Endodoc

In my last entry I discussed the rather contentious topic of how physicians order/should order laboratory tests.  I say “contentious” because lately there has been intense scrutiny by governmental agencies, physician specialty groups, and the like, to  cut down on the extraordinary health care costs in the U.S.  Anyway, just the other day, it was brought to my attention that I had not addressed the question of what to with the test result.  Last weekend, I was grading medical student tests (one of my least favorite pastimes).  At our medical school, the curriculum is so-called “problem-based.”  This means that for the most part, teaching is tied to problem-solving rather than to the classic approach of mostly lectures for the first 2 years and then, exposure to patients and their problems.  I think the curriculum is good but in my opinion, its one serious downfall is that even the tests are problem-based, that is, essay questions about a clinical problem.  So there I was last weekend, grading 300 long essays.   The details of the case are not important- the patient likely had a stroke.   The clinical documentation included a brief medical history, a physical examination, and results of the initial laboratory tests ordered in the emergency room.  The results for 2 of the many ordered tests (I believe most of the tests were ordered appropriately) were abnormal;  the serum sodium level was just below the lower limit of normal while the serum calcium level was just above the upper limit of normal.  I was fascinated by the different approaches students took in problem-solving the 2 minimally abnormal test results.  About 25% of the students (these were end of third year students who are  supposed to be pretty savvy) acknowledged the abnormal calcium and sodium results but noted that the results were barely out of the normal range and that they would probably just repeat the tests at some point and that these findings were not likely related to the patient’s primary problem.   A few of the students, never mentioned the test results while most of the rest gave the sodium and calcium results the kind of attention one would give an EKG that showed a serious cardiac arrhythmia- they wrote and wrote what the tests results might mean and what further testing they were going to do.  So how come, only about 25% of the students knew how to approach the sodium and calcium results correctly but the rest were way off course?  That’s what I want to discuss a bit in this entry.

What Does a “Normal Range” Mean?

I do not want to get all technical here, but what goes into establishing a normal range (really called ” reference interval) is rather complicated and is heavy into statistics.  I will try to keep it simple.  Basically, every laboratory is supposed to establish its own  reference interval for every laboratory test it performs.  Every pathologist and clinical chemist knows how this is supposed to be done.  One takes x number  of people (usually 50-100) who are presumably normal with respect to the test in question, and performs the test on them.  A mean value is calculated as is the normal range (usually the mean +/- 2 standard deviations or SD).  If the test values follow a “normal” distribution (you know the familiar bell-shaped curve), then the mean +/- 2 SD comprises about 95% of values in a healthy population.  In statistical terms, this means that out of 100 normal people, 5 individuals are likely to have their test results either above or below the 2 SD reference interval.  I told you this was complicated.  All you need to know is that people who are entirely normal have a reasonable chance of having a laboratory test result that is outside the reference interval.

Do All Laboratories Calculate Their Own  Reference Intervals?

Many laboratories actually do not calculate their own  reference intervals although as far as I know, all large commercial laboratories do this.  It is quite a bit of work and a small laboratory in a hospital or in doctor’s office is not going to want to mess with it.  Instead, they use either the  reference interval that comes in the packaging with the test kit they use or use some published reference interval.  Unfortunately, even if the laboratory does a great job in performing the test, the test results may not fit so well with the reference interval the laboratory uses.  For example, if the published serum free thyroxine level normal reference interval is 1.1 ng/dl +/- 0.5 (mean +/- 2 SD) but if the laboratory normal reference interval is actually 1.3 ng/dl +/- 0.5, many reports will be interpreted by the ordering physician as either normal or abnormal when the opposite is true.  Another important example is HbA1c, the test that quantifies average plasma glucose over the previous 2-3 months and is now widely used to screen for/diagnose diabetes or glucose intolerance.  A level 6.5% or greater is considered diagnostic for diabetes but only if the test is performed in a laboratory that has test results aligned (basically standardized) to those in the Diabetes Control and Complications Trial (DCCT) Reference Laboratory.  That approach obviates the need for the laboratory to establish its own reference interval (I still think it is a good idea for the laboratory to do that if it is at all practical).  I didn’t even mention the fact that for many laboratory tests there are age and sex differences in the  reference interval.  If this is not appreciated by the physician, serious errors in interpretation of the test result can be made.  For example, serum alkaline phosphatase is much higher in growing children than in adults.  In a child, a serum alkaline phosphatase of 300 U/L might be just fine, while in an adult it likely means either liver or bone disease.

Back to the Slightly Elevated Serum Calcium and the Slightly Low serum Sodium

In the “real” world, not the world of medical student tests, physicians must frequently figure out what do do with a test result that is outside the reference interval.  First, as I discussed in my earlier entry, no test should be ordered without a good reason.  Second, the test result must be reviewed and interpreted; some physicians are so busy that they often do not even look over the tests they have ordered or just scan them, looking for the test results listed as “out of range.”  Sometimes a test result is abnormal yet it falls just inside the reference interval.  Remember, just because a test result is outside the reference interval it is not always abnormal, that is, related to some medical problem.  In much the same way, just because a test result is inside the reference interval, that does not mean all is well.  Borderline low and high test results need to be scrutinized.  Maybe they mean something and maybe not.  That is more of the art and science of medicine.  How do medical students learn about these things?  I am not sure.  Based on the test I just graded, maybe we do not do such a good job in teaching them either how to order tests in an artful and scientific way and in figuring out what to do with the test results.

The Most Important Part of Sorting Out Test Results

In my opinion, arguably the most important part of interpreting laboratory test results is sharing the information with the patient and discussing what the results might or might not mean.  In this age of electronic medical records, e-mail, etc., I am amazed at how many otherwise excellent physicians do not have a systematic method of keeping track of what tests they have ordered for their patients and what the test results turn out to be.  Worst of all, they do not have a systematic way of getting in touch with their patients to let them know what the test results are and what it all means.  All patients deserve to be “in the loop.”

