Januvia Virtually Identical to Glipizide over 2 Years--Another Misreported Study

NOTE (April 2, 2013): Before you take Onglyza or Januvia please read about the new research that shows that they, and probably all incretin drugs, cause severely abnormal cell growth in the pancreas and precancerous tumors. You'll find that information HERE.
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A recent study compared the effect of taking the very cheap generic sulfonylurea drug glipizide to the new extremely expensive drug Januvia. The abstract reports the results as if they meant that Januvia was far superior to glipizide in preserving insulin secretion, reducing weight, and avoiding hypos.

Fortunately, the entire study is available online for free, and I was able to see the actual statistics. What they showed, very clearly, was that the differences here were statistically significant--i.e. they probably weren't attributable to random variation--but not significant in terms of the impact on patient health.

Given that Januvia costs $190 a month and glipizide costs $4 a month (on many pharmacy generic drug savings plans) it's worth taking a closer look at the statistics.

Here's the full text article:

Safety and Efficacy of Treatment with Sitagliptin or Glipizide in Patients with Type 2 Diabetes Inadequately Controlled on Metformin: A 2-year Study. T. Seck et al,. Int J Clin Pract. 2010;65(5):562-576.

The study involved 1172 people with starting A1cs ranging from 5.8 to 9.1%, divided
into two groups. All took metformin and half each took Januvia or glipizide. As is common with randomization, there were subtle differences between the groups. Most significantly the glipizide group had 5.6% more males than the Januvia group and the glipizide group as a whole started out with a greater BMI, a slightly higher fasting glucose, and more members with very high A1cs.

I mention this because the statistically significant differences between the two groups turn out to be very small which would make you take into consideration the statistically significant differences at the start of the study in the two test groups.

All study participants were eating the extremely high carbohydrate diet prescribed by the American Diabetes Association for the two years of the study.

Only 44% of those who started the study were still in it at the end of the study. The main reason for discontinuation was blood sugar rising to dangerously high levels. 52% of the discontinuations which means 29% of all people in the study were excluded from the study results because they developed extremely high blood sugars.

How high? Here are the criteria used to drop people from the study:

Throughout the study, patients were discontinued if they failed to meet prespecified, progressively stricter glycaemic control criteria. From randomisation through week 6, patients were discontinued for fasting plasma glucose (FPG) > 15.0 mmol/l (270 mg/dl); after week 6 through week 12, FPG > 13.3 mmol/l (240 mg/dl); after week 12 through week 18, FPG > 12.2 mmol/l (220 mg/dl); after week 18 through week 30, FPG > 11.1 mmol/l (200 mg/dl); after week 30 through week 52, HbA1c > 8.0%; and after week 52 to week 104, 7.5%.

While I'm pleased to see that ethics were used in this study, so that people whose fasting blood sugars remained high enough to cause blindness and amputation were eventually removed from the study, the researchers gave very little attention to the differences between the two groups in this regard.

In fact far more people were dropped from the study after a year because Januvia was ineffective for them--84 compared to 58 in the glipizide group.

So all the results reported in the abstract were for the minority whose blood sugar remained at what was still dangerously high levels--waking daily with fasting blood sugars as high as 199 mg/dl.

Now lets look at the people who stayed in the study. Rather than quote all the many numbers here, I'm going to refer you to the graphs you will find on this page:

Medscape: Study Results with Graphs

As you can see the differences between A1c in the two groups never exceeded .2% and that difference only occurred early in the study and disappeared at its end. Fasting plasma glucose was virtually identical in both groups throughout the study and was showing an upward trend that is minimized because those one in three people with more strongly rising fasting blood sugars were dropped from the study in stages as it progressed.

Most importantly, the meal tolerance test result graphs show that the glipizide group was producing significantly LESS insulin and C-peptide at the outset of the study and had higher blood sugars at outset than the Januvia group, which calls into question the randomization.

Even so, the differences in insulin and blood sugar during the meal test, while statistically significant are functionally unimportant.The Januvia group started out with blood sugars that rose to about 234 mg/dl (13 mmol/L) 90 minutes after eating and after 2 years those post meal blood sugars were rising to about 230 mg/dl (12.7 mmol/L). This is a level high enough to guarantee complications.

In the glipizide group, at outset the 90 minute post meal blood sugar was rising to 252 mg/dl and it didn't change after two years.

How significant the difference is between the two groups is unknown given that one started out so much worse than the other.

The differences in insulin production over the course of the study were small, but the Januvia group produced more insulin than at baseline, though it obviously had very little effect on blood sugar.

