; 168 (1-2); 66)].
  • Also, the effect of B12 deficiency on CAN in the study was not particularly large. Part of this is that there were very few patients (0.6% of their population) who they defined as having vitamin B12 deficiency (that being below 125 pmol/l in this study, though many consider the cutpoint to be <148 pmol/l, which translates to <200 pg/ml), so the lowest quartile had lots of patients who were probably not actually B12 deficient. And the likely reason for the low B12 deficiency rates was that the standard clinical practice in that area was to check B12 levels in patients every other year. They did not test for methylmalonic acid or homocysteine, which might have been relevant in those with borderline B12 deficiency (35% had B12 levels between 125 and 250 pmol/l, though others consider borderline to be between 148 and 221 pmol/l​, or 200-300 pg/ml). Also, the fact that the effect was particularly evident for the E/I ratio with deep breathing suggests that a parasympathetic abnormality may predominate, and parasympathetic denervation is in fact typically the first abnormality in CAN, leading to increased sympathetic tone.
  • Of note, several different studies, but not all, show that those with peripheral neuropathy associated with B12 deficiency do improve with B12 supplementation, though the degree of improvement tracks inversely with both the extent and duration of disease.

So, my take on this is that given the clear importance of vitamin B12 for several aspects of health (neurologic, psychiatric, hematologic), and that some of these manifestations may be pretty subtle/very hard to detect early on, I personally think it makes sense to check vitamin B12 levels in the elderly as well as those on metformin and PPIs. And now, perhaps more so in diabetics overall, perhaps when they reach the ripe old age of 50 or so.

Primary Care Corner with Geoffrey Modest MD: Metformin in those with CKD, CHF, CLD

6 Feb, 17 | by EBM

By Dr. Geoffrey Modest

A systematic review from the VA synthesized data on use of metformin in patients with chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease (CLD) with hepatic impairment (see doi:10.7326/M16-1901). The goal was to assess all-cause mortality, major adverse cardiac events (MACEs), and other outcomes in patients with these underlying diseases (patients with these diseases having been the ones in whom the FDA initially had warned against using metformin).


  • 17 observational studies that included patients with CKD, CHF, or CLD with hepatic impairment were analyzed. These studies compared patients on diabetes regimens that included Metformin vs those that did not.


  • CKD
    • 6 studies were included, with sample sizes ranging from 1246 to 11,481 patients, median age ranging from 65 to 76. Only one study reported median daily metformin dose (1100 to 1900 mg in the different subgroups)
    • All-cause mortality
      • 22% lower for patients on metformin, HR 0.78 (0.63-0.96)
      • 2 studies reported CKD severity subcategories:
        • eGFR of 30 to <45 had neither benefit nor harm
        • eGFR of 30 to 60 had clear benefit of around 38%
        • eGFR <30 (one study) had neither benefit nor harm
      • MACEs:
        • 2 studies were evaluated, finding no difference in outcomes with metformin in the subgroups of patients with eGFR <45
        • And much, much more hypoglycemia in those on non-metformin-based regimens (specifically, glyburide or insulin)
      • CHF
        • 11 observational studies were included, with sample sizes from 346 to 13,930 patients, median age 55 to 77 years old. No studies included median metformin dose
        • All-cause mortality:
          • 22% lower for patients on metformin, HR 0.78 (0. 71-0.87)
          • 2 studies reported CHF severity subcategories:
            • One study looked at LVEF, finding that both an LVEF of 30-39% and LVEF<30% had a nonsignificant 13% decreased mortality; another study looked at patients with LVEF < 40%, finding a nonsignificant 21% decrease
          • MACEs:
            • The relative chance of readmission for CHF during follow-up was 13% lower for patients on metformin: HR 0.87 (0.78-0.97)
            • The relative risk for cardiovascular mortality was 23% lower in those on metformin (their figure shows that the three studies that looked at this found statistically significant improvement with metformin, but their overall summary said it was nonsignificant?????)
          • CLD
            • 3 observational studies included, with sample sizes ranging from 82 to 250 patients, median age 60-61. No studies reported median metformin dose.
            • All cause mortality:
              • The one study with low risk of bias (n=250) found significantly longer survival: HR 0.43 (0.24-0.78), regardless of cirrhosis severity. Post hoc analysis found a positive association between metformin and survival only in those with nonalcoholic steatohepatitis, though the number of patients in the other subgroups was small.
            • The other studies in those with moderate-to-high risk of bias showed a trend to lower all-cause mortality with metformin