For years, I have found it fascinating that if two patients with virtually identical clinical circumstances go to two different physicians who have similar medical training, the patient management plans often differ considerably.  For example, let’s say that both patients are 14 year old females with histories of fatigue and weight gain over the previous 6 months.  Let’s also say that both physicians obtain excellent medical histories and perform equally excellent physical examinations and find no specific clues to the reason for the patients’ signs and symptoms.  Both physicians then consider the likely possibilities and formulate plans.  At this point, the physicians take somewhat different approaches.  The first physician, Dr. Jones  decides to order a few basic laboratory tests such as a blood count, urinalysis, and, perhaps, a thyroid profile (maybe a free T4 and TSH), planning to see the patient back for follow-up in 3-4 weeks.  The second physician, Dr. Smith,  also decides to order some laboratory tests; perhaps the same tests that the first physician ordered but in addition,  a fasting lipid profile, a pregnancy test, a metabolic panel (various tests of blood chemistries, liver function, etc), HbA1c (a test for diabetes mellitus), Serum insulin (to evaluated the patient for insulin resistance and, perhaps the metabolic syndrome, a 24-h urine for free cortisol (to rule out Cushing’s disease), an EKG and chest X-ray (to look for heart disease), and a nutrition consult.  The physician also plans to see the patient back in 3-4 weeks.  So, how is it that Dr. Jones orders a few basic studies,  while Dr. Smith orders many more tests (as well as a consultation).  Certainly, the costs for the visits differ significantly, by about $500-$1000.  Which physician is right?  Are they both right?

Do Physicians Order Unnecessary Laboratory Tests and Procedures?

There are endless data, especially in the past few years, to show that as a group, physicians order far too many laboratory tests and procedures.  The recent interest in this phenomenon is to a great extent related to efforts to bring some measure of control to U.S. health care costs.  For example, a recent report in the New York Times  addressed the question of laboratory tests and procedures, focusing on a report by 9 major medical specialty groups in which 45 tests and procedures that have no proven benefit to patients were  listed.   The newspaper article was entitled “Endless screenings don’t bring everlasting health,” and was written by Lisa Schwartz and Steven Woloshin.  There has also been a measure of pressure brought to the question of whether physicians who own a stake in a laboratory, order more tests (performed in the physician-owned laboratory) than those who have no financial interest in ordering the test other than, perhaps, a charge for interpreting the test result (see “Doctor’s stake in a lab affects biopsy rate, ” written by Mitchell, JM., in Health Affairs, April 2012).  To me, the most interesting data are those from a study carried out a few years ago in which the investigators studied whether physicians ordered fewer tests when the prices of the test were listed on the order form.  As it turned out, when the prices were listed, doctors actually ordered about 20% fewer tests.  Clearly they didn’t “need” those tests, but just wanted them.  That’s the good news.  The bad news is that after a year, when the prices were taken off the ordering form, the docs, reverted to their original ordering behavior.  Recent studies have found very similar results.  For example,  hospitalists at the Johns Hopkins Hospital in Baltimore studied how often common but expensive laboratory tests were ordered with or without the cost of the test listed (“Knowing costs affects lab test ordering“).  They found that over a 6-month period November 2009-May 2010, there was an average decrease of about $16,000 billing per test when costs were displayed on the order form compared with a 6-month period 1 year earlier.  This was just for one hospital.  The investigators, led by Dr. Leonard Feldman, concluded that much of the reason for the excessive test ordering was simply a lack of awareness of how much tests cost.  The investigators acknowledged that they did not have any data to show that patients’ outcomes were not affected adversely by stingy testing.   So, the excessive ordering is not always related to to either personal financial benefit or other factors such as medico-legal concerns.  What is it due to?  Beats me, but I think it is to a great extent a “reflex” action and one of convenience- if I order everything I might need right now, I will know what’s what sooner. That’s just my theory.  It might be mostly a question of personality- those docs who require immediate gratification vs. those who can tolerate waiting for answers?  We can gain some insights from a recent study entitled, “Why do physicians order unnecessary preoperative tests? A qualitative study,” written by SR Brown and J Brown (Family Medicine 2011;43:338-43).  the investigators interviewed 23 physicians and nurse administrators and found that the main reasons for ordering unnecessary tests were as follows: practice tradition, belief that physicians wanted the tests performed, concern about medicolegal issues, concern about possible surgical delays, and lack of awareness of evidence and guidelines.

How Should Physicians Order Laboratory Test and Procedures?

I do not believe most medical students and resident physicians are taught the “art” of ordering laboratory studies and procedures.  That gap in training is to some extent, related to the fact that many of the patients seen by students and resident physicians have either acute illnesses where time is of the essence or are patients for which reliable follow-up is quite uncertain.  So, it’s sort of “catch while catch can.”  In the real world, physicians are generally not in such a rush and they would do well to stage their testing unless the situation is urgent.  Why order every test you might need at the first encounter when starting with a few simple basic tests would suffice?  Sometimes, I hear that the blitz is performed because it causes less inconvenience for the patient- they won’t need to come back for a test that is needed based on the initial basic testing.  In my opinion, that argument is nonsense.  It certainly makes no economic sense.  If one is worried about the possible need for another venipuncture, extra blood can be drawn initially and stored, to be assayed as needed.  Laboratories do it all they time.  That’s what freezers are for.

Another side of the question of what to order, is the importance of explaining to the patient exactly what tests were ordered and why.  Many physicians just do not take the time to explain this to their patients.  Maybe, sometime the docs just don’t know exactly why they ordered what they ordered?

Finally, there is the question of letting the patient know what the tests showed and what it all means.  I am astonished how many physicians have no organized way to communicate test results with their patients.  It is really shameful.  Have any of them ever heard of e-mail or even the U.S. postal service?  In my view, if a physician takes the time and trouble (for the physician and patient) to order a laboratory test or procedure, the least the doc can do is get back to the patient with the test result and interpretation/plan in timely fashion.  Some physicians are super at this task and some are horrible.

