News You Missed: Actos Strongly Linked to Retinopathy

I mentioned this in my "Updates to Blood Sugar 101" blog, but because that blog doesn't get a lot of traffic, I think it is worth repeating here.

A new study has disturbing news for people who switched to Actos thinking it was a safe drug. This study was published in an Ophthalmology journal, rather than a diabetes journal, and seems to have been completely ignored by the diabetes press.

Here's the study:

Glitazone Use Associated with Diabetic Macular Edema Donald S. Fong. Am J Ophth Volume 147, Issue 4, Pages 583-586.e1 (April 2009)

This study analyzed the records of 170,000 people with diabetes treated by Kaiser Permanente Southern California. The researchers found that

In 2006, there were 996 new cases of ME. Glitazone users were more likely to develop ME in 2006 (odds ratio [OR], 2.6; 95% confidence interval [CI], 2.4 to 3.0). After excluding patients who did not have the drug benefit, did not have an eye exam, and had a HgA1c <7.0, glitazone use was still associated with an increased risk of developing ME (OR, 1.6; 95% CI, 1.4 to 1.8).

It's worth noting, too, that the Science News report of this study adds, "Most of the glitazone users in the study were taking pioglitazone (Actos)."

Since the whole point of lowering blood sugar in diabetes is to avoid blindness, this study gives yet another reason to avoid Actos (and Avandia). Slightly more than one person out of every 200 in this huge group of patients developed macular edema. And those taking Actos or Avandia (but mostly Actos) were more than two and a half times as likely to develop retinal swelling leading to vision loss than those not.

This was true even in those with very well controlled blood sugar--A1cs below 7%.

I've been receiving a steady stream of angry, hostile comments from an anonymous poster (the tone suggests one person) whenever I post about TZD-related issues. This may be an investor--this blog is often cited in posts on investment discussion boards when I discuss new drug side effects. But I'll give them the benefit of the doubt and assume this is someone who is getting very good blood sugars on one of these drugs.

The person has never put anything in their comment which casts doubt on the research I cite. Mostly they express fury that I'm threatening their beloved drug. I don't post the comments that contain only personal attacks or cites to old drug-company supported research "proving" the safety of the drug without examining the new side effects that more recent research has discovered.

But let me say here that I do understand that a few people see much better blood sugars while taking Avandia or Actos and that this might make someone respond strongly to research findings that make it clear that these drugs are dangerous. That person may say, "I've looked at the risks and it's worth it to me to take this drug." Perhaps it is.

But a lot of us learned some very interesting about risk during last year's stock market meltdown. People who invest in the stock market always claim to understand the risks. Always. The problem is that studies always show that people assume that the "risks" they can accept will happen to someone else. It is only when they lose their life savings in a risky investment that they finally understand that while risk may be expressed in percentages, when you get whatever it is you are risking, you get it 100%.

So when you consider the "risk" of a side effect from a drug, if that risk is high enough to be taken seriously--i.e. much more likely than, say, being struck by lightning or being elected president--you have to imagine yourself sitting in the doctor's office being told you've got that side effect.

Which is why when you consider this new research you have to ask yourself, is your better blood sugar worth the loss of your optic nerve?

And you also have to ask yourself, is your doctor even aware of this possible side effect? The otherwise excellent doctor who prescribed Avandia to me several years ago had never heard that it caused edema or heart failure, though at the time this was very well documented. He brushed off my concern that it might have any negative impact on the heart, though this doctor was the one who sent me for test after test looking for heart disease because I'd had diabetes long enough he was certain I must have it. (I didn't) Shortly after our discussion, Avandia's connection with heart attack became known.

So if your doctor assures you that Actos (or Avandia) is safe, ask him if he's heard about the major Kaiser study published by Dr. Fong linking these drugs to macular edema. If he brushes this question off without giving you a very good reason why can be certain you aren't at risk of it, you need to spend spend sometime thinking about what "risk" really means and you need to ask yourself if the benefits you are getting from this drug would thrill you, even if you ended up losing your vision.

