**Transcript of Cyberseminar**

**Evidence‐based Synthesis Program (ESP)**

**Predictors and Consequences of Severe Hypoglycemia in Adults with Diabetes**

***A Systematic Review of the Evidence***

**Presenter: Hanna E. Bloomfield, MD, MPH**

**Disscussants: Leonard Pogach, MD, MBA, FACP**

**Bernie Good, MD, MPH**

**June 25, 2012**

**Transcript of Cyberseminar**

**Evidence‐based Synthesis Program (ESP)**

**Predictors and Consequences of Severe Hypoglycemia in Adults with Diabetes**

***A Systematic Review of the Evidence***

**June 25, 2012**

Interviewer:Four our audience we have one presenter and two discussions today.  Our presenter is Dr. Hannah Bloomfield, she is with the Evidence-based Synthesis Program Center at the Minneapolis VA Medical Center and we have two discussants, first is Bernie Good and I’m sorry Bernie I’m feeling – I cannot – I had your Bio here and it disappeared; I apologize.  

Bernie Good:No problem.  I’m the chair of the Math; I’m a primary care physician at the VA Pittsburgh Health Care System.

Interviewer:Thank you.  And Leonard Pogach is our other discussant.  Dr. Pogach joined the East Orange VA Medical Center in 1981 following completion of his fellowship in endocrinology, diabetes and metabolism at the Boston University Medical Center.  He is the National Program Director for Endocrinology, Diabetes in the Office of Specialty Care, Patient Care Services.  At this point Hannah I am going to turn things over to you.

Dr. Hannah Bloomfield:Hello everybody, welcome.  That’s a picture of me since you can’t see me.  So we’re going to talking about predictors and consequences of severe hypoglycemia in adults with diabetes today and I would, of course like to acknowledge my co-authors and collaborators who are listed here as well as the expert panel and reviewers also listed here.  

This report is based on research conducted by our Evidence-based Synthesis Program in Minneapolis and we have no conflict of interest.  The Evidence-based Synthesis Program as you can see on this slide is sponsored by QUERI.  It’s established to provide timely and accurate syntheses on health care topics and it builds on staff and expertise already in place at these particular sites.  We are in Minneapolis.

Hopefully the evidence syntheses that we provide will help inform clinical policies, performance measures and other things we do in the clinic.  Each of these – each of these syntheses has a steering committee and technical expert panel as well as external peer reviewers and policy partners all of whom were listed on a previous slide.  

So now to get to the actual study that we did, Predictors and Consequences of Severe Hypoglycemia in Adults with Diabetes.  As I probably don’t need to tell anybody on this call the prevalence of type 2 diabetes has been increasing due to the epidemic in obesity primarily and the prevalence is estimated to be about 25% FDA at this time.  So a lot of our patients have diabetes.  As you all probably know having diabetes is associated with an increased risk of cardiovascular disease and national guidelines have emphasized very tight glucose control primarily because there is some evidence that it will prevent microvascular complications.  However tight control has also been associated with a bad effect, which is symptomatic low blood sugar hypoglycemia.  So the purpose of this systematic review with the answer to these three questions.  

What is the incidence of severe hypoglycemia in adults with type 2 diabetes who are taking an anti-diabetic medication?  What are the risk factors for severe hypoglycemia in this population and what are the consequences of severe hypoglycemia?  Our methods included a Medline search for trials, observational studies and systematic reviews covering the time period from 1950 through November of 2011.  Looking for the population of adults with type 2 diabetes who are on diabetes medication. 

We define severe hypoglycemia as an episode with typical symptoms that resolved after treatment administered by another person.  For our first two questions we excluded studies with fewer than 500 subjects or less than six months duration.  The literature search is outlined here; we came up with 2353 abstracts.  After an abstract review we excluded about 2,000 of those.  We did full text review on 439 articles and after that review another 320 were excluded so we ended up with 119 articles, we then found another eight and you can see at the bottom of this slide how many articles were included in this review for each of the three questions.  

So we’re going to start with the first question which has to do with incidence.  There were 60 studies that were reported in 72 articles.  Most of these were randomized controlled trials and most of them were funded by drug companies.  Five specifically looked at intensive versus standard control.  Only 12 out of the 46 randomized trials were rated as good quality.  Severe hypoglycemia was seen infrequently in studies of medications listed here, Metformin, Glinides, Detemir, TZDs, GLP-1 Analogs and DPP-4 inhibitors.

The highest rates were seen for insulin and Sulfonylureas.  For insulin there were two studies looking at NPH monotherapy with a total of 763 patients and in those studies combined the incidents of severe hypoglycemia was 9.3% over a weighted mean average duration of 31⁄2 years.  For Glargine there were three long term studies for two years and the incidents was 4.1% and there were five studies less than one year and the incidents was 1.6%.  For Lispro there were two studies, incidents of severe hypoglycemia was 3.6% over 1.3 years.  For the Sulfonylureas overall there were 13 studies that we pooled, total of 9,000 patients and the incidents of severe hypoglycemia was 1.2% over 2.3 years.