The Future

It will be interesting to see how much pressure is put on physicians various “expert panels,” insurers, and governmental agencies (e.g., Medicare, Medicaid) to cut back on ordering tests?  It is already happening, particularly for various screening studies.  I do worry that some of our patients will suffer because of ill-advised recommendations based on epidemiological data (the kind that look at how many people we need to screen for this or that disease to save 1 life or to detect 1 cancer.  Good medical care is not always about maximum cost effectiveness.  But, there is no question that we as physicians could do better in the way we order laboratory tests and how we use the results to guide our therapies.

A number of months ago (September, 8, 2011) I wrote an entry about risks vs. benefits in treating medical disorders.  I used as an example the “story” about diethylstilberterol or DES which was used to treat women to prevent miscarriages and was years later found to cause vaginal carcinoma in daughters of these women.  The moral of the story was that the risks, including unknown risks must be worth the potential benefit of the treatment whatever the condition.  Here we go again- this time it’s about growth hormone.  12/22/2010, the FDA issued a Drug Safety Communication entitled ” Ongoing safety review of Recombinant Human Growth Hormone (somatotropin) and possible increased risk of death.” (www.fda.gov/Drugs/DrugSafety/ucm237773.htm.htm).  The FDA announced that a study conducted in France called the Sante Adulte GH Enfant (SAGhE) study, found that some patients treated with growth hormone injections for diagnoses of idiopathic short stature, idiopathic growth hormone deficiency, and gestational short stature (intrauterine growth retardation) showed increased risk of death compared to individuals in the general population of France.  At the time, the U.S. Pediatric Endocrine Society notified all members about the study and emphasized that the study results were only preliminary and that more data would follow.  Pediatric endocrinologists were urged to continue to treat their patients with growth hormone injections as before, pending further study results.  08/04/2011, the FDA issued an update (www.fda.gov/Drugs/DrugSafety/ucm265865.htm) that it was reviewing the SAGhE study and had found some potential flaws in the study design but that further data were expected in the Spring 0f 2012 and that health care professionals should continue to prescribe and use recombinant growth hormone according to the labeled recommendations.

What’s the latest?

Just today, I got a memo from the Pediatric Endocrine Society that the SAGhE study results had been published along with 3 editorials/commentaries about the study.  I want to call the study results and the editorials and commentaries to your attention.  The bottom line from the study data is that mortality rates were increased about 30% in adults who  had been treated with recombinant growth hormone as children.  The study population included almost 7000 subjects who started treatment between 1985-1996.  The increased mortality was mostly related to cardiovascular and bone tumor causes.  The investigators stressed the need for additional studies of long-term mortality and morbidity after growth hormone treatment in childhood.  The editorials/commentaries were written by noted authorities in the U.S. and Europe and generally supported the need for further studies and basically recommended one of two approaches- either, be careful to make certain that until more data were available that patient selection for growth hormone treatment include a careful risk/benefit assessment, or, full speed ahead while we await more data.  I will offer no comment regarding which of the two “camps” I am in.  It’s all pretty creepy.  I do remember that when the first cases of vaginal cancer in daughters of DES-treated mothers were reported and when the first case of Creutzfeld-Jacob disease in a young adult treated with cadaveric human growth hormone surfaced, many “experts” were not much impressed with the preliminary data.  I hope it’s not those stories all over again, but this time about recombinant human growth hormone.  No matter what the study shows when all the dust clears, we as health care professionals must not forget that even unknown risks must be factored into risk/benefit assessments no matter what the condition.

References:

Carel J-C, et al: Long-term mortality after recombinant growth hormone deficiency or childhood short stature: preliminary report of the French SAGhE Study.  J Clin Endocrinol Metab 2012;97:416-25 (February 1, 2012).

Sperling MA. Editorial:Long-term therapy with growth hormone: bringing sagacity to SAGhE. J Clin Endocrinol Metab 2012;97:81-3.

Rosenfeld RG, et al. Commentary: Long-term surveillance of growth hormone therapy. J Clin Endocrinol Metab 2012;97:68-72.

Malozowski S. Editorial: Reports of increased mortality and GH: will this affect current practice? J Clin Endocrinol Metab. 2012;97:380-83.

FYI: There is a very important (and interesting) article in the NYT today.  The piece is entitled “Food for thought” and was written by Jeff Gordinier.  Basically, the article reviews the idea of “mindful eating” a concept that most likely comes from a book written by Brian Wansink, entitled “Mindless eating: why we eat more than we think,” published a while back by Bantam books.  Dr. Wansink is a professor of marketing at Cornell University in Ithica , NY.  As an aside, I am excited that he will be coming to the University of Missouri to lecture at our annual Bond Life Sciences & Society Symposium March 16-18, 2012 (the conference is called “Food Sense”).  Anyway, the NYT article  discusses in considerable detail the concept of thoughtful eating as a way to both enjoy eating more and perhaps, to eat healthier.  Don’t be put off by the rather Buddhist bent to the discussion.  Trust me, it’s good stuff and we would all benefit from reading the article and putting the advice to work for ourselves.

If you find the NYT article interesting, I strongly recommend that you consider tracking down a copy of Professor Wansink’s book (it’s only about $3.00 new on Amazon) and learn something about the psychology of how we eat, particularly why we all eat so much (mostly too much!).  Professor Wansink is the one who did all those fascinating studies about the effects of the size of the container (e.g., glass or plate) and how much we consume.

In deciding what to write about, I try my best to steer clear of the political side of medicine.  But, today’s NYT has 3 articles that I just couldn’t ignore.  Basically, all three are opinion pieces that address from different directions, one of the most important problems facing U.S. health care, the question of cost.  The first piece was entitled, “What we give up for health care,” and written by Ezekiel J. Emanuel, the brother of Chicago, Illinois major, Raum Emanuel.  The second piece was entitled, ” The dangerous notion that debt doesn’t matter,” and written by Steven Rattner, a Wall Street executive.  The third piece was entitled, “The money traps in U.S. health care,” and written by Philip M. Boffey.

