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: Canagliflozin decreases macrovasc disease???

19 Jun, 17 | by gmodest

by Dr Geoffrey Modest

Another study assessed the role of a sodium-glucose co-transporter 2 inhibitor, this time canagliflozin, and its effects on cardiovascular and renal outcomes in patients with type II diabetes (see DOI: 10.1056/NEJMoa1611925 ). A drug company supported study.


— this report involved 2 trials with 10,142 participants with type II diabetes and high cardiovascular risk, randomized to canagliflozin vs placebo, followed a mean of 188.2 weeks. All had HgbA1c between 7 and 10.5%, had a history of symptomatic atherosclerotic cardiovascular disease, or were at least 50 years old and had 2 or more risk factors (which included diabetes of at least 10 years duration). Patients were from 667 centers in 30 countries. 96% participants completed the trial.

— mean age 63, 36% women, mean duration of diabetes 13.5 years, 78% white/13% Asian/3% black, 18% current smoker, 90% history of hypertension/14% heart failure/56% CAD/19% cerebrovascular disease/21% peripheral vascular disease (66% overall had a history of cardiovascular disease), 2% amputation, BMI 32, blood pressure 137/78, A1c 8.2%, 70% with normal albuminuria/22% microalbuminuria/8% macroalbuminuria

— baseline diabetes therapy: 50% insulin/43% sulfonylurea/77% metformin/4% GLP-1 inhibitors/12% DPP-4 inhibitors

— the 2 studies overall were similar, though in one study patients received canagliflozin 300 mg vs canagliflozin 100 mg vs placebo, the other canagliflozin 100 mg with an optional increase to 300 mg vs placebo

— primary outcome: composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke.


— for those on canagliflozin (vs placebo):

— the use of other antihyperglycemic agents was 9.3% lower.

— HgbA1c -0.58%, BMI -1.60, blood pressure -4/-1 mmHg (p<0.001 for all comparisons). LDL and HDL were higher with canagliflozin, though the ratio was similar

— the primary outcome was lower with canagliflozin, 26.9 vs 31.5 per 1000 patient-years, a 14% decrease with HR 0.86 (0.75-0.97), p<0.001 for noninferiority, p=0.02 for superiority

— these outcomes were broadly consistent across prespecified subgroups, though those on baseline diuretics did significantly better (34%, HR 0.66, p<0.001) and those not on diuretics had a trend to doing worse

— the pre-specified secondary renal outcomes (progression of proteinuria with >30% increase and a change from either normoalbuminuria to microalbuminuria or from micro to macroalbuminuria) overall were not statistically significant, however there seemed to be a possible benefit of canagliflozin in terms of progression of albuminuria, HR 0.73 (0.67-9): regression of albuminuria with HR 0.60, as well as for the composite outcome of the sustained 40% reduction in eGFR plus need to renal replacement therapy plus death renal causes, HR 0.60 (0.47-0.77)

— adverse reactions: overall 7% less common in those on canagliflozin, but of note there were twice the number of amputations, 6.3 vs 3.4 participants per 1000 patient-years, HR 1.97 (1.41-2.75), in 71% at the level of the toe or metatarsal, and especially those with a prior history of amputation or peripheral vascular; fracture risk was also higher, occurring in 15.4 vs 11.9 per thousand patient years, p=0.02; and, as per prior studies of SGLT-2 inhibitors, there were more cases of osmotic diuresis, volume depletion, and mycotic genital infections in women in those on canagliflozin, though not urinary tract infections.


–reviewing their graphs, there were several major differences in the groups of canagliflozin:

–the HgbA1c was significantly lower, was down to 7.5 by week 26, slowly increased to 7.8 by week 150, and ultimately to around 8.0 by week 300. placebo was pretty consistently around 8.2-8.3

–mean weight decreased to 87kg with canagliflozin but remained around 89-90 kg with placebo

–blood pressure was 131/74 with canagliflozin but 136/76 with placebo

–the graphs for cardiovascular events:

–deaths from cardiovascular causes, nonfatal MI or nonfatal stroke: curves separated at around 52 weeks of treatment, then paralleled after 104 weeks

–death from cardiovascular causes: nonsignficant. curves initially separated favoring canagliflozin then merged together after 260 weeks

–nonfatal stroke: also nonsignificant and similar to cardiovascular deaths

–nonfatal MI: also nonsignificant, though did separate after 104 weeks and remained separate

–other outcomes:

–death from any cause: nonsignificant

–heart failure hospitalizations: signficantly better with canagliflozin, HR 0.67 (0.52-0.87) with separation early, by 26 weeks

–renal: clear benefit beginning by 78-104 weeks for progression of albuminuria and the composite of 40% reduction in eGFR, requirement for renal replacement therapy or death from renal causes [though it seems that lowering A1c itself seems to be renoprotective from many studies, and those on canagliflozin had lower A1c levels!!!]