When you look at the intensive control studies, so these are studies that randomized people to either very intensive control of their glucose versus standard control, there were five of these studies overall the pool, the incidents of hypoglycemia, severe hypoglycemia again in the standard groups of 3.1%, it was 7.6% in the intensive group and this is over an average weighted follow-up time of about five years giving a relative risk of 2.4.  So people in the intensive randomized to the intensive groups were 2.4 times more likely to experience severe hypoglycemia than people randomized to standard control.  

However since most of the studies as I’ve just told you about were randomized controlled trials and many of them were drug company sponsored we decided to try to gain a more population based perspective on hypoglycemia incidents so what happens outside a randomized trial.  What happens in normal situations?  So we reviewed all the abstracts to find the articles with data for more representative groups. We did not include any drug clinical trials and we used more liberal inclusion criteria so we allowed studies that had fewer than 500 patients or lasted fewer than six months.  We used a definition of severe  hypoglycemia that was not quite as rigorous.  They hypoglycemia had to be symptomatic but it did not have to require the assistance of a third person.  And we also include studies that didn’t actually have true incidence data such as cross sectional survey where the “incidence data” has gotten by patient recall.  

So for this additional search we looked again at the 1914 excluded abstracts and the 320 excluded articles based on these new criteria I just showed you and we identified an additional 16 articles.  These 16 articles included 13 survey studies, five of these were six month studies in people on oral agents only and in these the incidents of symptomatic hypoglycemia was 1 to 13% and if you just counted hypoglycemia requiring medical assistance the incidents was 1 to 4%.  There were also three one year studies which were in patients on insulin only and the incidents of hypoglycemia requiring any assistance was 12 to 17% and was 2% for hypoglycemia requiring medical assistance.  There was only one prospective study which would have been – which is really the best study design, this was a one month community study based in Scotland, only 173 adults. They were asked to prospectively record the incidents of hypoglycemia requiring assistance and in one month it was 3%.  

In terms of VA-specific data four of our included studies were of VA patients.  Two additional VA studies did not meet our inclusion criteria or were published later but altogether these studies do suggest that VA patients may experience higher incidence rates than the general population.

The limitations for this – for this part of our study are that the data mostly came from drug companies sponsored trials, which enrolled highly selected patients and since they were not specifically designed to look at hypoglycemia there was probably some ascertain and bias.  The population based data that we looked at suffers from problems of patient recall and lack of standard definitions.  

So in summary for this question the incidents of severe hypoglycemia in people with diabetes on medications is about zero to 3% per year, it’s highest for insulin sulfonylureas and regimens targeting tight control we do need prospective population based studies both in VA and outside of VA to get a better handle on the true incidents.  

We’ll move on now to the second question which is what are the risk factors for severe hypoglycemia in adults with type 2 diabetes on one or more hypoglycemic agents, so this is the risk factor question. 

For this question we identified 31 articles on 28 studies.  We are only going to report on the 12 studies that use multi varied analysis.  These included two randomized trials, two cohort studies, four cross-sectional studies and four case controlled studies.  We did not include transient causes of hypoglycemia, for example missing a meal, excess exercise, alcohol use or acute infection.  All of the studies that we included met the pre-specified definition of severe hypoglycemia which was typical signs or symptoms requiring the assistance of a third person.  The data in this – for this question were not suitable for pooling because they would vary in lengths of follow-up.  Different studies evaluated different sets of risk factors in very different populations. So we were unable to pool the data.

These are all results. The independent risk factors consistently associated with risk of hypoglycemia include lower educational level in African American race.  A history of past low blood sugar.  Renal insufficiency.  Not renal microvascular complications such as neuropathy, dementia and longer diabetes duration.  Finally as we noted before intensive diabetes control is also a risk factor for hypoglycemia.

Here I’ve listed the independent risk factors that are not consistently associated with risk of hypoglycemia in the literature that we surveyed, gender, age and body mass index.  Although I will note that in the two largest studies higher age and lower body mass index were significantly associated with higher risk.  

And finally there’s a whole host of risk factors that have been thrown out there that really have been inadequately studied, this includes a history of, hypoglycemia unawareness, certain genetic markers, marital status, smoking, alcohol consumption, poly pharmacy, recent discharge from the hospital, congestive heart failure and use of Ace inhibitors.  So those – those are out there as possibilities but have not been rigorously evaluated.