Basically, the Raum and Boffey articles opine on the fact that U.S. health care costs are extraordinary and that if we do not find a way to bring costs down quite a bit, we will have very difficult decisions about what other things we hold near and dear (e.g., education, infrastructure, national defense) that we will need to cut back on.  The Rattner article focuses on the long-term dangers of high U.S. debt.  I found the data in the Bossey piece on comparative costs for various medial services in Britain, Canada, France, Germany, and the U.S., particularly interesting.  For example, the average cost for cataract surgery in the U.S. (public and private sector) at $14,764 beats the closest competitor by $11,412.  It is truly breathtaking how much we in the U.S. (physicians, hospitals, and clinics) charge for routine medical services relative to the rest of the world, particularly since our outcomes are not generally superior to outcomes elsewhere.

In my opinion, based on my reading of the 3 articles in the NYT, at some point, the U.S. will have to go on a health care cost diet.  I predict the diet will be very difficult for us (the general public and the health care providers) to start and to follow.  How in the world will we be able to keep all the stakeholders reasonably happy with the process and the result?  This is scary stuff.

I will be giving a lecture to the Family and Community Medicine Department resident physicians at the University of Missouri Health Sciences Center in a few days.  I thought I would post the lecture outline which includes what I think are important references about diabetes care.  It is interesting that in preparing the talk, I looked over some of my notes from previous talks to the same group.  The oldest talk was in 1979 and the most recent, in 2009.  I was surprised how little things have changed over the past decade in terms of new and important information on diabetes patient care.  Maybe that’s because we made so much progress in the 1980s and 90s?  Anyway, I was a bit surprised.  I do have one minor correction to make to the outline- in the table on medications for patients with type 2 diabetes, just the other day, the FDA rejected the drug dapagliflozin, a sodium-coupled glucose co-transporter inhibitor (see reference 22).  I don’t know why the drug did not get FDA approval but I suspect it was because of so little long-term data on side-effects.

The ABCs of Diabetes Mellitus

1. What is Diabetes Mellitus: Insulin deficiency; Hyperglycemia; Chronic Complications

2. Classification: Type 1 diabetes (B-cell destruction, usually leading to absolute insulin deficiency); Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance); Other specific types (genetic defects of B-cell function, genetic defects in insulin action, diseases of the exocrine pancreas, endocrinopathies, drug or chemical induced, infections, uncommon forms of immune-mediated diabetes, other genetic syndromes sometimes associated with diabetes); Gestational diabetes mellitus

3. Diagnosis

1. HbA1c = or >6.5%.  The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.*
2. FPG= or >126 mg/dl (7.0 mmol/l).  Fasting is defined as no caloric intake for at least 8 h.*
3. 2-h plasma glucose = or >200 mg/dl (11.1 mmol/l) during an OGTT.  The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.*
4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose = or > 200 mg/dl (11.1 mmol/l).

*In the absence of unequivocal hyperglycemia, criteria A-C should be confirmed by repeat testing.

4. Initial Presentation

1. Type 1 diabetes
2. Type 2 diabetes

5. Initial Management

1. Type 1 diabetes
2. Type 2 diabetes

6. Ongoing Management

1. General Principles/Care goals: Best outcomes with comprehensive, well-organized, patient-centered approach; General care goals: HbA1c <7%; LDL-cholesterol <100 mg/dl; blood pressure <130/80

7. Monitoring for Complications/Associated Disorders

Retinopathy

Nephropathy

Neuropathy

Cardiovascular diseases

Autoimmune disorders (in patients with type 1 diabetes): thyroiditis, pernicious                            anemia, celiac disease

8. Screening for Diabetes?

9. The Future?

References:

1. American Diabetes Association (ADA) Clinical Practice Recommendations.  On an annual basis, the ADA publishes diabetes care recommendations in the journal Diabetes Care (www.diabetes.org/diabetescare).  This very useful resource is updated every January.
2. www.endodoc.org.  This is my medical blog and it contains quite a number of entries on various aspects of diabetes care as well as other endocrine and health care topics.
3. Gwande A: The bell curve.  What happens when patients find out how good their doctors really are?  The New Yorker, December 6, 2004, p 82-91 (www.newyorker.com/archive/2004/12/06/04).
4. Ishani A et al: Effect of nurse case management compared with usual care in controlling cardiovascular risk factors in patients with diabetes: a randomized controlled trial.  Diabetes Care 2011;34:1689-94
5. Hu Y et al: Short-term intensive therapy in newly diagnosed type 2 diabetes patients partially restores both insulin sensitivity and B-cell function in subjects with long-term remission. Diabetes Care 2011;34:1848-53
6. Fajans SS, Bell GI: MODY: history, genetics, pathophysiology, and clinical decision making. Diabetes Care 2011;34:1878-84.
7. Nathan DM et. al.: Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy.  Diabetes Care 2008;31:1-11.
8. The Action to Control Cardiovascular Risk in Diabetes Study Group (ACCORD): Effects of Intensive Glucose Lowering in Type 2 Diabetes.  N Engl J Med 2008;358:2545-59.
9. The ADVANCE Collaborative Group:  Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes.  N Engl J Med 2008;358:2560-72.
10. Nathan DM, et. al.: Impaired fasting Glucose and Impaired Glucose Tolerance: Implications for Care.  Diabetes Care 2007;30: 753-9.
11. Diabetes Prevention Program Research Group.:  Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin.  N Engl J Med 2002;346:393-403.
12. DCCT Research Group:  The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-term Complications in Insulin-Dependent Diabetes Mellitus.  New Engl J Med 1993;329:977-86.
13. DCCT-EDIC: Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med 2000;342:381-89.
14.  DCCT/EDIC Public Website: slides can be obtained 6 months after publication of data.  http://www.gwu.edu/Edic/.  In addition, Susan Hitt the DCCT/EDIC Study Coordinator (Hitts@health.missouri.edu) can furnish you with a full list of DCCT/EDIC publications, abstracts, and presentations.
15. UKPDS: Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Diabetes Study (UKPDS) Group.  Lancet 1998;352:837-53.
16. UKPDS: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.  Lancet 1998;352:854-65.
17.  National Glycohemoglobin Standardization Program (NGSP) website: http://www.ngsp.org.
18. Goldstein DE et. al.: Tests of Glycemia in Diabetes.  Diabetes Care 2004;27:1761-73.
19. Sacks DNB et. al.: Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus.  Clin Chem 2002;48:436-72.
20. Nathan DM et. al.: Translating the A1c assay into estimated average glucose values. Diabetes Care 2008;31:1473-8.
21. Gilbert RE, Marsden PA.: Activated Protein C and Diabetic Nephropathy.  N Engl J Med 2008;358:1628-30.
22. Nauck MA et al: Dapagliflozin versus glypizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin.  Diabetes Care 2011; 34:2015-22.
23. Bunck MC et al: Effects of exenatide on measures of B-cell function after 3 years in metformin-treated patients with type 2 diabetes.  Diabetes Care 2011;34:2041-47.
24. DeFronzo RA et al: Pioglitazone for diabetes prevention in impaired glucose tolerance.  N Engl J Med 2011;364:1104-15.