Significantly, the glipizide group did not see any deterioration in insulin production which should be reassuring to those like Dr. Bernstein who believe that the insulin stimulating drugs cause beta cell burnout.

Though the abstract reports more hypos in the glipizide group, in practice the difference between the groups was, again, very small in absolute numbers because only 1/3 of the glipizide subjects who had hypos had more than 1 hypo over 2 years.

There was a tiny difference in weight in the two groups. The Januvia group lost an average of 3.5 pounds (starting from a baseline average weight of 194.7 lbs for the Januvia group.) The glipzide group gained an average of 1.54 pounds starting from an average of 198.7 pounds.)

These weight changes are negligible in functional or for that matter, even cosmetic terms.

The abstract suggests that other side effects were pretty much the same between the two groups, but here I have to point out that they missed something important.

As I have blogged many times before, Januvia works by suppressing the DPP-4 gene which produces a peptide that is used for many different things. It helps regulate glucose secretion, yes, but it also plays an important part in how the immune system functions.

The side effects that occurred more frequently in patients taking Januvia were those that probably reflect changes in immune function: cystitis, urinary tract infection, pain in extremity and asthma. "Weight decrease" was also listed as an adverse effect which probably has to do with Januvia's ability to induce anorexia, a side effect I personally experienced when I took it for 3 months which is related to the impact of GLP-1 on the brain.

Arthritis, sinus pain, sciatica and contact dermatitis--i.e. rash--were also higher in the Januvia group. The FDA received many reports of serious drug related rashes among people taking Januvia which makes me think that the rashes reported here might not have been "contact dermatitis" at all, but a reaction to the drug.

Bottom Line: The abstract of this study will be used by Merck sales reps to convince doctors that Januvia is far superior to glipizide for their patients because it causes weight loss and increases beta cell function. But now that you've seen the actual results, you can see this simply isn't true.

Januvia and glipizide failed for 54% of those who tried them over two years and over one years far more people found it worthless compared to those who tried glipizide. The impact on blood sugar was functionally insignificant for both. The tiny amount that Januvia lowered blood sugar on average was not enough to make any difference in health. Nor was the change in weight.

At the end of the study, the average patient taking either of these drugs was experiencing extremely high blood sugars both fasting and after meals--blood sugars that we know from a huge amount of research are high enough to cause all the nightmare complications of diabetes.

So what were patients taking Januvia getting for the extra $186 a month they were paying to take Januvia rather than glipizide?

Beats me. The satisfaction of knowing they were providing shareholders of Merck with great profits?

Given that we know that inhibiting DPP-4 may encourage the growth of melanoma, ovarian cancer, lung cancer and prostate cancer, the tiny "gains" achieved on average by Januvia are hardly worth the expense or risk

But don't expect your doctor to know this, because all he or she will ever hear about is the abstract which ignores the high drop out rate, the study design that eliminated those who failed, and the fact that none of the results, whatever their statistical significance ever reached functional significance.

Real Life Gets in the Way of Blogging

Just a word of apology for steadfast Friends of the Blog. As many of you know, I'm in the middle of fulfilling a three book contract with HarperCollins/Avon. I'm finishing up my second novel and it is taking my full concentration in a way that is making it hard to devote the time and attention I usually put into following the diabetes news.

I've been keeping an eye on things, and commenting here and there, but it will be a while longer until I can write more of the substantive, well-researched posts you've come to expect from me.

For those of you who are new to the blog, there is a wealth of information stored in the back issues of this blog which you can find by clicking on the Blog Archive links you'll find to the right of this post. And, of course, the Main Blood Sugar 101 Site presents the most important facts and findings relevant to the whole spectrum of blood sugar disorders, broken out by topic.

My first novel, Lord Lightning, will be coming out September 28th. It's a Regency-set Historical Romance, which should entertain those of you who enjoy Romance novels. My favorite authors in the genre are Laura Kinsale, Jo Beverley, Loretta Chase, and Mary Balogh. If you like their work, you probably will enjoy mine.

 

He's Cured? Family Doctors' Diabetes Treatment Gets Even Worse

A medically naive friend called me up all excited yesterday. He'd just been to his family doctor--the one who diagnosed him with diabetes last year based on his fasting plasma glucose, and guess what. The doc told him he wasn't diabetic anymore!

Unfortunately for my friend, this was not because my friend had improved his blood sugar. Far from it. His fasting blood sugar had gone as high as 138 mg/dl (7.7 mmol/L) over the past few months.

The reason the doctor told him he wasn't diabetic was that his A1c was 6.4%. The doctor exlained that "the definition of diabetes has changed" and by the new definition, you need an A1c of 6.5% to have diabetes.