So for this question the limitations are primarily a fear of publication bias, negative studies are unlikely to be reported so people may have done studies looking at potential risk factors and if the risk factors didn’t show an association with hypoglycemia they may not have been – they may not have been reported in the medical literature.  The risk factors that we did identify include lower education level African American race, past hypoglycemia, renal insufficiency, non-renal microvascular complications, dementia, longer diabetes duration, intensive diabetes control, possibly higher age and possibly lower body mass index.  

Our final question had to do with the consequences of severe hypoglycemia and this is how we conceptualize what an ideal study design would have been to answer this question.  You would assembly a cohort of people with diabetes who are on medication.  You would follow them up over time to see who developed a hypoglycemic event and who didn’t.  At the time of a hypoglycemic event you would note who had complications and who didn’t then you would continue to follow people over time and then at a certain period of time, probably years you would evaluate outcomes and compare outcomes in the people who did get hypoglycemic events compared to those who didn’t.  And you would basically have a relative risk. That would be an ideal study design.

So the features of that study that I just described to you would be – it would be a population based study, it would be prospective and it would be controlled meaning that people with diabetes on medications who did not have hypoglycemia would also be followed forward in time to look at their outcome.  Unfortunately most of the studies we found were very far from this ideal.  We found 59 articles on 53 studies.  We divided the consequences into two categories, complications at presentation and then long term outcomes including all cause mortality, cognitive impairments and quality of life.  

Complications at presentation, the best study that looked at this was published in the archives of internal medicine in 1997.  It was a retrospective cohort study of almost 20,000 Tennessee Medicaid enrollees, age greater than 65 who were taking oral hypoglycemics or insulin.  It was population based.  It wasn’t a prospective study but a retrospective cohort study is almost as good as a prospective cohort study and it did not include the control group.  So it included people with diabetes on medication, it followed them forward in time for the development of a hypoglycemic event and then it looked at complications that occurred at the time of the hypoglycemic event.  

So what did they find? They had 586 persons with a first episode of a serious hypoglycemia event that occurred outside the hospital and that resulted in an emergency room visit, a hospitalization or death.  5% of these episodes were associated with catastrophic complications including stroke or TIA, MI, injury and death in the percentages that you see here.  Terms of long term outcome, mortality the best data comes from the accord and advance study, these were large randomized controlled trials, even though they were randomized controlled trials they had liberal entrance criteria so that’s why I gave them a plus/minus on the population based criterion, they were prospective with long follow-up and they had a controlled group meaning they did follow forward in time people with no episodes of hypoglycemia to see what their death rates were.  

The bottom line on this is that severe hypoglycemia was associated with an increased risk of death in both accord and advanced and here’s the actual data.  You see down the first column the studies and then across the top you have mortality in the intensive and standard groups, subdivided into weather patients had hypoglycemia or not.  So if you just look at the web numbers that’s the incidents of death in people who did not have severe hypoglycemia so you see 1.2%, 1.0%, 1.8%, 1.9%.  So under 2% was the mortality for people who did not have an episode of severe hypoglycemia.  

Here on this slide we see the mortality in people who did have a history of severe hypoglycemia and again if you look at the red numbers in this table you’ll see that the numbers – ignore the 12.5% for now but you’ll see numbers about 2.8, 3.7, 3.6, 5.1 all higher than the numbers you saw on the last slide.  So there is an increase risk of mortality in both the intensive and standard groups in people who got severe hypoglycemia. The 12.5% is based on only one death out of eight people in the UK PDF trial so that’s not really very relevant.  

Moving on from mortality to other long term outcomes cognitive impairment was evaluated into two high quality cohort studies. Both of these were population based, only one of them was prospective, both had control groups.  However I’m not going to show you one of them which was 2009 because it was severely underpowered, it only followed 205 people for less than two years.

So really that leaves us with this study by Whitmer which was published in 2009, it looks at 16,667 patients with diabetes from a health care plan in California.  They followed them 3.8 years after an event, after an event of hypoglycemia to see whether there was developmental dementia or not and they did this in a group of 1,465 people who had one or more episodes of hypoglycemia.  So in that group of people with one or more episodes the risk of having dementia over 3.8 years of follow-up was increased by 68% compared to people who did not have any episodes of hypoglycemia and you can see the 95% confidence intervals there.  So there was a slightly increased risk of dementia in those with one or more episodes of hypoglycemia who were followed for almost four years.  

Interviewer:Hannah I’m sorry I just want to interrupt –

Dr. Hannah Bloomfield:In terms of other long term outcomes, quality of life was studied in eight cross sectional studies, five had one out of three of our quality indicators, two had two out of three and one had no – none of the quality indicators are not going to report on that one.  So here is the seven studies that had fairly decent quality that reported on quality of life.  And you can see that in all these studies if you look at the HRQOL, which means health related quality of life column there are down areas meaning that the health related quality of life was significantly worse in people reporting hypoglycemia compared to those reporting no severe hypoglycemia.  And similarly the degree of worry and fear in the – in people was significantly increased in those reporting severe hypoglycemia compared to those who had no episodes.  All these results are significant at least at the PD less than .05 level. 