You might also want to ask your doctor what the warning signs of macular edema are--and whether your once a year appointment with the eye doctor is sufficient to protect you from it.

 

Go Easy on the Advil, Motrin, Ibuprofen etc.

Another study has added to the evidence we already have that suggests that nonsteroidal antinflamatories, the "non-aspirin pain killers" you buy over the counter at the pharmacy are bad for you.

The latest study, published in the journal Neurology was hoping to prove that taking these drugs would lower the incidence of dementia. Instead it found the opposite.

Here's the study: Risk of dementia and AD with prior exposure to NSAIDs in an elderly community-based cohort. J. C.S. Breitner et al. Neurology 2009, doi:10.1212/WNL.0b013e3181a18691)

The researchers "followed 2,736 dementia-free enrollees with extensive prior pharmacy data, following them biennially for up to 12 years to identify dementia and AD."

What they found was:

Contrary to the hypothesis that NSAIDs protect against AD, pharmacy-defined heavy NSAID users showed increased incidence of dementia and AD, with adjusted hazard ratios of 1.66 (95% confidence interval, 1.24–2.24) and 1.57 (95% confidence interval, 1.10–2.23)

This did not surprise me at all, for reasons that were not cited in any discussions of this study.

Many people do not realize heavy use of NSAIDs has been linked to high blood pressure and that there appears to be a lifetime dose that dramatically raises the risk of developing end stage kidney disease. I have written about this with appropriate journal citations HERE.

One of the studies cited on that page, published in Archives of Internal Medicine , concluded:

[Men] who took acetaminophen six or seven days a week had a 34% higher risk of hypertension. Those who took NSAIDs six or seven days a week had a 38% higher risk and those who took aspirin six or seven days a week had a 26% higher risk.

High blood pressure is a known cause of vascular dementia, and the older and more fragile people are, the more likely high blood pressure is to damage tiny capillaries in their brains.

An earlier study published in the New England Journal of Medicine in 1994 looked at the connection between painkiller use and the development of End Stage Renal Disease [ESRD], i.e. kidney failure. It concluded:

A cumulative dose of 5000 or more pills containing NSAIDs was also associated with an increased odds of ESRD (odds ratio, 8.8)

I am pretty certain this study was done before the advent on the market of the extremely high dose OTC forms of NSAID so it is likely one "pill" was less than the "extra strength" pills many people take today.

This should be a wake up call for people with diabetes given that people with diabetes are very likely to already have kidney damage thanks to years of undetected high blood sugars before diagnosis and to doctors describing dangerously high post-meal blood sugars as "safe" when we know kidney disease is associated with blood sugar spikes in the range between 135 mg/dl and 270 mg/dl. (Research HERE and discussion HERE)

A lifetime dose of 5,000 pills means 3 pills a day for five years. Given that many people take double or triple dose pills up to six times a day, the limit described on the label, it would be possible to hit this dangerous lifetime dose within a year.

It's not clear if the damage is being done to the kidney, which causes high blood pressure, or the other way around--that the drug is causing high blood pressure through some other means which then damages the kidney.

Whatever the explanation, we know high blood pressure is a major cause of vascular dementia, which is the kind of dementia that afflicts many of the elderly--and that vascular dementia is the form most prevalent among people with diabetes, as discussed in this earlier Blog Post.

The reason chronic use of NSAIDs is such a concern is that doctors tell people to take them for the chronic pain caused by arthritis, a condition extremely common in older people for which there is no truly effective pharmaceutical treatment.

So it looks like it's time to start rethinking your use of these NSAIDs. There isn't really much in the way of alternatives. Tylenol is worse, and has a lower lifetime dose associated with kidney failure, so that isn't a solution either.