This is completely not true. The "definition" of diabetes is stated in a document created by the American Diabetes Association (ADA) an industry-funded charity that made itself the self-appointed authority on medical treatment of diabetes, despite the fact that it is controlled entirely by those who profit from treating diabetes, NOT by people who have it. The document is:

The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20: 1183–1197, 1997

This proclamation (whose troubling history you will find discussed in detail HERE) was amended after a huge outcry by the world diabetes community with this:

Follow-up Report on the Diagnosis of Diabetes Mellitus The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care Diabetes Care 26:3160-3167, 2003

It is still in effect. As you can see by reading it, Type 2 Diabetes is diagnosed with one of these three criteria:

1. Fasting plasma glucose greater than 125 mg/dl (7 mmol/L).

2. Two hour glucose tolerance test value greater than 199 mg/dl (11.1 mmol/L)

3. Repeated random readings--i.e. taken at any time--over 200 mg/dl (11.1 mmol/L)

What changed is that the ADA now recommends the use of the A1c--a test that can be performed in the doctor's office--to diagnose diabetes.

International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes.
The International Expert Committee: Diabetes Care July 2009 vol. 32 no. 7 1327-1334. doi: 10.2337/dc09-9033

This additional diagnostic criteria (which doesn't replace the earlier criteria) diagnoses diabetes when A1c is 6.5% or greater.

As is always the case, the ADA based this recommendation largely on data collectd in non-Western populations whose genetic forms of diabetes are different from those found in most Americans. As you can see HERE in the graphs the ADA experts supply, Americans (NHANES study) have a different pattern of developing retinopathy than do the Pima and Egyptians. But it is the Pima data the ADA used to set their diagnostic criteria for Americans. And they set the cutoffs at the level where Pima began to show retinal damage.

The ADA continues to define "diabetes" as if diabetes and retinopathy (retinal damage) were the same thing. In fact, retinopathy is a later diabetic complication. By the time people begin to show signs of retinopathy they will have had demonstrable nerve damage (neuropathy) for many years. This is because diabetic nerve damage is a much earlier complication, as is heart disease.

In any case, despite the ADA's arbitrary choice of the 6.5% A1c as the bottom of the diabetic range, the graphs the ADA supplies show that retinopathy shoots up as soon as A1c exceeds 5.9%.

And, as if that weren't enough of a concern, the in-office A1c tests doctors often use--because they can bill insurance far more than they pay for the test kits--is extremely inaccurate. They can be off by as much at .5% (i.e. giving a reading of either 6.0% or 7.0% when a lab result would be 6.5%.) You can read what independent studies have found out about the accuracy of doctor's office A1c tests HERE.

BETTER DIAGNOSTIC CRITERIA

We know from the research you can read about HERE that the onset of neuropathy does not bear any relationship to A1c. It correlates strongly, instead, to post glucose challenge readings over 140 mg/dl (7.7 mmol/L). This has been confirmed by several studies run by neurologists.

We know from research you can read about HERE that heart disease incidence rises significantly as one hour post-challenge blood sugars go over 155 mg/dl and that several studies have found the risk of heart disease rising in a straight line manner as soon as A1c moves up out of the middle 4% range and becomes significant at the A1c of 6.0%.

Kidney disease appears to be associated with A1c, too. It rises after A1c is greater than 6.0%. However, in the case of kidney disease, strong fluctuations in blood sugar seem to play a part. A blood sugar that surges high and then comes back down may give a modest A1c but it will still damage the kidneys. Details HERE.

The A1c might be a helpful screening tool for finding people with full fledged diabetes who are unaware that they have it. But based on the study you can read about in this earlier blog post, anyone with an A1c over 5.5% should be given a glucose tolerance test--the gold standard for diagnosing diabetes, or if that is cost prohibitive, they should use a meter to check their blood sugar after eating to see how high blood sugar is rising. Repeated blood sugar tests over 200 mg/dl (11.1 mmol/L) at any time are diagnostic of Type 2 diabetes.

Relying solely on the A1c is a mistake, as is made clear by this study:

A1C and Diabetes Diagnosis: The Rancho Bernardo Study. Caroline K. Kramer, et al. Diabetes Care Care January 2010 vol. 33 no. 1 101-103.doi: 10.2337/dc09-1366

which found:

The limited sensitivity of the A1C test may result in delayed diagnosis of type 2 diabetes, while the strict use of ADA criteria may fail to identify a high proportion of individuals with diabetes by A1C ≥6.5% or retinopathy.