In addition three of these studies looked at anxiety and depression and productivity and found that anxiety and depression were increased in people who had severe hypoglycemia compared to those who didn’t and it was also associated with decreased productivity.  

Accidents and trauma, we looked at but there were no high quality studies to report the large accord trial did note that there were no difference in the number of motor vehicle accidents in which the patient was the driver between the group that was intensively controlled and the group that just had standard control.  

So in summary for this question there is evidence that severe hypoglycemia decreases quality of life, is associated with increased mortality, may lead to cognitive impairment and increases hospital and ER utilization.  I didn’t show you that data but that’s in our report which you can look at if you’d like.  Limitations of this data is that there were very few high quality studies so more – more investigation in this area would certainly be welcome.  

So in conclusion patients with diabetes on medications have an increased incidents of severe hypoglycemia, it’s difficult to quantify exactly how high but it is not negligible. Several co-morbidities, demographic and treatment related factors increase the risks, severe hypoglycemia has a negative effect on quality of life and can lead to serious outcomes including death and intensity of glucose control is the risk factor most amenable to intervention.

National recommendations in 2011 the ADA stated that the goal A1C for most patients with diabetes should be less than 7%; however they’ve made an evidence based U-turn on this and most recently just a few months ago they came out with a new set of guidelines which advocated the more patient centered approach with a less stringent goal of 7.5 to 8 being appropriate for some people.  And their patient centered approach is illustrated here basically what they say is the glycemic control should be more stringent or less stringent depending on all these factors along the left side of the slide.  

So for more motivated and adherent patients you might have more stringent target A1C’s. For patients who are at high risk of hypoglycemia you should have less stringent.  Patients who have new diabetes you might want to be more stringent, where people with long standing diabetes you should probably be less stringent.  Life expectancy – a long life expectancy you might want to be more stringent, a short life expectancy less stringent.  If there are no co-morbidities you might tend towards a more stringent A1C.  If there is a person has few or severe co-morbidities probably less stringent is the wiser course.  Same thing for established vascular complications and finally depending on the resources and support system available to the patient you might want to change your target A1C based on that.  

Of course the VA is always ahead of everybody else and since 2010 the VA DOD guidelines have recommended what the ADA is just now getting around to, which is individualized goal based on co-morbidities, life expectancy, risk of hypoglycemia, presence of pre-existing microvascular complications and patient preferences.

So here is the guidelines for – that were published in 2010 which I believe are still the most recent guidelines and basically what the VA is telling us here is you should take into account life expectancy and presence or absence of microvascular complications and based on those two factors you should establish a goal A1C personalized for your individual patients.  Clearly you can see that in – for some patients a goal A1C of 8 to 9% is considered appropriate.

So at this point I am going to turn over the discussion to our discussion – discussants that’s Dr. Good on the left and that’s Dr. Pogach with I guess members of his team on the right.  If you have any further questions at any point in the future please feel – about this systematic review please feel free to contact me.  Thank you.

Interviewer:Dr. Good you should have just gotten the pop up on the screen, there we go.  

Dr. Good:I wonder if it would be possible to mute the background sound we’re getting?

Interviewer:Yeah I don’t know where – I’m – what I’m going to do is I’m going to mute everyone and then I’m just going to un-mute your line here.  Dr. Pogach I’m going to need you to pout your pin number in on your phone, it should be up on that dashboard on the right hand side of your screen, dial pound, your pin number and pound or we’re not going to be able to un-mute you.  Okay Dr. Good you should be un-muted.

Dr. Good:Thanks a lot.  Well Dr. Pogach and I were asked to provide a few comments about this systematic review and so first off we would like to congratulate Dr. Bloomfield and colleagues for an outstanding comprehensive review. We believe this review provides significant insights into the incidents of serious hypoglycemia and veterans with diabetes.   In addition the identification and risk factors for hypoglycemia is very important information to those clinicians treating patients with diabetes.  Because tight glycemic control is encouraged by many organizations without consideration for those at high risk for serious hypoglycemia, we remain concerned that the veteran population is very prone to this complication especially those patients with complex medical conditions as is often the case in VA.

We’d like to take a few brief moments to look at several of the landmark type 2 diabetes control studies as mentioned by Dr. Bloomfield in our response here.  So on the Accord trial which included VA sites in addition to non-VA sites found that severe hypoglycemia is associated with greater mortality in both the intensive and standard treatment arms.  Specifically as Dr. Bloomfield reviewed in Accord there was an increased mortality of 2.8% in intensely managed patients who had one or more severe hypoglycemic episodes compared to those with no episodes, that was 1.2% and this was statistically significant.  This pattern was also seen in the standard control group with even more advanced patients with severe hypoglycemia 3.7% versus 1% of those without hypoglycemia.