TABLE 1. Medications for Patients with Type 2 Diabetes

Insulin

Medications that stimulate insulin release

1. Sulfonylureas (SURs): Advantages- long-term experience, inexpensive, oral administration; Disadvantages- weight gain, ?increased risks for cardiovascular diseases, hypoglycemia
2. Glinides (e.g., repaglinide, nateglinide): Advantages- shorter-acting than SURs, only occasional hypoglycemia; Disadvantages- expensive, GI side-effects, weight gain

Medications that enhance insulin action

1.  Incretin mimetics (glucagon-like peptide agonists, or GLP-1 agonists such as exenatide): Advantages- weight loss, infrequent hypoglycemia, can be given weekly; Disadvantages- expensive, requires injections, frequent GI side-effects
2. Incretin sustainers (dipeptidyl peptidase-4 inhibitors or DPP4 inhibitors such as sitagliptin): Advantages- oral administration, rare hypoglycemia; Disadvantages- costs, GI side-effects
3. Amylin-like agents (e.g., pramlintide): Advantages- ?weight loss; Disadvantages- hypoglycemia, injections tid, costs
4. Thiazolidinediones or TZDs (e.g., pioglitazone):Advantages- improved lipid profiles, no hypoglycemia, ?prevent/slow loss of insulin secretory capacity; Disadvantages- costs, weight gain, fluid retention and heart failure

Medications that inhibit glucose absorption from the gut or reabsorption from the kidney

1. Alpha-glucosidase inhibitors (e.g., acarbose): Advantages- ?weight loss; Disadvantages- costs, GI side-effects (frequent), tid dosing
2. Sodium-coupled glucose co-transporter (SGLT2) inhibitors (e.g., dapagliflozin): Advantages- rare hypoglycemia, weight loss; Disadvantages- UTIs, polyuria, costs, uncertain risk/benefit ratio

Medications that decrease hepatic glucose production (e.g., metformin): Advantages- no hypoglycemia as monotherapy, inexpensive, oral administration, ?weight loss; Disadvanages- rare lactic acidosis, GI side-effects (generally mild)

This morning I read an article in the NYT that actually made me feel sorry for health insurance companies and wonder just how affordable the Affordable Heath Care Act will be.  The article was entitled “Learning to be lean.  With few proven models, health sector takes on childhood obesity,” and was written by Reed Abelson.  Apparently, the new federal health care law, among its many provisions, requires both health insurers and employers to pay the cost of screening children for obesity and providing them with appropriate counseling.  This has health insurers scrambling to find what just what appropriate counseling might be.

I don’t need to remind any of my readers that childhood obesity is a big (no pun intended) problem; about 30% of children are considered overweight (the politically correct terms are “at risk for overweight” and “overweight.”  Please don’t ever call a child obese.  Anyway, there are considerable data in the scientific literature to show that childhood obesity is a risk factor for adult obesity and its many health problems.  So, screening for overweight or whatever we want to call it is appropriate as is conveying the information to parents.  This task is not terribly complicated or costly- just a quick height and weight measurement, calculation of a BMI, and information about what the data mean.  This information should be part of any well child medical care visit and the information can also be provided to parents through the schools, something already done in many places.  So far so good.  But what about “appropriate counseling” for those children found to be overweight?  As the NYT article notes, there are few if any proven models (how about no proven models with good long-term success?) to chart a way forward for insurers and employers.  So, is the U.S. health care system (to the extent we have a system) now taking the tack of requiring health insurers and employers to do the research and determine what constitutes appropriate counseling? It’s sort of like requiring insurers to screen for cancer and when a diagnosis is made, to do the research to find the most effective therapy.   In my opinion this is not health care reform at its best.  We should not identify health care problems such as childhood obesity and then require action that is very likely to be time and money poorly spent.  Good intentions do not justify unproven interventions.

I do not want to seem like a total grinch about this subject.  I like many provisions in the Affordable Health Care Act and I  would recommend that we screen children for weight status along with other health measures and require that health care providers offer nutritional counseling  (covered by the health insurer) on an annual basis, much like Medicare already does for people with diabetes mellitus.  That would be a reasonable start and one that might make the Affordable Health Care Act more affordable than the road we seem to be going down.  We must not outpace the science with our desire to do all that is possible in an effort to make our children healthy.