  • Metformin is accepted as the first line drug for diabetes in the US and other countries that I know of. It is such a good and appropriate drug, given both its positive effects on diabetes (including its being weight-neutral or leading to weight loss) as well as data suggesting decreased cardiovascular disease and all-cause mortality. As a result, many clinicians have been using it despite FDA precautions/contraindications, with estimates that 20-30% of patients have been prescribed metformin who have had these precautions/contraindications. The FDA itself has been progressively relaxing these restrictions. In 2006 they removed CHF as a contraindication (though acute or unstable CHF remains a precaution). In addition in 2016, the FDA changed the warning for CKD to be based on eGFR instead of creatinine, making approximately 1 million additional patients with moderate CKD eligible to receive metformin. See blogs noted below for other studies promoting the use of metformin.
  • Most of the above conclusions were based on studies which had low strength-of-evidence, moderate risk-of-bias. However there was consistency in their finding that metformin therapy was associated with reduced all-cause mortality among patients with moderate CKD, CHF, or CLD; fewer CHF admissions among those with moderate CKD or CHF; and a much lower hypoglycemia rate among those with moderate CKD
  • There are other concerns about a meta-analysis such as above, including the fact that they don’t have data on doses of metformin for most studies, what other medications were being used in addition to metformin (the studies did not have rigorous details about which patients were on which other hypoglycemic medications), whether there was “confounding by indication” (where people might have been selected to be on or off metformin based on unknown individual clinical considerations), or even more than baseline data on metformin use in most studies (i.e. patients may have started on metformin but somewhere during the study had stopped it; or alternatively patients may have started off metformin but then put on it during the course of the study)

But, bottom line, these studies reinforce not just the safety of metformin in what had previously been considered concerning underlying comorbidities, but strongly suggest a significant benefit of metformin-based regimens. I.e., there really is an imperative to use metformin as the first-line therapy. We know through our clinical practice that metformin’s major adverse reactions are GI. This is clearly less the case in those on lower doses or if metformin is taken with meals. The somewhat skimpy data suggest that much of the benefit of metformin is conferred by much less than full doses (one oft-repeated quote is that about 80% of the benefit of metformin is by giving 1000mg vs 2000mg). My personal experience is that many people get much better glucose control on just 500mg once a day (which is my starting dose, though I leave it there if there is good control, as happens pretty frequently), and I even have a person on 250mg (1/2 tablet) because of GI intolerance, who seems to get benefit…

Relevant past blogs: is a systematic review of studies in patients with chronic kidney disease, finding for example no cases (as in, zero) of lactic acidosis in 70,490 patient-years on metformin​  which gives the updated FDA changes for metformin prescribing in those with CKD, with reference to a study of 813 patients with creatinine >6 who did NOT have increased mortality on low dose metformin (<= 500 mg/d), as well as the study finding that metfomrin induces changes in the microbiome, which leads to decreased insulin resistance.

Primary Care Corner with Geoffrey Modest MD: Microbiome 2

24 Jan, 17 | by EBM

By Dr. Geoffrey Modest

This is the second of two blogs on the microbiome, inspired by a recent review that highlighted several other health-related data besides the non-caloric artificial sweeteners (see Lynch SV. N Engl J Med 2016;375:2369).