Once you are diagnosed, the A1c is a very poor guide to how well you are faring.

Why? Because your number one goal after diagnosis is to avoid nerve damage, blindness, kidney damage, and heart disease. Even the ADA's own data shows that in European populations these all become significant as A1c hits 6.0% and when post-meal blood sugars are higher than 155 mg/dl (8.6 mmol/L).

The family doctor's reliance on the A1c greater than 6.5% to define diabetes means that you won't be told you ARE diabetic until you have sustained organ damage. If you let the doctor treat you only enough to keep your A1c between 6.5 and 7% (or higher) as most do, you are almost guaranteed to develop the classic diabetic complications over time.

Your doctor won't see the development of these complications as a sign his treatment is inadequate. Doctors expect people with diabetes to develop complications. That's because all their patients with diabetes who follow the ADA treatment guidelines do. It is also because most doctors don't realize complications are caused by high post meal blood sugars, not any independent disease process. So they do not tell patients that the single best thing they can do to preserve their health is to cut down dramatically on the carbohydrates they eat, which are what raises their blood sugar.

Those of us with diabetes who have not developed complications because we have pursued very tight control are often ignored by our doctors because they assume we don't really have diabetes. This has been my own experience. That my diabetes hasn't progressed over 12 years and that my A1cs have stayed in the 5% range is seen by my doctors as suggesting that I must not really have diabetes no matter what my readings are after a meal filled with high carbohydrate foods. They find it impossible to understand that my good outcome is because I've made hard choices with every meal I eat to ensure that I keep my blood sugars below the danger point as much as possible.

If you want to be a typical person with diabetes--one with painful feet, recurrent, resistant infections, deteriorating kidneys, and troubling growth of abnormal capillaries in your retina, by all means, use the ADA diagnostic criteria. Don't consider yourself diabetic until you have already developed early retinopathy. Follow the ADA's dietary recommendations and flood your blood stream with carbohydrates at every meal. Test only your fasting blood sugar, not the post meal blood sugars that correlated with complications. Keep your A1c at the 7% level where 75% of all Type 2 diabetics develop retinopathy. Enrich the drug companies, hospitals, surgeons, cardiologists, and family doctors who will earn more and more as you as you deteriorate and use more of their products and services.

Or get smart. Keep your A1c in the 5% range at all times--and lower if possible. Keep your post meal blood sugars under 140 mg/dl (7.7 mmol/L) at every meal, which you do by lowering your carbohydrate intake. Use only safe diabetes drugs in conjunction with limiting carbohydrate intake.

You can learn more about how to do that HERE.

Your doctor will tell you you don't have diabetes. And if we define "diabetes" as "on the verge of going blind, losing your kidneys, and having a heart attack" you won't.

If your doctor uses the fact you "don't have diabetes" based on the A1c test to deny you blood sugar test strips, and prescriptions for helpful drugs like metformin, find a new doctor who is better educated about diabetes, even if it means making a longer drive or paying a bit more.

It's your eyes, kidneys and heart that suffer when your doctor is too busy to understand what he reads in the pre-chewed newsletters, funded by drug companies, that he or she uses to "keep up with diabetes research." It's you who go blind, end up on dialysis, or die of a heart attack when he's wrong.

 

More Insight into the "Normal" A1c

This year the American Diabetes Association told U.S. doctors to use the A1c as the first line diagnostic test for diabetes, rather than the fasting glucose test they'd long preferred. This is an improvement. The fasting glucose test missed a lot of diabetes until people had had dangerously elevated post meal blood sugars for as long as a decade.

But the A1c is still an imperfect tool for diagnosis, because, while it works well in large studies where you want a fast way to summarize the blood sugar status of thousands of people, it often fails in individuals.
Anemia, abnormally long-lived red blood cells, and some genetic conditions may give an individual an A1c test result that has no relationship to that individual's actual blood sugar level.

The only test that accurately determines whether a person has abnormal blood sugar is the Oral Glucose Tolerance Test (OGTT). Unfortunately, this test is expensive and time consuming so it can't be used for routine screening.

The current formula used to equate an A1c to a blood sugar is the ADAG formula. I've created a calculator that will let you convert any A1c result into the average blood sugar that is supposed to correlate to it. You can find it here:

A1c/Average Glucose Calculator

Remember that the average glucose is an abstract concept that bears only a slight relationship to actual blood sugar. You can have an average blood sugar of 150 mg/dl by veering from 40 mg/dl (a serious hypo) to 260 mg/dl--both dangerous blood sugar levels, or you can get it by having a blood sugar that varies between 140 and 160, a pre-diabetic blood sugar that, while it is high enough to cause problems, causes only slow developing problems that take years to manifest.