–it is unclear how much of the benefit from canagliflozin is related to the protective effects of this drug, given the substantial differences in HgbA1c, weight and blood pressure. the change in renal outcomes would largely be expected from these differences, as per many prior studies (unfortunately the authors did not compute the expected effect attributable to these A1c changes, but they would certainly go a long way to explaining the differences). and the differences in macrovascular outcomes (their primary outcomes) similarly may be explained largely by these differences in the constellation of better A1c, blood pressure, and weight loss in the canagliflozin group

–also, there is no comment in the article or the supplementary materials about the differences in treatment in the placebo group: they comment that the use of other antihyperglycemic agents was 9.3% lower with canagliflozin but do not comment on what additional meds were used in the placebo group. was it potentially harmful agents (eg rosiglitazone)? more sulfonylureas (which do not seem to help and may hurt cardiovascular outcomes)? more GLP-1 agonists (which would make their results more impressive, given that these do seem to be cardioprotective)

–and it is concerning about the increase in both amputations and fractures with canagliflozin.  Bones do not seem to fare well.

–also, see prior blogs on another SGLT2 inhibitor empaglifozin, where I found the study also quite flawed. And, it is important to remember, these SGLT-2 trials were both drug-company sponsored. and, it would not be so surprising to find that these trials are designed to achieve the results that the drug companies would like….  for example, they could have designed this canagliflozin trial so that the A1c levels in both the drug and placebo groups matched!!!! we could then sort out how much of the problem was related to the A1c differences and how much to the drugs used (they would also need to describe what drugs were used….)

so, how to proceed?

–these SGLT2 inhibitors possibly do decrease cardiovascular events (at least this has been shown for 2 different ones, though I think both studies are pretty flawed, as above). it should be kept in mind that  the FDA does warn about ketoacidosis and severe urosepsis with these drugs (see​ ), and there are reports of acute kidney injury as well as a pretty high incidence of genital mycotic infections.​

–i personally am still more impressed with the studies on GLP-1 agonists. they seem to be cardioprotective, I am consistently shocked at how well they work in lowering A1c levels, and they are quite targeted (the most common problem I have seen is GI, though a few cases of itchy rash/apparent allergy to one of them, though subsequent use of another was well-tolerated). And, they have been around for a long time ( exenitide has been used in Europe for >10 years).

Primary Care Corner with Geoffrey Modest MD: Does glucose home-monitoring help???

15 Jun, 17 | by gmodest

by Dr Geoffrey Modest

A recent article added to some prior literature suggesting that glucose self-monitoring is not so effective in type II diabetics not on insulin (see doi:10.1001/jamainternmed.2017.1233 ).



— 450 patients were enrolled in this pragmatic, open label randomized trial, of which 418 completed the final visit. All were in established primary-care relationships in North Carolina, had a hemoglobin A1c between 6.5% and 9.5%, and were randomized into one of 3 wings: no self-monitoring of blood glucose (SMBG), once daily SMBG, or once daily SMBG with enhanced patient feedback including automatic tailored messages delivered via the meter that were intended to educate and motivate patients with an algorithm that took into account the blood glucose value, time of day, and relationship to food intake.

— Median age 61, 46% male, 33% black/62% white, 60% high school or some college/34% college or higher, BMI 33, 38% with low health literacy, mean duration of diabetes 6 years, 3 comorbidities, current use of SMBG 75%, diabetic meds were metformin 80%/sulfonylurea 36%/TZD 5%/DPP-4 inhibitor 9%

— baseline hemoglobin A1c 7.6%

— Primary outcomes were: hemoglobin A1c level and health-related quality of life at 52 weeks



— testing adherence declined in both of the SMBG groups (though more so in the group with messaging!): daily testing overall going from around 95% initially to 60% at 12 months; for the no SMBG group, 24% tested at least a few times/month and only 9% tested less than once/month

— follow-up hemoglobin A1c’s were:

— no SMBG: baseline 7.52, follow-up 7.55

— SMBG, no messaging: 7.55, follow-up 7.49

— SMBG, with messaging: 7.61, follow-up 7.51

— there was no significant difference between hemoglobin A1c levels across all 3 groups (p=0.74), with estimated adjusted mean A1c difference:

— SMBG with messaging vs no SMBG: -0.09% (-0.31% to 0.14%)

— SMBG vs no SMBG: -0.05% (-0.27% to 0.17%) [as a reference here, a 0.5% difference (10x this difference) is considered to be clinically significant]

— there was no significant difference in health-related quality of life.