  • ​The microbiome is huge, with 9.9 million microbial genes represented, as found from studying 1200 people in the US, China, and Europe. And it has >1000 species of microbes
  • Although the microbiome was previously felt to develop after birth, bacteria are found in the placentas of healthy mothers, in the amniotic fluid of preterm infants, and in meconium. And, the mode of infant delivery does influence postnatal microbial exposure: intravaginal delivery does seem to confer an infant microbiome taxonomically similar to the maternal gut and vaginally microbiota. Also the infant microbiome does become more similar to the adult one with the cessation of breast-feeding, and over the years bacterial diversity and functional capacity expand. The microbiome becomes less diverse in elderly, which could reflect coexisting conditions and age-related declines in immunocompetence.
  • Things that affect the microbiome include sex, age, diet, exposure to antimicrobial agents, changes in stool consistency, PPIs and other meds, travel, malnutrition, exercise (the effect of exercise on the microbiome is pretty clear in mice, not so clear in humans, since it is hard to sort out the effect of exercise vs different diets in those who exercise more). Also, host genetic features, host immune response, xenobiotics (including antibiotics), other drugs, infections, diurnal rhythms (see below), and environmental microbial exposures.
  • Clostridium difficile infections
    • This is probably the most advanced and practicable microbiome application. See for many studies and analyses. However about 90% of patients affected with severe, recurrent antibiotic-resistant C. difficile infections respond to fecal microbial transplants
  • Effects on immunity:
    • There are data that the infant microbiota at one month of age is significantly related to allergy in two-year-old children and to asthma in four-year-old children. Several of the products of the higher risk microbiota are associated with subclinical inflammation, which precedes childhood disease. Also other studies have found that children born by cesarean section, who do have differences in their microbiota, are more likely to develop type I diabetes, celiac disease, asthma, hospitalizations for gastroenteritis, and allergic rhinitis.
  • Obesity/metabolic syndrome/insulin resistance/diabetes
    • There are several studies finding that there are significant differences in the microbiome between obese and lean human subjects, with a decrease in Bacteroidetes and an increase in Firmicutes species in obese individuals. Studies have shown that taking microbiome samples from pairs of identical human twins, one lean and one obese, and placing them into genetically identical baby mice, have found that the mice with the microbiota from the obese twin develops more weight gain and more body fat, along with a less diverse microbiome, than those from the lean twin. Also, interestingly, women in their third trimester of pregnancy have an altered microbiome, which, when transplanted into mice, leads to more obesity, and that pro-obesity microbiome is more efficient in extracting energy from food [one common clinical issue with overweight/obese patients is that they may often eat much less than others but still do not lose weight, which has been shown in several studies, and attributed to their being more efficient in metabolizing foods. But perhaps this is mediated through the microbiome???]
    • Some proteins elaborated by E. coli stimulate glucagon-like peptide-1 (GLP-1) secretion, which could augment glycemic control in diabetics, where this hormone is less active than in nondiabetics. In addition, E. coli can elaborate peptide YY (produced in the ileum in response to feeding), which can activate anoxeretic pathways in the brain, mediating satiety.
  • Atherosclerosis/cerebral artery occlusion
    • There are pretty convincing studies that eating red meat leads to changes in the gut microbiota, which leads to increase production of trimethylamine-N-oxide (TMAO), which is a very strong risk factor for human atherosclerotic disease. And feeding meat to vegetarians does not increase TMAO until there are these microbiota changes from recurrent red meat diets. See blogs listed below for more details. Also, experimental data on mice show that cerebral arterial occlusion leads to 60% less damage in those with microbiota which are sensitive to antibiotics; mice given probiotics have less impairment after spinal cord injury.
  • Cancer
    • In mice, specific gut bacteria (most clearly shown for Bifidobacterium) enhance the efficacy of cancer immunotherapy, delaying melanoma growth. Human data has shown that certain microbiota species (B. Thetaiotaomicron or B. fragilis) can improve the effects of anti-tumor therapy targeting cytotoxic T-lymphocytes-associated antigen 4.
  • Autism
    • There are even some suggestive data that the microbiome may play a role in autism spectrum disorders. MIA mice, a maternal immune activation mouse model, exhibits autistic-like behavior, gut microbiome dysbiosis, increased gut mucosal permeability, and an increase in 4-ethylphenylsulfate (4EPS, a metabolite of gut bacteria). Injection of 4EPS into healthy, normal mice results in anxiety. And, feeding the MIA strain of mice a strain of Bacteroides fragilis normalized these adverse gut changes and decreased behavioral abnormalities, associated with decreasing circulating 4EPS levels. There are other neuropsych issues potentially related to the microbiome: gut bacteria can produce several neurotransmitters (eg norepinephrine, serotonin, dopamine, GABA, acetylcholine), and can change emotional behavior of mice (which seems to be related to central GABA receptor expression).
  • Other diseases with suggestive data of a linkage to microbiome dysbiosis include inflammatory bowel disease, kwashiorkor, juvenile rheumatoid arthritis, and multiple sclerosis. Also, in mice, stress leads to altered microbiota (less Bacteroides and more Clostridia), and in humans undergoing bariatric surgery, there are huge differences in the microbiome by either the Roux-en-Y gastric bypass or vertical banded gastroplasty, and this microbiome transplanted into germ-free mice leads to reduced fat deposition, suggesting that these microbiome changes themselves might play a direct role in decreasing adiposity (see Tremaroli V. Cell Metabolism2015; 22:228)​. And perhaps the changes in the microbiome, through the gut-brain relationship is part of the reason for the documented improvement in memory noted after bariatric surgery.
  • Diurnal rhythms (see Thaiss CA. Cell. 2014; 159: 514): the gut microbiota has diurnal variations that reflect feeding rhythms; humans with jet lag have dysbiosis; this jet lag leads to microbiome changes promoting glucose intolerance and obesity and are transferable to germ-free mice.