If you are diagnosed using a Oral Glucose Tolerance Test (OGTT) you should be called diabetic if your blood sugar goes over 200 mg/dl but some tests only look at the 2 hour number and diagnose you if that is over 200 mg/dl. It might have come down after going as high as 300 mg/dl the first hour, so the reliance on one reading may miss the accurate diabetes diagnosis.

If your blood sugar on the (GTT is over 140 mg/dl (7.7 mmol/L) at 2 hours but under 200 mg/dl (11 mmol/L) you'll be told you have "prediabetes" which many doctors treat as unimportant. It isn't unimportant. Blood sugars in that range are high enough to cause heart disease, "diabetic" nerve damage, and "diabetic" retinal damage. (Details HERE)

What A1c Is Normal?

A study just published in Diabetes Care gives more insight into what really is a "normal" A1c. It analyzed the data from 2,494 Australian clinic patients to come up with the range that seemed to correlate to diabetes and then applied it to another 6,015 people to see if it could be used as an effective screening tool.

A1C for Screening and Diagnosis of Type 2 Diabetes in Routine Clinical Practice.
Zhong X. Lu, et al. Diabetes Care April 2010 vol. 33 no. 4 817-819. doi: 10.2337/dc09-1763

This study found:

1. An A1c under 5.5% was a good indicator of normal blood sugar (probably determined with a OGTT, though this isn't stated in the abstract.)

2. An A1c over 7% was almost always an indicator of diabetes.

3. In those with A1cs of 5.6% to 6.9% between 61.9–69.3% had "abnormal glucose status."

What you should take from this is that if you are given an A1c screening test, you need to ask your doctor what the actual result was. If it is over 5.5%, you should test your blood sugar with a meter at home. You can learn how HERE)

If you see blood sugars routinely over 140 mg/dl (7.7 mmol/L) two hours after meals, consider yourself as having "prediabetes" and take steps to lower your blood sugar. You'll find instructions HERE.

If your A1c is much lower than predicted by your average blood sugars, it is possible you are one of the people for whom this test isn't accurate. You can read more about that HERE.

A1c Doesn't Correlate to Complications anywhere NEAR as Well as Post-Meal Blood Sugar

Whatever your A1c might be, keep in mind that the reason doctors rely on it is because is is cheap, and they don't have the time to look at your blood sugar logs to see what is really happening. That's why after your diagnosis most doctors use the A1c, exclusively, to measure your progress and likelihood of developing complications. Unfortunately, that is where it fails the most.

A lot of research makes it crystal clear that post-meal blood sugar highs predict the development of complications much better than A1c. This is because as mentioned above, the same A1c may reflect widely different patters of blood sugar behavior.

The weight of the evidence suggests that blood sugars that rise over 150 mg/dl(8.3 mmol/L) cause complications, especially if they stay elevated over that level for more than a brief time. A two hour reading of 150 mg/dl should set alarm bells ringing no matter what your A1c might be. Conversely, if you are keeping your two hour readings at 100 mg/dl(5.6 mmol/L) or lower, and still have a high A1c, you are almost certainly less likely to develop the classic diabetic complications.

Two different studies of neuropathy found that the only measure of blood sugar control that correlated with the presence of neuropathy was the 2 hour OGTT result. Neither A1c or fasting glucose had any predictive value.

Most doctors consider any A1c under 8% as "good control." My lab still prints that on their lab result sheet. If you think blindness and amputation are good, that might be an okay level. For those of us who want normal health, a normal A1c is required. The Australian study suggests that level should be 5.5% or under.

NOTE: Dr. Richard K. Bernstein, for whom I have immense respect insists that only a 4.3% A1c is normal. But I have seen people with 5.4% A1cs whose numbers after eating any amount of carbohydrate was never over 115 mg/dl (6.4 mmol/L).

That makes me think that Bernstein's number is defining "normal" in a way that eliminates all but a tiny percentage of the population, which means that though the 4.3% A1c might be perfect, it probably isn't at all normal. If you can get lower than 5.5%, great--especially if the low reading isn't due to anemia which gives very low readings no matter what your blood sugar might be.

My own A1c is always considerably higher than my post-meal testing would predict, as are those of many people I hear from. I don't have any classic complications 12 years after diagnosis, so I no longer stress about this. Watch actual highs by testing routinely 1 and 2 hours after meals, and you'll know exactly how you're doing and can ignore concepts like "average" which aren't as helpful as "actual."