— there was no significant difference in adverse events including frequency of hypoglycemia, healthcare utilization, or insulin initiation

— there was no significant difference in almost all of the secondary outcomes, including the diabetes empowerment scale, diabetes treatment satisfaction scale, and the communication assessment tool.



— prior studies have been mixed on the role of SMBG in non-insulin using patients, though more than 75% do regular SMBG

–there were several limitations of the study, many noted by the authors: this study really reflected whether it was useful to continue SMBG, since most patients had already been doing so (ie, not whether initiating SMBG mattered for those not doing so); and there was a selection bias in that all participants were willing to be randomized into a group not using SMBG. Also, about 40% in the daily testing group stopped doing so (though not sure what that means, since they don’t say whether this is decreasing testing to 6x/week or 1x/month…)


the bottom line here: I think that it can be useful to have some home-based glucose monitoring for a few reasons, including fuller details on blood sugar swings during the day, with the potential:

–to elucidate to the patient what tends to make the blood sugar go up or down (eg, it was the last meal with rice which raised the blood sugar, or doing exercise lowered it….). This real-time feedback can well inform the patient on what lifestyle issues either improve or worsen blood sugars, leading to appropriate tweaking of them. in my experience, after suggesting to patients that they monitor their blood sugar 1-2 hours after a meal, that the patients are better able to identify triggers to higher blood sugars. and, sometimes, they are able to modify their diets

–to adjust medications to cover these higher or lower levels, if lifestyle changes would not help

–but I think that the main message from this study, as well as prior ones, is that our primary focus as clinicians should not be primarily to strongly encourage/berate patients about checking their blood sugars at home, but to focus on lifestyle changes and medication adherence. as I have mentioned in prior blogs, I think that diabetes treatment is one of the hardest issues I deal with in clinical medicine. it brings to the fore the multitude of issues and obstacles to treating this complicated disease, including the difficulty in eating well/exercising (access to good foods, ability/time to cook healthy meals, access to good exercise venues including safe streets to walk on/time to do so in our overprogrammed lives, and generally competing with a culture and with persuasive advertising to eat poorly, sit at home watching TV, work 2 jobs to survive, etc, which are perhaps the most important underpinnings for our diabetes epidemic.)  these are the hard issues for our patients, and i think the primary ones to focus on. And really focusing on  the importance of SMBG​ can actually dilute/divert this pivotal message of the importance of lifestyle changes.

Primary Care Corner with Geoffrey Modest MD: Hemoglobin A1c reduction and decreased cardiovascular event

8 May, 17 | by gmodest

​by Dr Geoffrey Modest

A recent cohort study found an association between those patients who achieved an early reduction in HbA1c with metformin and a significant reduction in subsequent cardiovascular events (see DOI: 10.2337/dc16-2271).



— a population-based cohort study in northern Denmark from 2000-2012 assessed 24,752 new-onset diabetics 6 months after initiating metformin therapy

— median age 62.5, 55% males. Median follow-up 2.6 years

— primary endpoint: subsequent rates of acute myocardial infarction, stroke, or death, controlling for baseline HbA1c and other confounding factors (age, sex, year of starting metformin therapy, microvascular and macrovascular complications, obesity, alcoholism, antiplatelet drugs, statins, antihypertensives, psychiatric medications, achieved cholesterol target, and use of other unspecified glucose lowering therapy). socioeconomic status was adjusted by using education as a proxy.



— those who achieved A1c <6.5% tended to be older (> 70yo), female, and more likely to have initiated metformin later in the study (between 2010-2012), tended to have slightly more microvascular and macrovascular complications at baseline, take more preventative medications, and have less obesity. They also tended to have lower baseline A1c initially.

— those with the greatest point reductions in A1c tended to be younger, had lower prevalence of macrovascular complications, less comorbidity, and took fewer preventive medications. They also tended to have the highest baseline A1c and received more additional glucose lowering therapy.

— During the follow-up, there were 439 incident MIs, 594 strokes, and 1845 deaths.

— the risk of a primary end-point, compared with an achieved HbA1c <6.5% in the adjusted model, was:

— 6.5-7%: 18% increased risk, HR 1.18 (1.07-1.30)

— 7-7. 5%: 23% increased risk, HR 1.23 (1.09-1.40)

— 7.5-8%: 34% increased risk, HR 1.34 (1.14-1.57)

— >8%: 59% increased risk, HR 1.59 (1.37-1.84)

— these results were consistent for the individual outcomes, age groups, presence or absence of comorbidity at baseline, or socioeconomic status.