  • We should approach these studies on the microbiome with caution: some of the most impressive studies were done in animals in highly controlled conditions, and predictions in humans based on the studies is always fraught. For example, in general the use of probiotics in human adults has not shown as dramatic a response as found in rodents. (Although an interesting study of human neonatal probiotic supplementation in the first month of life was associated with a 60% reduction in the risk of pancreatic islet cell autoimmunity, a precursor to type 1 diabetes, before school-age). In addition, a stool sample may not be an adequate proxy for the microbial content of the entire GI tract. And, most of these studies have focused primarily on bacterial species in the microbiota, not taking into account the many other types of microorganisms found or their complex interactions.
  • One concern I have in general is our tendency towards reductionism. The microbiome appears to be a quite complex organ, composed of many different varieties of organisms which undoubtedly interact with each other in complex ways, and which are influenced by many known and undoubtedly unknown external cues (diet, antibiotic use, etc., etc.). So, for example, simply attempting to manipulate that microbiome through the introduction of one species or another of probiotics (i.e., our usual medical fix) may not deal with the complexity of this situation.
  • There have been a slew of other blogs on the microbiome over the years. See . One particularly interesting finding in one of the blogs was that one of metformin’s major action might be in its effects on the microbiome (see, which also reviews some of the TMAO data.
  • So, although I am pretty convinced of the importance of a healthy microbiome, it does seem to me that the major initiative should be around lifestyle changes overall: a healthy diet (and specifically one which is predominantly vegetarian), adequate exercise, perhaps adequate sleep (would be great to have more data on the effect of sleep patterns overall on the microbiome and if changing those patterns changes the microbiome), and minimizing exposure to unnecessary antibiotics (both in humans and in animals that make it into our food chain).

Primary Care Corner with Geoffrey Modest MD: Artificial Sweeteners Microbiome1

23 Jan, 17 | by EBM

By Dr. Geoffrey Modest

As mentioned in prior blogs, I think that the microbiome represents a very important mediator between the external environment and health/disease. A few recent articles supplement and strengthen this understanding. The first in a series of two is a study reinforcing the potentially deleterious effects of non-caloric sweeteners on the microbiome and health outcomes. The second (to be sent tomorrow) is a broader description of our understanding of the microbiome overall and its potential relationship to health.

​Non-caloric artificial sweeteners (NAS) were developed from the biological perspective that these potent sweeteners (more than 100 times sweeter than sucrose) are non-caloric and  are excreted unchanged; they should therefore be an important sugar alternative to help people lose weight and control glucose intolerance. Although a study done in the 1980s, prior to DNA sequencing capabilities, did show that saccharin could alter the rat microbiome, it is only relatively recently that we understand the fuller effects of NAS on both the microbiota as well as clinical outcomes. Many of the clearest studies were done on animals, since it is easier to control the environment completely and isolate the effects attributable to NAS. A recent study looked further into the relationship between NAS, the microbiome, and the clinical effects (see Suez J. Gut Microbes 2015; 6(2), 149). This is an update of a prior article in Nature (see prior blog:​ )


  • The human weight control studies here are a bit mixed. However it should be noted that most of the comparisons were between individuals consuming NAS to those consuming caloric sweeteners, with very few comparing NAS consumption to avoiding all sweeteners.
  • Several studies have shown NAS leads to weight gain in rats (including saccharin, sucralose, aspartame and Stevia), and are associated with increased adiposity
  • NAS can also induce hyperinsulinemia, impaired insulin tolerance, impaired glucose homeostasis, and worsened atherosclerosis in genetically susceptible mice
  • It should be noted that there are some genetically-altered mice where there are some discordant defects: some with decreasing glucose and insulin levels but increasing adiposity, and in some cases hyperinsulinemia

Details of the current study:

  • Mice drinking water supplemented with high doses of commercial saccharin, sucralose, or aspartame, after 11 weeks had marked glucose intolerance, as compared to controls drinking water, sucrose, or glucose.
  • Further studies of saccharin showed that mice on different baseline diets (e.g. high-fat or other) and at different doses of saccharin had increased glucose intolerance
  • The glucose intolerance induced by NAS was ameliorated by prior dosing with antibiotics (ciprofloxacin and metronidazole, in an attempt to sterilize the gut)
  • There were specific changes in the microbiome associated with NAS, including enrichment of Bacteroides and some Clostridiales and decreases in Lactobacilli and some other members of Clostridiales, several of the microbiota changes previously associated with type II diabetes in humans
  • Fecal microbiomes from mice consuming either water or commercial saccharin were then transplanted into germ-free mice, finding that those germ-free mice receiving the saccharin-associated microbiome developed glucose intolerance
  • In 381 nondiabetic humans, NAS consumption was associated with increases in BMI, blood pressure, hemoglobin A1c, and fasting glucose levels. Also there were changes in microbial taxa in the microbiome: more Actinobacteria, Enterobacteriales, and certain Clostridiales.
  • A preliminary small-scale human study found that supplementing the regular diet with higher doses of saccharin led to elevated glycemic responses in four of the seven volunteers, those 4 had microbiome alterations. And when these microbiomes were transplanted into germ-free mice, these mice also developed the same abnormal glycemic responses. Of note, in two of these 4 volunteers, their microbiome changes reverted to normal within 2 to 8 weeks.