Like clockwork, every year, starting in early November and running well into the new year, newspapers and magazines are packed full of articles to warn us about the well-known holiday season weight gain and what to do about it.  This year was no exception.  In this entry, I want to highlight what I think were some of the most interesting articles.  I don’t need to remind you that we in the U.S. are, as a group, on the heavy side.  How did we get that way?  Many studies have documented our  slow but steady weight gain beginning in early adulthood, averaging about 2-2.5 lbs each year.  That doesn’t seem like a big deal, but you can do the math- 2 lbs/yr X 30 yr = overweight. Studies have also shown that most of the annual weight gain actually does take place in November and December.  So, can we do anything about holiday-induced “weight creep?”

The first article I recommend to you is entitled “the Fat Trap,” and was written by Tara Parker-Pope (NYT Magazine, Sunday January 1, 2012).  Ms. Parker-Pope bemoaned the fact that it is difficult to lose weight and summarized a study carried out by a group of European investigators (Sumithran P et. al.: Long-term persistence of hormonal adaptations to weight loss.  N Engl J Med 2011;365:1597-1604).  Fifty overweight people were put on a 10 week weight loss program.  The investigators measured a large number of hormones related to appetite at baseline, 10 weeks, and after 62 weeks.  They found that weight loss was associated with both increased appetite and increased levels of the appetite-stimulating hormones.  Unfortunately, most of the patients regained the weight they lost and still had increased appetite and increased levels of the appetite-stimulating hormones at 62 weeks.  The investigators concluded that mediators of appetite encourage weight gain.  Ms. Parker-Pope put it more bluntly: once we become fat, most of us despite our best efforts will probably stay fat.

The second article I recommend to you is entitled “New way calories can add up to weight gain,” written by Ron Winslow (Wall Street Journal Wednesday January 4, 2012).  Mr. Winslow summarized a study published that day in the Journal of the American Medical Association or JAMA (lead author George Bray from the Pennington Biomedical Research Center, Baton Rouge, LA).  The investigators fed 25 men and women about 1000 excess calories every day for 56 days but with diets that varied in the percentages of protein and fat  they contained (carbohydrates were about 40% of total calories for both diets.  The investigators found that although the subjects ingesting the low protein diet gained the least weight (about 7 lbs), they had as much gain in fat mass as the subjects on the normal and high-protein diets, whose excess weight gain was largely related to a gain in lean body mass.  The investigators concluded that “fad” diets with widely varying proportions of fats, carbohydrates, and fats, may not be the way to go in dieting, but rather, should focus on decreasing total calories and fat content.  In addition, the data showed that the BMI, a traditional way of assessing a patient for weight status, may not be very good at picking out those who have high body fat mass as opposed to high lean body mass.  As an aside, on the same page as the Bray study report, is a report by the same journalist, Ron Winslow,  on a Swedish study touting the health benefits of bariatric surgery for weight reduction (“Procedure’s benefits go beyond weight loss”).

The third article challenges Parker-Pope’s pessimistic view of weight reduction efforts.  It is entitled “Be it resolved,” and was written by John Tierney (NYT Sunday, January 8, 2012).  The article is all about the power of New Year’s resolutions to help people lose weight.  Tierney recently co-authored a book with Roy F. Baumeister entitled “Willpower: rediscovering the greatest human resource”.  I confess that I have not read the book, only the newpaper article.  Dr. Baumeister is a social psychologist at Florida State University.  The lengthy article presumably summarizes the book’s message: setting goals is most useful if the goals are accompanied by firm (written down) resolutions,  and that it is possible to reinforce one’s willpower; studies have shown that setting goals without concomitant resolutions, is far less likely to result in long-term successl.  I cannot say that I was much impressed with the recommendations other than that they are logical but  rather complicated,  and it is my guess that anyone willing to do all the things that are recommended to make the resolution work, doesn’t dare fail.  I can’t think of any good reasons not to try the resolution advice.

The last article also appeared in the Sunday January 8. 2012 issue of the NYT.  It was entitiled “Young, obese and in surgery: youth procedures rise, despite doubts,” written by Anemona Hartocollis.  I found the article well written but very disturbing.  I will offer no other comments.  Read the article and let me know what you think.

Conclusions

So, it’s another year, another few more pounds, and no new sure-fire ways to trim down and stay trimmed-down.  As I have tried to emphasize in a number of earlier entries on weight loss therapies, almost every diet out there works in the short run but fails in the long run.  I am convinced that for most people, the best way to lose weight and keep it off is to REALLY, REALLY want to lose weight (?maybe goals and resolutions?) is to aim for weight loss of no more than 1 pound per month (my wife’s mantra), to eat only moderate amounts of healthy foods (a la Michael Pollen) with only small amounts of meats/fatty foods, few if any highly processed foods (particularly potato chips and french fries-a painful task), no sugared sodas and sport drinks, AND to exercise regularly- at least 30 minutes 3 days/week.  Good luck.

For quite some time, I have been thinking of  writing a piece about high-fructose corn syrup (HFCS).  HFCS consumption, mostly in soda drinks and highly processed foods, has grown steadily over the past 30-40 years and now represents a sizable percentage of both total carbohydrate and total calorie intake in the U.S.  HFCS has been both praised as a low cost nutrient and vilified as one of the primary causes of our obesity and diabetes epidemics.  A few weeks ago, I saw an ad on TV that was promoting HFCS as healthful “corn sugar,” implying that somehow that HFCS was a natural (and healthful) nutrient derived from corn.  Not surprisingly, the ad was produced by the Corn Refiner’s Association (CRA) and was clearly part of a PR campaign.  The ad was criticized by several food industry watch dogs, including the U.S. Food and Drug Administration (FDA) and  representatives from the sugar maker’s industry; accusing the CRA  of false advertising.