— the clearest association between higher A1c and worse clinical outcomes was in patients >70 years old.

— a 4% absolute decrease in HbA1c was associated with a 20% decreased risk of a primary outcome; lesser degrees of risk reduction were not statistically significant



— observational data from many studies are quite consistent that there is an increased risk of atherosclerotic disease in diabetics, and that this increase starts early in the prediabeticrange (eg A1c 5.5-6), especially in men, and increases with increasing A1c. The data on decreasing risk by lowering A1c is less clear, and seems to be dependent on the medication used. Some medications have some reasonable support for cardiovascular benefit, including metformin, pioglitazone, and GLP-1 agonists (I am very suspect about empaglifozin, see below). It is important to know that the published target of getting the A1c’s as low as possible, around 7% or even lower, are based on decreasing risk of microvascular complications found in several studies, not the really important macrovascular ones (80% of diabetics die from cardiovascular causes). Which is not to say that microvascular complications are not important…

–As noted in prior blogs, the ACCORD study questioned the utility of lower A1c targets for macrovascular protection but (I think) is overquoted and has led to a more lackadaisical approach to diabetes management. See blog noting that “A subgroup analysis of this ACCORD study actually found that those who achieved a lower A1c in fact did better (in terms of cardiovascular endpoints), 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., those in the intensive therapy group who had medication-flogging to improve their A1c had worse outcomes even at a much higher A1c). See Riddle MC. Diabetes Care; 33:983.” Also see the blog which goes into more detail on ACCORD. So, my conclusion was that the lower the A1c, the better in terms of macrovascular complications in ACCORD, but only if this lower A1c can be achieved easily with meds (and, reinforcing the above comment, the choice of meds may be extremely important. For example, in the ACCORD study, 91% of those in the aggressive treatment arm took TZDs, and mostly rosiglitazone, known to increase cardiac mortality!!!. Interestingly in this current study, those >70yo did better cardiovascular-wise if their A1c were low with metformin, which suggests that age may not be the decisive factor in targeting A1c goals, but perhaps other things (comorbidities, longevity predictions), though my sense is that currently clinicians are somewhat more hesitant to be aggressive with older patients, quoting the ACCORD trial

–one peculiar aspect of this study to me was why did so many patients have high A1c’s 6 months after starting metformin? My clinical experience, with a few dozen new-onset diabetics (though not the 24.7K in this study), is that they uniformly respond to metformin with essentially normalization of their A1c, independent of how high their initial A1c was. Even patients with A1c’s in the 15-18% range decrease to <7% with just metformin 500 mg once a day. The purported explanation for this is that they have glucotoxicity, whereby the increased blood sugar leads to decreased insulin effectiveness (as shown, for example, in decreased insulin-mediated glucose uptake into muscle), and this is true in laboratory situations with both diabetics and nondiabetics.  Typically new-onset diabetics need insulin injections early on to help decrease the blood sugar, thereby decreasing the glucotoxicity for which their struggling pancreas cannot compensate with more insulin production, and then, when their blood sugars are lower, their marginal endogenous insulin reserves work. And in my experience exogenous insulin can uniformly be stopped, typically within 1-2 months, and some do not even need to continue the metformin (at least for months to years, when their pancreases get increasingly tired).

–and, why did those with high A1c’s 6 months after starting metformin do so poorly? was it simply poor glucose control? or, were those who did not achieve a low A1c fundamentally different from those who did, perhaps in unmeasured ways?? did they have diabetes longer, leading to more atherosclerosis (ie, was the increase in cardiovascular events really just lead-time bias, where those with longer duration of diabetes before diagnosis had more atherosclerotic disease just because they had diabetes for longer)? Or, is their diabetes fundamentally different: do the ones who easily achieve really low A1c levels have a different, “mild” type of diabetes and would not get heart disease for a really long time anyway, while others have great difficulty getting their diabetes controlled, have more complications, but the complications have nothing to do with the A1c level achieved but with the fact that they just have “aggressive” diabetes???