  • NAS is consumed by approximately 32% of adult Americans.
  • The microbiome can be rapidly altered by diet, as noted in diets rich in fat (for example, see
  • There are a remarkable number of largely unregulated food additives in the current food supply, many added for purely commercial ends, such as preservatives to extend the shelf life of some foods. I believe this NAS data challenges the concept that even those ingredients that are not absorbed and internalized could conceivably adversely affect the human microbiome. The main point here is not that all additives or chemicals are necessarily bad, but that we should be very circumspect about assuming that they are probably benign based on our often incomplete models (i.e. It did make intuitive sense at the time that a non-absorbed sweetener would lead to less obesity and diabetes; but as our understanding and models have expanded/become more complex, our “intuitive” sense has changed). But, I think all of this reinforces what Michael Pollan (author or many books, including The Omnivore’s Dilemma) has suggested: it really does make sense to eat natural foods, especially ones which our bodies have evolutionarily adapted to, and avoid foods with ingredients that your grandmother would not know.

In my practice, I have focused on trying to get patients to decrease their consumption of sodas, and with some reasonable success. I think this is often the low-hanging fruit (though less healthy than other fruits), and at least most of my patients say they have dramatically decreased or eliminated sodas by either substituting water (best) or water slightly flavored by fruit juice. For regular sodas, the attempt is to decrease the consumption of high-fructose corn syrup (a bad actor with multiple bad effects, including increasing uric acid levels), was well as “diet” sodas (commenting on the fact that they really are not benign, non-sugar alternatives, as above). I think my patients have been able to change this soda habit by our regularly and repeatedly targeting this issue (with motivational interviewing) over the past several years, especially with my patients who are overweight, glucose intolerant/diabetic or hyperuricemic.

Primary Care Corner with Geoffrey Modest MD: FDA broadens indication for empagliflozin to include cardiovascular protection!!!

8 Dec, 16 | by EBM

By Dr. Geoffrey Modest

The FDA just extended the indication for the diabetes drug empagliflozin (Jardiance) to include reducing cardiovascular mortality in those with diabetes and cardiovascular disease. Their press release (see ) states that they looked at postmarketing data, though their original approval 2 years ago indicated that they requested 5 years of post-marketing data.

See my prior blog critiquing the original study leading to FDA approval ( )

Primary Care Corner with Geoffrey Modest MD: Prediabetes and cardiovascular risk: a lower cutpoint?

5 Dec, 16 | by EBM

By Dr. Geoffrey Modest

A recent systematic review/meta-analysis assessed the association between prediabetes by different definitions and all-cause/cardiovascular mortality (see


  • 53 prospective cohort studies with 1,611,339 individuals were followed a median of 9.5 years.
  • The researchers assessed different criteria for defining glucose intolerance:
    • Impaired fasting glucose
      • IFG – ADA (American Diabetes Association): 100 to 126 mg/dL
      • IFG – WHO (World Health Organization): 110 to 126 mg/dL
    • Impaired glucose tolerance: 140 to 200 mg/dL, which is consistent across guidelines, based on 2-hour plasma glucose during an oral glucose tolerance test
    • Raised hemoglobin A1c:
      • ADA: 5.7 to 6.4%
      • NICE guidelines (UK): 6.0-6.4%
    • They specifically looked for the following endpoints: composite cardiovascular events (combination of coronary heart disease, stroke, or “other type of cardiovascular disease”), coronary heart disease, stroke, and all-cause mortality.


  • As compared to normoglycemia (only statistically significant associations are reported below),
    • Risk for composite cardiovascular disease was increased 13% for IFG – ADA, 26% for IFG– WHO and 30% for impaired glucose tolerance
    • Risk for coronary heart disease was increased 10% for IFG – ADA, 18% for IFG– WHO, and 20% for impaired glucose tolerance
    • Risk of stroke was increased 6% for IFG– ADA, 17% IFG– WHO, and 20% for impaired glucose tolerance
    • All cause mortality was increased 13% for IFG– ADA, 13% for IFG– WHO, and 32% for impaired glucose tolerance
    • Note: the observed increased risk occurred with fasting glucose as low as 100 mg/dL
  • In terms of A1c:
    • Those in the 5.7 to 6.4% range had an increase of the composite cardiovascular disease of 25% and coronary heart disease 28%
    • Note: they found that the risk of composite cardiovascular events and coronary heart disease were higher in people with an A1c in the 5.7 – 6.4% vs. the 6.1 – 6.4% group (i.e., the lower numbers mattered)