Here Comes The Judge

What got me to actually sit down at the computer and start writing was a recent news report in my local newspaper (the Columbia Daily Tribune, Friday, October 21, 2011, page 5B; columbiatribune.com) that U.S. District Judge Consuelo Marshall issued a ruling that a false advertising lawsuit filed by the sugar industry against the CRA could go forward.  The CRA had argued that the lawsuit should be dismissed because HFCS is equivalent to sugar in the way it is metabolized and that the lawsuit was “an attempt to stifle a national conversation about the merits of HFCS versus sugar.”  In addition, the CRA lawyers argued that educational campaigns form the CRA shouldn’t be considered advertising.  The judge dismissed those claims stating that the CRA’s educational campaigns constitute commercial speech and that the industry group is not insulated from federal false advertising regulations just because its “educational” statements relate to a public health issue.  I almost forgot to mention that the CRA had asked the FDA’s permission to use the term “corn sugar” rather than HFCS in both advertising and product labeling.  As far as I know, the FDA has not ruled on the request.  So, what is this all about?

What is HFCS anyway?

To understand what HFCS is and isn’t, we need to discuss a little basic chemistry.  Don’t be afraid, it’s not complicated.  To most people, the word “sugar” means good old table sugar, a sweet-tasting white crystalline substance called sucrose and which is composed of a molecule of glucose and a molecule of fructose.  Another word for sugar is saccharide.  So,  sucrose is a disaccharide; glucose and fructose are six-carbon monosacharides.  Another important disaccharide is lactose (milk sugar), which is composed of a molecule of glucose and a molecule of galactose.  Saccharides are a class of carbohydrates, molecules that are composed of carbon, hydrogen, and oxygen.  Carbohydrates, along with proteins and fats are the basic body building blocks.  Sugars can be composed of many monosaccharide molecules linked together, called polysaccharides, which are important storage forms of sugars in both animals and plants.  Although all sugars (by definition) are sweet, there is a large difference in the sweetness of individual sugars: fructose is the sweetest sugar, almost twice as sweet as glucose.

Sucrose comes mainly from sugar cane (60%) and from sugar beets (40%).  Sugar cane was first found in Papua New Guinea and was domesticated about 10,000 years ago.  The discovery of beet sugar was not until about 250 years ago.  The history of sugar is a fascinating one which has been chronicled by N Deerr in The History of Sugar (volumes 1 and 2, London, Chapman and Hill Ltd., 1949 v-258/1950 v-259-636).  An excellent summary of the subject was written by M. Gracey, N Kretchmer, and E. Rossi (A glimpse into the history of sugar, in: Sugars in Nutrition, Ed. M. Gracey, N. Kretchmer, and E. Rossi.  Nestle Nutrition Workshop Series, Vol 25; Nestec Ltd., Vevey/Raven Press, Ltd., N.Y., 1991).  I can assure you that HFCS is no more controversial than sugar itself, which has been considered by many historians to be most responsible for slavery (both in the U.S. and globally).

Anyway, for a variety of reasons, beginning in the 1970′s, HFCS was introduced as an ingredient in many processed foods.  HFCS is made from corn syrup, a liquid composed mostly of glucose molecules.  It is commercially available from a number of manufacturers, but perhaps, the best known form of corn syrup is Karo Syrup (ACH Food Companies, Inc.).  Corn syrup is made first by milling corn into corn starch, and then adding an enzyme, alpha-amylase, which breaks the starch into oligosaccharides (small chains of glucose molecules).  The next step is adding another enzyme, glucoamylase (also know as gamma-amylase) which results in a syrup consisting of only glucose molecules.  To make HFCS, the corn syrup is converted into fructose by another enzyme, D-xylose.  The manufacturing process results in HFCS with 90% fructose (HFCS 90) or 42% fructose (HFCS 42).  HFCS 90 is used to make HCFS 55, which is used to sweeten sodas and various sport drinks.  HFCS 42 is used in many processed foods including some yogurts, frozen desserts, breakfast cereals, and baked goods, and has about the same composition as sucrose.

How much sucrose and HFCS do Americans actually consume?

You may find it hard to believe, but since 1970, U.S. consumption of HFCS has risen from zero to about 40 lbs/yr/person.  At the same time, consumption of sucrose has decreased from about 70 lbs per person to about 40 lbs per person.  Net (total) sugar consumption has risen from about 80 lbs/yr to about 100-120 lbs/yr.  Thus, virtually all of the increase in total sugar consumption is the result of increased consumption of HFCS in its various forms.  But, the ratio of fructose to glucose intake has remained about the same over time

Why is HFCS so widely-used?

The development of HFCS was to a great extent the result of political and economic circumstrances.  Cane sugar quotas in the U.S. have kept the price of can sugar high while corn subsidies have made growing corn relatively inexpensive.  The bottom line is that it is cheaper to make HFCS than to process cane sugar.  It is also important to note that HFCS has some desirable qualities; It mixes well with foods and keeps foods moist.

How is HFCS metabolized?

Remember that HFCS and sucrose are composed of glucose and fructose molecules.  It is the fructose that most experts have focused on as a possible health culprit, beyond the fact that sugar in the form of glucose, sucrose or fructose add calories to the diet- about 4 calories/gram consumed.  Metabolism of glucose is relatively simple.  Glucose can be used by all cells in the body for energy, it can be stored in the form of glycogen (long chains of glucose molecules, much like starch, and used as a building block for polysaccharides.  Fructose, on the other hand, is taken up mainly by the liver and can be converted into glucose, glycogen, triglycerides  and some fatty acids.  It is the role of fructose in fat metabolism that has generated the most controversy.  There are considerable data in both animal and humans that consumption of large amounts of fructose raise triglyceride levels and increase insulin levels, promoting insulin resistance.  Does fructose promote cardiovascular disease?  Does fructose promote the development of diabetes mellitus? Does high fructose intake stress the liver?  These are just some of the questions that have been raised about dietary consumption of fructose, and by extension, consumption of HFCS.

Is HFCS metabolized differently than sucrose derived from cane and beet sugars?