–also, unfortunately, in the above study there were obvious important unmeasured factors, including smoking, BMI, diet, physical activity, social support, patient motivation, etc. which really could affect their results. And there may also have been an inherent bias that clinicians tried to get better blood sugar control in patients who were healthier and they felt had a better prognosis, so actually had less cardiovascular disease because of that? (this is hard to sort out in an observational study as this one)

—  As a side issue, studies like this one from Denmark, as well as others from most European countries, showcase the advantages of their having extensive medical databases, linkages to prescription data, linkages to social/demographic data, and nearly 100% followup.  The US, with the most expensive medical system in the world, unfortunately pales in comparison (?reflecting different priorities in public health???)…


so, why do I bring up this article, given the above limits of the interpretability of such an observational study?  a few reasons:

–I think there probably is value to more aggressive diabetes treatment to lowering cardiovascular events (and, again, this is what kills diabetic patients). and I think the results of the ACCORD trial weigh much too heavily on the various guidelines, since this study (i think) was quite flawed

–I think that we should really move towards using diabetes medications which have the clearest cardiovascular benefit (eg metformin, GLP-1 agonists, as opposed to insulin and sulfonylureas) as a priority, vs just focusing on achieving the best “number” for our A1c’s (untested, just my thought), though it is clear that A1c level is important for the microvascular complications

–I think studies like this one should stimulate us to question our model of disease (diabetes, here). Is it one disease or a combination of different ones with different outcomes but we lump them together (sort of like breast cancer: some are really aggressive and spread even before we can even detect them. some slowly increase in size and are easily treated but may not change life expectancy much…..)?

–and, I think it is a clinically useful and important intellectual activity to look at studies like this one (which I do think has some validity) in order to reflect on and critique the study; think about its potential biases, assumptions and limitations to its generalizability; and figure out if or how it should be incorporated into our understanding of the disease and how we should treat patients (though oftentimes these studies raise more questions than they answer, but maybe the questions are more advanced as we see more studies and get more data…..).  This is one of my main impeti (?plural for impetus) for doing these blogs. I think that overall in medicine we are deluged/overwhelmed daily with huge numbers of medical articles, guidelines, etc. And my concerns are that in many cases we just hear about/read the bottom line: does the med work?? etc. And the studies are mostly funded by drug companies. And they design them to optimally get the result they want. And many of the details of the study are buried in the text (and, more and more, buried in the supplemental material, for which one needs either a subscription to the journal or access to a medical library, but in any event takes even longer to sort out). See empagliflozin blog listed below as one of many examples of what I think is a poorly designed drug-company sponsored study. And nowadays the drug companies seem to have greater access to the media, who also publish a not-so-in-depth review, and they certainly have much more access to direct-to-consumer advertising, both of which may push us to prescribe these drugs.  So, all in all, it is getting much harder to read the onslaught of medical information critically, decipher it, and apply it appropriately. And I hope these blogs help a little …..


See here and here for blogs critiquing the empaglifozin study, suggesting that the accepted cardiovascular benefit is not so clear when one scratches the surface of the article. It also comments on the benefits found with metformin and pioglitazone in other studies.  Though I should add that the FDA does have warnings about these SGLT-2 inhibitors (such as empagliflozin) causing acute renal injury, ketoacidosis, urosepsis/pyelonephritis, and genital mycotic infections  (see


See blog on liraglutide, a GLP-1 agonist, which I think really does have significant cardiovascular benefit, as well as powerfully lowering A1c levels

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

11 Apr, 17 | by gmodest

by Dr Geoffrey Modest

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



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

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

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

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



— Mean change in hemoglobin A1c at 2 years:

–decreased 0.85% with pump treatment

–decreased 0.42% with multiple daily injections

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

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

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

— secondary outcomes:

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

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

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

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

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



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

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


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

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

4 Apr, 17 | by gmodest

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

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

4 Apr, 17 | by gmodest

By Dr Geoffrey Modest

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


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


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

— for anticonvulsants:

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

   — gabapentin, 5 RCTs, not effective, low SOE

— serotonin-norepinephrine reuptake inhibitors/antidepressants:

   — duloxetine, 7 RCTs, large effect, moderate SOE

   — venlafaxine, 2 RCTs, large effect, moderate SOE

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

— opioids

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

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

— topical agents

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

— other agents

   — dextromethorphan, 3 RCTs, not effective, low SOE

   — mexiletine, 5 RCTs, not effective, low SOE

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

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

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



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

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

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

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

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

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

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

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

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


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

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

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


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

15 Mar, 17 | by EBM

By Dr. Geoffrey Modest

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


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


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


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

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

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

Primary Care Corner with Geoffrey Modest MD: Diabetic Neuropathy Guidelines

14 Mar, 17 | by EBM

By Dr. Geoffrey Modest

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

Summary of points:

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


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

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

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

Primary Care Corner with Geoffrey Modest MD: 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.

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