  • Overall, the study found that there was an increased risk of cardiovascular disease and all-cause mortality with fasting glucose as low as 100 mg/dL or a hemoglobin A1c of 5.7%. So, they strongly support the ADA definitions of prediabetes, which have not been accepted at this point by the European Society of Cardiology, the European Association for the Study of Diabetes, or the European Diabetes Epidemiology Group.
  • This review is useful given that individual published studies have found mixed results on the actual cutpoint of impaired fasting glucose associated with increased cardiovascular disease.
  • However, this study did not have data on the future development of diabetes during the follow-up period, and other data suggest that diabetes increases cardiovasc outcomes more than prediabetes
  • They did find that the risk of all-cause mortality was actually significant higher in the impaired glucose tolerance group than in the groups with other definitions of prediabetes, suggesting that impaired glucose tolerance may be a stronger risk factor for all-cause mortalitythan other definitions of prediabetes, though not for cardiovascular disease
  • Other studies have suggested that impaired glucose tolerance is associated with increased risk of cancer mortality in Australia as well as in Mauritius
  • Of considerable importance is that the more aggressive definition by the ADA includes lots more people, 36.2% of those in the US and 50.1% in China, for example. i.e., this is a huge public health issue
  • The ADA does now recommend considering pharmacologic therapy in patients with impaired glucose tolerance and impaired fasting glucose as well as at least one of: age <60, BMI >35, family history of diabetes in first-degree relative, high triglycerides, decreased HDL, hypertension, and hemoglobin A1c >6.1%

So, the main reason I bring up this issue is to make sure we’re all aware of the significant increase in cardiovascular and all-cause mortality associated with glucose intolerance, even at the remarkably common A1c level of 5.7% (and this raises the issue of what the lower limit really is, in terms of cardiovascular outcomes. And, about 80% of diabetics die ultimately die from CVD, even though those with this level of A1c only very slowly progresses to diabetes, if at all). Basically, I do think it is really important for us to aggressively pursue nonpharmacologic therapies to decrease both the glucose intolerance and these adverse consequences. In addition, I think the increased risk for cardiovascular disease at lower levels of glucose intolerance should be factored into our overall preventive strategies around atherosclerotic disease, including not just more aggressive nonpharmacologic therapies (e.g., strongly reinforcing managing the other cardiovascular risk factors, BMI, etc., esp. through diet, exercise….), but also perhaps an earlier initiation of statins and perhaps aspirin.

Primary Care Corner with Geoffrey Modest MD: HTN Goal in Diabetics without CVD

7 Nov, 16 | by EBM

By Dr. Geoffrey Modest

A large Swedish population study found that in diabetics with no previous cardiovascular disease, there were progressively fewer cardiovascular events as the systolic blood pressure was lower (see


  • 187,106 patients in the Swedish national diabetes register for at least 1 year, <= 75 yo, and no known cardiovascular disease (CVD), from 2006-2012 with mean follow-up of 5.0 years. From 861 primary care units and hospital outpatient clinics
  • Most of the demographics got worse as the cohort in each 10-mm group of BP increased: median age was 55 in the lowest SBP group vs 64 in the highest; duration of diabetes 4.8 vs 6.8 years and the higher SBP group was more likely to be on more aggressive diabetes management;  LDL 2.8 vs 3.0 mmol/L but HDL 1.3 in all; more micro/macroalbuminuria in those with the highest SBP; and the mean number of BP meds was 0.7 in the SBP 110-19 cohort vs 1.1 in the 130-139 cohort vs 1.6 in the >160 mmHg cohort


  • ComparingSBP 110-119 mmHg vs those with SBP 130-199:
    • Non-fatal MI, RR 0.76 (0.64-0.91, p=0.003), 24% risk reduction
    • Total acute MI, RR 0.85 (0.72-0.99, p=0.04), 15% risk reduction
    • Non-fatal CVD, RR 0.82 (0.72-0.93, p=0.04), 18% risk reduction
    • Non-fatal coronary heart disease, , RR 0.88 (0.79-0.99, p=0.04),12% risk reduction
    • There was no suggestion of J-shaped relationship, except for heart failure and total mortality, and this was only significant for the lowest SBP group
  • Figure below shows that there was a consistent relationship between SBP and non-fatal CVD events over the course of the study. For all of the CVD endpoints, this relationship held, even after controlling for age, sex, duration of diabetes, type of diabetes treatment, HbA1c, smoking status, LDL, HDL, triglycerides, micro/macroalbuminura; as well as thiazide diuretics, loop diuretics, calcium antagonists, spironolactone, b-blockers, and drugs for heart disease. Of note, they did not control for those on vs not on antihypertensives, which may be important.