There is considerable controversy whether HFCS has unique properties such that it is metabolized differently than sucrose derived from cane or beet sugar.  In my opinion, there are no credible data to show that HFCS and sucrose are metabolized differently or that the fructose in HFCS is any different than frucose in sucrose or fructose in fruits, honey, maple sugar, agave syrup or brown rice.

So, what’s the problem?

In my opinion, the problem is that we in the U.S., consume far more calories than we need and many of those calories come from foods containing various sugars, including HFCS.  The latest data show that Americans currently consume, on average,  about 130 lbs of sugar a year which works out to be almost 40 teaspoons of sugar every day.  It’s extraordinary.  We have twin epidemics of obesity and diabetes mellitus and plenty of cardiovascular disease to go around.  We don’t need to single out a single food or food additive (i.e., HFCS) as the reason for our many ills; there is plenty of blame to go around, including our fondness for inactivity.  But, it is clear that if we curb our sugar intake, we will benefit.  I am neither defending or condemning the use of HFCS in foods.  I seriously doubt that if tomorrow, the use of HFCS in foods and drinks were banned, it would have any impact on the prevalence of obesity, diabetes or heart disease.  We  will still eat too much (including an extraordinary amount of the various sugars) and exercise too little.

If you find this subject interesting, I urge you to read an article by Mary Franz (“High-fructose corn syrup: what’s the fuss about?,” published in Diabetes Self-Management, May/June 2011, pages 33-37) and an article by Gary Taubes (“Is sugar toxic?,” published in the New York times Magazine, April 17, 2011).  The Taubes article discusses the highly controversial views of Robet Lustig, a physician from the University of California San Francisco.  Don’t miss the Lustig video on You-Tube which is a lecture he gave in 2009 entitled “Sugar: the bitter truth.”  I’m not saying whether I agree or disagree with Lustig’s views, but………..

Finally, what about calling HFCS corn sugar?  In my opinion, it’s clearly false advertising.  Why don’t the corn growers just call HFCS something like “sugar derived from corn?”  Or, maybe, just continue to call it HFCS?

In several previous entries I have discussed the issue of risks vs. benefits regarding this or that medical therapy, generally use of some medication where sufficient data have not been obtained to determine long-term risks. The other day,  I was going through my pile of New England Journal of Medicine (NEJM) issues from January-June 2011,  working on a continuing education program offered by the journal (it “forces” me to actually read each of the issues which come weekly), I spied a short article that I had not noticed previously, entitled ,”Long-term effects of in utero exposures- the DES story,” written by Annekathryn Goodman, John Schorge, and Michael Greene, all professors at Harvard Medical School in Boston and serves as an important reminder about the importance of assessing “risk vs. benefit” for medical therapies.

The Diethylstilbesterol (DES) story

DES is a synthetic nonsteroidal estrogen that was developed in the late 1930s.  It was widely used as a supplement to cattle feed (to fatten them up) and in humans as estrogen replacement therapy and for treatment of prostate and breast cancers. In the late 1940s, one study showed that DES could prevent miscarriage if given early in pregnancy. Other studies had shown no benefit, yet DES was widely used for quite a long time despite very convincing data that accumulated showing no benefit with respect to miscarriages.  Eventually, doctors got the message and use of DES faded away.  Then, in 1971, the NEJM published results from a very scary study performed by Herbst et al., showing an association between DES use during pregnancy and development of a rare vaginal cancer (clear-cell adenocarcinoma) many years later in female offspring of these mothers.  I still remember when the news hit.  I was a pediatric resident physician and doing my pediatric endocrinology rotation.  Even back then I was reading the NEJM regularly (I have been a regular subscriber since 1965). I remember the many discussions we all had about the data. As it turned out, by the early 1990s, 431 cases of the rare cancer had been identified in young women exposed to DES in utero. The median age of cancer diagnosis was 19 years.  We now know that the mechanism for the development of the cancer was probably drug-induced abnormal development of the Mullerian ducts (these ducts develop into the uterus, fallopian tubes,  and a bit of the vagina).  It was all a nightmare for the mothers, the young women, and the physicians involved in their care.

What did we learn from the DES catastrophe?

I am not certain what the collective “we” learned from the DES story.  I do know what I learned- that all medical treatments, be they procedures or medications, have risks and benefits.  Many times we know what the potential benefits are for a given treatment, but do not know what the risks might be.  Thus, it is always important to consider and to weight unknown risks vs. the potential benefits.  This is no easy task but it needs to be done and physicians who do not do this, do a disservice to their patients.  The potential benefit of a given treatment must be compelling enough to counter the unknown risks of the therapy, whatever the therapy might be.  We (here I mean the collective “we”), keep learning this lesson over and over.  Just this week, I read an article (and two accompanying editorials) in the NEJM entitled ” Stenting versus aggressive medical therapy  for intracranial arterial stenosis.”  In summary, the study showed that stenting was associated with many more deaths than the medical therapy.  As it turned out, the stenting procedure was approved by the FDA in 2005 after a small non-randomized study showed benefit from the stenting vs. medical therapy.  Now the “experts” are moaning and groaning about the fact that FDA approval for the stenting procedure was probably inappropriate given the very limited data and that a large randomized trial should have been performed, which as it turns out was the substance of the current NEJM article.  Then there is the story about the “metal-on-metal” hip replacement devices that is turning out to be another medical therapy catastrophe (see “Medical Devices-balancing regulation and innovation, ” written by Curfman GD and Redberg RF in this week’s NEJM).  I could go on and on.  We as caregivers all need to go back and review the DES story and understand why we need to learn as much as possible about risks and benefits of any given therapy/device before we “jump in.”  Obviously, if a patient faces certain death and a new therapy comes along, it would not be appropriate to “sit on one’s hands.”  But, few new medical treatments meet that urgency standard.  Pressures from device manufacturers and pharmaceutical companies and the researchers who either developed or tested the treatments, should not trump the need for careful unbiased assessment of the risks and benefits of the proposed treatment.