Likewise in the advanced trial severe hypoglycemia was associated with significant adverse outcomes specifically severe hypoglycemia was associated with significant increase in the adjusted risks of major cardiovascular events of hazard ratio approaching 3.  Major cardiovascular events were also increased hazard ratio of 1.8, death from a cardiovascular cause increase with hazard ratio of 2.68 and death from any cause hazard ratio 2.7.  

Similar associations were apparent for a range of non-vascular outcomes including respiratory, digestive and skin conditions and all of these were significant.  Of course in VA there are no more relevant data than that which come from well performed VA clinical trials.  The VA diabetes trial or VADT in keeping with accord and advance also found that hypoglycemia was a powerful predictor of cardiovascular death.  The hazard ratio was statistically significant at greater than four fold.  Also of no advanced age and prior cardiovascular events were also significant predictors of future adverse cardiovascular events.  

Thus all three of these landmark studies demonstrated an increased risk of morbidity and mortality from severe hypoglycemia, that is from Accord, Advance and VADT.  Association with adverse outcomes was greatest in those control arms with rather modest hemoglobin A1C’s achieved at 7.5, 7.0 and 8.4% respectively. The risk was greater in subjects with chronic co-morbid conditions.  Do we believe that it is unlikely that post hoc observational data sense will disentangle the relationship of hypoglycemia to outcomes specifically is hypoglycemia more likely to occur in patients already prone to serious adverse health outcomes or is hypoglycemia itself an independent risk factor?

We do know that many risk factors for hypoglycemia are common and indeed these risk factors maybe underrepresented in clinical trials.  Dr. Pogach recently reported in Veterans with diabetes under the age of 65 years of age that they frequently have risk factors for hypoglycemia, specifically 30% of these patients were on complex glycemic regimens, 5.4% have a decreased life expectancy, 6.3% had advanced complications, 9% serious medical conditions, 4.2% with serious neurologic conditions, 21.5% with serious mental health conditions and finally 28% met the definition for poverty and disability more than 50% was noted in 31% of the patients in that study.

So to summarize the veteran population is at high risk for serious hypoglycemia due to age and other risk factors both medical and socioeconomic. The incidents and prevalence of serious hypoglycemia is not likely to be known with greater certainty without weighted population health surveys.  Clinicians need to balance benefits of tight glycemic control with potential harms associated with hypoglycemia especially in vulnerable veterans.  Finally PBM, pharmacy benefits management group will address the issue of anti-glycemic safety among those high risk veterans in the near future.  

So to summarize again, thanks to Dr. Bloomfield and colleagues for their excellent work in those most significant issue for veterans and thank you also for the opportunities to comment.

Interviewer:And Dr. Pogach did you have any comments you wanted to make?

Dr. Pogach:No I want to thank again Minnesota for the ESP and Bernie for presenting, the only clarification I would make is that the 2010 VA guidelines we’ve actually been saying this since 1997 we pointed out that this is a way that type control – type control should be less than 7 only for younger health care people so we’ve really been about 15 years ahead of the – 15 years ahead of VA, not two years.  But it takes a while.

Interviewer:Great, thank you.  And for our audience I know I didn’t get a chance to say this at the beginning, we are taking questions if you do have any questions please use the Q & A screen in Go to Webinar to submit those questions into us.  Your Q & A screen is located on the dashboard on the right hand side of your screen, it may have collapsed against the side of your monitor; just use that orange arrow to open or collapse it against the side of your monitor, type the questions into us and I will be reading those over the call here.

The first question that we received here “Would you comment on alcohol use in hypoglycemia incidents”?

Dr. Pogach:This is Dr. Pogach, I’ll take a stab.  There are some studies, and I can’t remember the author right now from England actually where they could look at individuals who were transported to emergency rooms by the ambulances and clearly alcoholism, coupled with insulin is a high risk combination. The problem is and this is one reason why you will never know things with certainty is these are the types of indivuals, substance abuse, alcoholism, cognitive impairment, dementia, etc who we really can’t do surveys on but clearly it’s a problem.  

Interviewer:Okay thank you. The next question we have here “Are there data supporting A1C goals up to nine”?

Dr. Pogach: This is Dr. Pogach, I’ll try again.  The VADT study showed no overall benefit after nearly six years from a controlled value of 8.4 down to 6.9. The only benefit was actually a reduction in an increase in microalbumin to albuminuria but there was overall no improvement in the study.  So I think it would argue for the fact that given an A1C test is accurate within plus/minus about 0.5% that trying to maintain an A1C in the mid eights which gives you some breathing room on both sides can avoid more symptoms without compromising long term complications.   But again it’s an individual decision and choice, but it certainly doesn’t argue for less than 8% in individuals who are sick and have multiple complex conditions with decreased life expectancy.  