  • So, why is it so difficult to zero-in on a goal blood pressure in diabetics? This study suggests that lower blood pressure is better. But the various guideline groups have been increasing the BP goal lately, though based on no new evidence: the ADA (Am Diabetes Assn) in 2016 set the overall BP guidelines at the higher level of <140/90 (see and explicitly did not recommend it to be <130/70 in older adults, in conformity with JNC8 (which also has a higher goal than JNC7)
  • I think there could be various different explanations:
    • The current study focused on a less-sick population than most of the others: a younger cohort, who had no known baseline CVD, and some did not have treated hypertension
      • Is the diabetes itself different? (perhaps longer-standing diabetes creates end-organ changes which dictate different optimal BP goals)
      • Are we using diabetic medications which make things worse, and using more of them on patients with longer-standing and more treatment-resistant diabetes? Similarly with the antihypertensives?
        • In terms of diabetes control, a case in point here is the ACCORD trial, one of the major studies heralded as a reason to raise the target A1c. Those assigned to the “intensive control wing”, achieved an A1c of 6.4, but 91% were on a thiazolidinedione (TZD), vs an A1c of 7.5 in the less aggressively treated group but with 58% on a TZD. But the TZD of choice was rosiglitazone, which has the unfortunate tendency to increase cardiovascular outcomes (and is one of the reasons that I find it unfortunate that the FDA and most of us accept A1c as an acceptable clinical surrogate).
        • And, this brings up the issue of medication-flogging…. are those patients with easy-to-control diabetes or hypertension different? As in the first point, is there a fundamental difference in their pathophysiology or clinical outcome? A subgroup analysis of this ACCORD study actually found that those who achieved a lower A1c in fact did better, all the way down to an A1c of 6!!, but as the number of meds needed in the attempt to lower the A1c increased, they had worse outcomes (i.e., medication-flogging of patients to improve their A1c led to worse outcomes even at a much higher A1c). See Riddle MC. Diabetes Care; 33:983. An Italian observational study also found that the goal of A1c in terms of clinical outcomes was lower in those with fewer chronic medical conditions (see Greenfield S. Ann of Intern Med 2009; 151: 854).
        • This last point brings up the parallel issue: should the blood pressure goal be different in those with fewer chronic changes from long-standing hypertension (e.g. atherosclerosis, or changes in the local autoregulation of blood pressure at a microvascular level) vs those with perhaps newer onset hypertension with fewer of these changes? should we have different BP goals in those who easily achieve a blood pressure of 110-120 systolic if it can be achieved with 1-2 drugs, vs those with SBP of 140+ systolic, who would be struggling to achieve even close to the lower range with 4 drugs? It was certainly the case in the Swedish study that as the SBP of the cohort increased, there were more meds being used, distributed pretty evenly amongst the different types of meds.
        • The prior observational studies have often found a J-shaped relationship between blood pressure and CVD events in diabetics, though this has been questioned by the potential bias in observational studies that patients who had more bad outcomes at lower pressures did so because they were really sick at the start, and it was this increased morbidity that led to lower blood pressure. It is notable in the above Swedish study that the J-shaped curve did happen in those with lower blood pressure, but only for total mortality and heart failure, and not for the specific CVD outcomes, suggesting that there may have been issues that these patients with lower SBP were indeed sicker. In fact those who died in this Swedish study were likely to have had more comorbidities, since they had higher rates of smoking (32%), use of loop diuretics, spironolactone, and drugs for heart disease.
        • The ACCORD-BP study of diabetic patients (N Engl J Med 2010; 362: 1575), another wing of the above ACCORD study, found no overall benefit in 4733 patients in those achieving a systolic BP of 119 mm Hg vs 133.5 mm Hg, except for the prespecified secondary outcome of stroke, where there was a 41% decrease (p=0.01), but at the expense of an increase in serious adverse events (from 1.3% of the population to 3.3%). The absolute risk of stroke was 0.53%/yr vs 0.32%/yr, which translates roughly to 2.6% vs 1.6% over the 4.7 year study. The serious adverse events were largely hypotension/syncope/bradycardia or arrhythmia/hyperkalemia. The intensive group averaged 3.4 BP meds and the standard group 2.2. But, as opposed to many strokes, all of these serious adverse could be tracked and corrected, and there was no evidence of increased morbidity/mortality from these adverse events. Other trials, such as ONTARGET found a J-shaped curve, and the INVEST trial found no benefit if the SBP were lowered below 130, (though a subgroup analysis of ONTARGET found that it was those with a higher baseline risk who had CVD events, rather than the degree of reduction of the BP). These are the trials cited in JNC8 and the ADA guidelines as the reason to shoot for a higher SBP target.
      • So, my best guess is that lower SBP is better for those who don’t have lots of comorbidities and do have more easily treated hypertension, with the following caveats:

Also,, a recent meta-analysis found benefit of a goal SBP of around 130 to be better overall than 140.