Interviewer:Great thank you.  Dr. Bloomfield did you – were you able to get your line un-muted?

Dr. Bloomfield: Yes I did, I’m un-muted.

Interviewer:Okay perfect.  I was wondering.  So perfect.  For our audience, that is all of the questions that we have received so far; this is a great opportunity for you to get your questions in and answered by our panel here so please do not be shy, feel free to send in any questions that you have for any of – for Dr. Bloomfield or for either of our discussants today; this is a great time to do that.  And also I’ll mention to our audience – well hopefully we’re getting a few more questions typed in here.  When you leave the session today you will actually have a feedback survey that will pop up on your screen when you leave Go to Webinar if you could take a few minutes to fill that out, we really do take into consideration the feedback that you give us after the sessions for our current and upcoming sessions.  Just take a few moments to fill that out, we would very much appreciate it.

Okay great we have another question here.  “For in-patient insulin protocols is there evidence to support that a detemir-based regimen results in less hypoglycemia in an NPH based protocol”?

Dr. Bloomfield:We excluded from our review all in-patient, this was exclusively an out patient and since I’m not an expert on diabetes treatment I don’t feel like I can answer that.  I don’t know whether Dr. Pogach can.  

Dr. Pogach:I think that the whole issue of, first off there’s clearly an issue of excess mortality from the NICE sugar trial and that’s why the concept of tight control in ICU’s was backed off on. I think there’s general consensus that a protocol given mechanism, nurse managed, is an effective way of managing individuals. Aside from that I’m not aware of any studies that would prove the superiority of one regimen over another.  But the general message is that tight control in ICU’s at this point is not recommended.  Again, something that the VA did not endorse even though the ADA and ACE had endorsed it.  

Interviewer:Great thank you.  The next question will there be training for the providers to help them choose the A1C targets for their patients?

Dr. Pogach:Well two things, we’ve had guidelines out for a very, very long time. We have scan echo from the office of some special trade and I think that’s very important.  We also have the PBM has performances training and there’s over I think 2,000 in the country who are an extremely valuable resource and I recommend that you contact them, but it’s really up to providers, primary care providers to have a discussion with patients about the risk and benefits of therapy.  And for the first time the ADA finally concurred with what we’ve been saying for 15 years so my question is it’s obvious that we need to back off and we will be coming up with a pocket card in the near future for nationwide distribution.  I think the key is to get the word out there, it’s like many other things in medicine like PSA test for example, why are we doing it all the time saying we have to do it instead of patient choice.  

Interviewer:Great thank you.  The next question is “Have any studies addressed any correlation between extent of DSME classes to incidents of hypoglycemia.  In the VA we offer  extensive DSME classes to our vets in the out patient care setting”?

Dr. Bloomfield:That’s a really good question.  I don’t believe that we came across any although our search was not specifically designed to look at that, but I think that’s a really interesting question.

Dr. Good:There is another evidence based systematic review of diabetes self management that was done for VA and I – Len I don’t know if you remember if they specifically addressed that or not in that document; I don’t have it here handy.

Dr. Pogach:I’m not aware of any studies.  I think that – I’m not aware of that specific issue being evaluated.  So again part of the concern would be some of the people who would be at greatest risk would be people who are elderly, serious mental illness perhaps in our system chronic cognitive impairment, dementia, chronic kidney disease.

Interviewer:Great thank you.  The next question how do we overcome PCP reluctance to accept these higher targets?

Dr. Bloomfield:Well that’s also a good question.  I think that – I think that one of the things that I don’t even think we mentioned here today is that I believe that the performance measure for A1C in VA is you know you only get dinged if it’s greater than 9 and correct me if I’m wrong so we have actually as opposed to the [HETIF] measures – we have a very reasonable performance measure in this area.  So I’m not – I’m not really sure why providers are reluctant to go along with this, it seems like an opportunity certainly for provider education.  I don’t know if anybody else has comments?

Dr. Good:I’m a primary care provider also and I can say I think it’s a combination of things, some of the times there is patient expectation too.  Patients come to us from the outside and they’ve had it drilled into them that their hemoglobin A1C has to be less than 7 and ideally less than 6 and they come with that expectation. And indeed there are some patients who that may well be a very reasonable goal.  I do think though that some of the – in the past some of the VA performance measures did drive that in and it’s so deeply ingrained that it’s like things like LDL and PSA’s and things like this, we learn these things, it’s what we’re comfortable with.  

I really think that – I really have liked that table that’s been in the VA/DOD guidelines which gives the different targets and for me the take home message is there are patients that we really should try to do better with controlling their glucoses and that’s where probably our energy should be and rather than taking patients that are high risk for harm, aren’t going to live long enough to – almost certainly aren’t going to live long enough to see any benefit that we should back off on those and put our energies into those patients that are likely to live longest, who are able to deal with tighter control in a safe manner.

Dr. Bloomfield:I guess I could make one other comment on this, I gave a grand rounds on this subject about a year ago and one of the things I did was ask people in the audience – I did this here at the VA and asked people in the providers in the audience what they thought – what they thought the performance measured goal for A1C was in  -- was in VA and almost none of them, everybody was into that less than 7 thing, even when we were – we had the 9. So I do think there’s a lot of misinformation out there from other sources.  It might be something that’s amenable to simple education.

Dr. Pogach:I’d like to make a preposterous proposal that the entire VA HSR&D committee including QUERI develop tools as a collaborative simply about absolute number needed to treat, number needed to harm, the difference between an RCT and perhaps over generalization and the fact the epidemiologic studies show association but not causality and that’s really mostly what professional societies and CME’s are showing.  I don’t know, what do you think –

Dr. Bloomfield: It sounds good.  

Dr. Pogach:Hold a spot for us?

Dr. Bloomfield: Absolutely.

Dr. Pogach:Great maybe by January?

Dr. Bloomfield: If not December.

Dr. Pogach:Okay good, nice Christmas gift, thank you.

Interviewer:Okay thank you. The next question we have here “Did you find what might be the best practices for treating hypoglycemia”?

Dr. Pogach:This is Dr. Pogach, prevention.  Don’t over treat people.  I think you need to have an understanding with the patient when you start – especially when you start insulin.  This is truly patient center care, don’t over treat people, look at their social context and try and avoid [inaud.]  

Dr. Good:This is Bernie.  I think one of the things that really struck me in reading this systematic review that Dr. Bloomfield’s colleagues did was that there are things that predict these patients who are patients that are at risk and the one thing that keeps coming up is patients who have had hypoglycemia already, that’s a powerful predictor in addition to other things.  So you know I think my take home point is that when we see these patients that come in with their home glucoses and they bring in their machine and you see that they had a 40 and you ask them were they symptomatic and “yes they were” that should be a call that we need to step back and reassess our treatment regimen. Maybe really tight glycemic control is still important in that person but it really should sound an alarm that we really need to go back and rethink things and take those episodes very, very seriously because obviously they’ve done okay but now we want to prevent this in the future.

Interviewer:Great thank you. The next question we have here “Do you have any ideas for future research in this area even if it is retrospective in nature”?

Dr. Bloomfield:Well I think you can – I think there’s probably an opportunity to do a retrospective cohort study. The Tennessee study that I put up there which was a Medicaid study and it was a retrospective cohort study and what that means is the study is done after everything, all the data has accumulated but you identify your population as the population at risk at a certain time point and then you follow them forward for events.  So that’s what a retrospective cohort and it’s a pretty – it’s a pretty robust design but it can be done at one point in time without waiting that long.  And VA has a lot of data bases so that was done as you all know – so that was done in Medicaid and that was published in 1997.  So you know it might be interesting to do that kind of retrospective cohort study in VA data.  I think there may be some people at Bedford who, at the Bedford Health Services Research Center who are doing things like that, but that would be one thing to think about.  

You could also do that kind of retrospective cohort design to look at cognitive impairment associated with hypoglycemia in VA.  Those are just a couple of things that come to the top of my mind.   

Interviewer:Great thank you.  The next question we have here it seems that the default glycemic goal is less than 7% for patients and relaxing when indicated.  When it seems the default goal should be less than 9% and tightening if or when the patient and the provider have chosen that.  Can you suggest practical ways for VA to change that dynamic”?  

Dr. Pogach:The statement is a complete mis-representation with what our guidelines say so I would recommend that everybody review the guidelines which are on the VA quality performance web site and perhaps we can send an e-mail out after the conference call. But I think that we’ve always advocated to pick a target within a range, not a dichotamous measure that represent a sense of benefit and harms in the absence of validated risk engines that sort of has to be evaluated in collaboration with the patient.  

So it’s not a default of less than seven, nor default of less than 9; it’s really trying to sit down and deciding what an appropriate target is, noting that the values aren’t accurate.  A single test of 7.0 from a high quality lab could be plus or minus 0.5%, it’s not – this is not a disputable fact, took the VA/DOD pictogram developed by Dave Arin and has it on their clearinghouse and then you try to guide a patient to sort of achieve a target that you agree upon mutually through shared decision making over time recognizing it’s going to vary.  I think we need people to be clinicians again.

Interviewer:Thank you.  The next question that we have here “Are you familiar with the study of 7030 versus Detimer, the study was done in hospitalized non ICU population patients; if so do you think the study is a good study or flawed because of the incidents of hypoglycemia”?