Primary Care Corner with Geoffrey Modest MD: Glucometers Lower A1c’s in Non-Insulin Using Diabetics, a Little

31 Oct, 16 | by EBM

By Dr. Geoffrey Modest

BMJ just published a meta-analysis of randomized controlled trials (RCTs), finding that non-insulin using diabetic patients who self-monitored their blood sugars had improved glycemic control (see doi:10.1136/bmjopen-2015-010524 ). This analysis included several new studies, not available in prior reviews.


  • 15 RCTs were identified with 3383 patients
  • Results:
    • Those using SMBG (self-monitoring of blood glucose) had:
      • Lower HbA1c by −0.33 (−0.45 to −0.22); p<0.001 [the quality of evidence was rated as moderate]
      • Lower BMI by −0.65 (−1.18 to −0.12); p=0.02 [the quality of evidence was rated as low]
      • Lower total cholesterol (TC) by −0.12 (−0.20 to −0.04); p=0.003 [the quality of evidence was rated as high]
      • Lower waist circumference by -2.22 (-4.40 to -0.03); p=0.047 [no comment, but i assume that is in centimeters; the quality of evidence was rated as moderate]
      • No significant difference in fasting plasma glucose, systolic or diastolic BP, HDL, LDL, triglycerides, or weight
      • Subgroup analyses: no difference if Asian countries or US/Europe; A1C was improved in both short-term (<6 month, by -0.36%) or long-term studies (>12 month, by -0.28%). BMI and TC changes were only significant in the <6 month group. and though waist circumference was improved overall, it was not significantly improved in the subgroups, but was near-significant (p=0.06) only in the >12 month group (by -3.15); also similar A1C reductions were found in patient with newly diagnosed type 2 diabetes (T2DM) vs duration >12 months [no further analysis for really long-termers]; SMBG was significantly more effective in patients with lower A1C (<8%) vs higher
    • Adverse events: most common was the incidence of hypoglycemia (higher in SMBG group), though their rate (episodes/patient) was lower


  • Prior concern about SMBG reflect its high cost (21% of diabetic prescription costs in the US) and several studies suggesting its lack of efficacy in non-insulin using T2DM patients (e.g. Farmer AJ BMJ 2012;344:e486), even though currently 63.4% of T2DM use SMBG daily
  • The analysis, as with pretty much all meta-analyses, is limited by the quality of the studies included, their size, differences in methodology in general, degree of patient education, frequency of testing, and inherent biases associated with the more intensive medicalization in those doing SMBG
  • The decrease in A1C of -0.33% is often not considered to be clinically significant (typically defined as a change of 0.5%)
  • So, this study does suggest efficacy of SMBG monitoring, albeit perhaps of marginal clinical significance. As an intervention, it does medicalize patients much more than just taking a pill. And this has the potential for both positive and negative effects: the positive side is that it may empower patients in involving them more in taking ownership and treating their condition, and for some patients, this involvement might be important in helping them deal psychologically with a potentially devastating disease; the negative side is that for some patients it might create lots of anxiety and perhaps over-focus/dwelling on their medical problems and perhaps reinforce a more passive, “sickness” mentality which could decrease their ability to function.
  • This last difference exposes one of the contradictions of RCTs: they look at a large group of individuals, with some exclusions, but cannot really replicate the actual patient one is treating. It may well be that some patients who want to control their bodies and illnesses more, actually do much better with SMBG than decreasing their A1C by the 0.33% as above, perhaps using the daily blood sugar feedback as a motivation for more lifestyle changes (and, even if the A1C does not plummet, these lifestyle changes might have much broader healthful consequences). Others who may become more anxious or are not interested in this level of involvement, may get no benefit, or the experience might actually be negative. And the sum of these patients in the larger RCTs may then reveal only a mediocre outcome, obscuring the potential benefit for perhaps a lot of people. The real trick might be to figure out who is motivated by the SMBG and use this tool to help them with their diabetes management. And perhaps not using or stopping SMBG in those who do not really benefit. So, yet again, one size just does not fit all….

EBM blog homepage

Evidence-Based Medicine blog

Analysis and discussion of developments in Evidence-Based Medicine Visit site

Creative Comms logo

Latest from Evidence-Based Medicine

Latest from EBM