Dr. Bloomfield:I’m not familiar with that study, we didn’t look at any in-patient studies for this review.

Interviewer:Okay thank you. The next question then is “Do any of you use Kate Lorig self management program for veterans in your VA”?

Dr. Bloomfield:I don’t know.

Dr. Good:No idea.

Dr. Pogach:Yeah.

Interviewer:Okay thank you. The next question then “Is there any plan to make the clinical reminder for targeted patient centric A1C goal a required reminder rather than optional”?

Dr. Good:I think local sites can do whatever they want.  I don’t think we have any ability from this group to instill national reminders. 

Interviewer:Thank you, the next question “Will the providers or pharmacists be encouraged to instruct veterans on effects of hypoglycemia when initiating any of the meds that could potentially cause hypo such as the rule of 15 for treatment for hypo and making sure vets are aware of symptoms”?

Dr. Pogach:We educate every patient placed on any medication for potential harms and how to manage them; isn’t that what we should be doing for a living?

Dr. Bloomfield:It should be; yes.

Dr. Pogach:I mean I hate to – why can’t we be clinicians again and practice clinical medicine?  I mean you put someone in medication isn’t it our obligation for someone on the team to instruct patients what to look for?  I mean do we need to mandate everything; have we gotten that stupid?  I’m sorry I’m – for being a bit cynical but this is medicine in general guys –

Dr. Good:Len the only thing that I might add though is that I think – at least as a primary care provider I think I’ve become much more respectful of hypoglycemia and the concerns of it and so it may be that we sort of – the expected that in patients who are being treated with hypo – with diabetes that there would be hypoglycemia so yes, we tell them how to manage it or whatever.  But it may be that we need to have a heightened concern for it and tell our patients if they have any problems you need to contact us and let us look at things, look at your diet, look at how you’re – when you’re eating, how you’re eating and then look at your regimen and make the appropriate changes to obviate that problem.

Dr. Pogach:I don’t disagree but remember you have armies of educators out there and I understand that primary care may not have time to sit down with individual patients and go over things like exercise, diet, missing meals, etc. but really having – and again this is operating, you don’t need a CDE to go over the basics.  Probably every team should be able to handle this.  

Interviewer:Okay thank you. The next question we received, “Instead of hypoglycemia leading to dementia was it considered that dementia may lead to hypoglycemia”?

Dr. Bloomfield:It was indeed; that’s an excellent question and they – I believe that was investigated actually in the study I sited or at least in some of the studies that we looked at so that was always a problem and that’s why you do need prospective studies or at least retrospective cohort studies to try to disentangle that.  There is dementia as you probably noted also showed up on my slide as a risk factor for hypoglycemia so you do need to be very methodologically careful when you’re looking at that relationship, absolutely.  

Interviewer:Thank you.  The next question here, “The VA – some of these are not easily written, “The VA had changed the type of oral glucose to treat hypoglycemia if juice is not available from 15g to 24g to formulate which is different from the role of 15/15; how do you feel about this since it does not impact what we had done and is the golden rule”?  I apologize if that didn’t make sense.

Dr. Bloomfield: I’m not familiar with that rule in the VA.

Dr. Good:I’m not aware we have a specific policy on treating hypoglycemia but I would recommend that you might want to contact Dr. Sharon Watts on outlook who is a nurse practitioner in Cleveland who is – might be able to help you with that answer.  

Interviewer:Thank you and one last question here, “Just for clarification does the risk of complications increase when A1C levels are greater than 8.5 or is it 9.0”?

Dr. Pogach:The issue is it really is a matter of glucose exposure over time so from – and it becomes linear especially over 9 it becomes linear probably below 8 but it’s really for how long you have a higher level, so if you’re life expectancy is going to be very long and probably let’s say over 10 years I think that you can go for lower targets.  But remember the major finding that drove the study was laser therapy over a 10 year period; the number needed to treat to prevent an amputation was something about 1500 or 1700 and the number needed to treat to prevent a case of doubling of creatinine or worse was probably about 5000.  So it’s a matter of how high over how long which is why our guidelines emphasize life expectancy.

Interviewer:Great thank you. That is all of the questions that we have. Would any of you like to make any final remarks before we close out today?

Dr. Bloomfield:Not I.

Dr. Pogach:Thank you very much Dr. Bloomfield and Dr. Good.

Dr. Good:Thanks to everyone who dialed in; it’s nice to have all the questions and back and forth.  It’s been great, thanks.

Interviewer:Thank you to Hannah and Bernie and Len; we really appreciate the time that you put in to putting this together and presenting today. Obviously we have a lot of interest in the field so we really appreciate the time and effort that you put into this, for attendees thank you for joining us today and this will conclude today HSR&D cyber seminar.  Thank you.

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