Aspirin has recently been linked to a higher risk of brain microbleeds. The study is HERE and you can read a discussion HERE. Prophylactic use of Aspirin has been debunked as a way of preventing heart attack in people with diabetes, which is discussed HERE.

So what can you do if you have both pain and diabetes? Obviously, you can avoid taking painkillers for transient problems like sore muscles which heal themselves.

If you have chronic arthritis, the situation is tougher. The field of alternative arthritis treatments is rife with fraud and ripoff supplements, so if you decide to look for alternative treatments read what you find in a spirit of rampant disbelief. Some treatments that may be worth trying are Glucosamine and large doses of Omega 3 oils (fish oil).

But since pain can really take the fun out of being alive, there are times when a painkiller is necessary. If you do decide to take an NSAID look for the lowest dose that will work. Often you may find through experimentation that the effective dose is much smaller than the dose the label suggests.

For example, I find little difference between the effect on nerve pain from my ruined discs of 1/2 of a 325 mg Tylenol pill, the very smallest sold, and the full pill. When my kids were in elementary school, I used to give them the toddler dose when they were sick with fevers and it always lowered the fever even though the label prescribed a dose 4 times as high for their weight.

Take as few pills as you can and take each pill with an awareness that it is adding to your lifetime dose.

If you have arthritis, keep moving and explore options like warm water swimming to help with joint pain.

If you haven't yet developed arthritis be very careful to avoid the kinds of overly aggressive exercise that stresses on joints and is likely to cause arthritic changes as you age.

Running is a good example of a popular form of exercise that tears up knee joints. Weight lifting can also do enormous damage over time to joints when people train too aggressively.

Walking is a much safer form of exercise for people who plan to keep their bodies going into their 80s or 90s and hope to keep their brains functional through the life of that body.

Study: Good News About Diabetes and Heart Attack

A study published in JAMA that is in the medical new today deserves the attention of anyone with diabetes who wonders what their chances are of having a heart attack and what factors correlate with that likeliness of heart attack.

The study was run to determine whether expensive screening of people with diabetes who had no symptoms of heart disease was worth doing. It concluded it wasn't.

It's helpful to know this if you are asymptomatic but your doctor is still trying to push you into having expensive tests, which , as cardiologist Dr. Davis points out, have a high false positive rate and often result in unnecessary, expensive, and dangerous medical procedures.

But two other findings that came out of this study should give hope and reassurance to all people with diabetes who strive for good control. Because what the press is not reporting about this study is that it found far fewer heart attacks than expected in this population and that some truly significant risk factors emerged from it that are not the ones you usually hear about.

Here's the study:

Cardiac Outcomes After Screening for Asymptomatic Coronary Artery Disease in Patients With Type 2 Diabetes: The DIAD Study: A Randomized Controlled Trial. Lawrence H. Young, et al. JAMA. 2009;301(15):1547-1555.

In brief, what they did was start out with 1,123 people with Type 2 Diabetes who had no symptoms of heart disease. Half were screened with radioactive stress tests half were not. The study lasted for 7 years with a mean follow up per person of 4.8 years. .

How Did The Researchers Define "No Symptoms of CVD"

It's important to note how "no cardiovascular disease" was defined in this study. The researchers explain it meant:

• No angina pectoris or chest discomfort evaluated with a positive Rose questionnaire
• No stress test or coronary angiography within the prior 3 years
• No history of myocardial infarction, heart failure, or coronary revascularization
• No abnormal rest electrocardiographic results, ie, pathological Q waves, ischemic (≥1 mm depression) ST segments, deep negative T waves, or complete left bundle-branch block
• No clinical indication for stress testing.
• No severe asthma, cancer, or severe liver or kidney disease.

These Diabetics had Far Fewer Heart Attacks than Expected

In the "Limitations" section of this study the authors write "The cardiac event rates were significantly lower than originally anticipated at the time of the design of the study."

In fact, in this group of 1,123 people with mediocre blood sugar control whose age mostly ranged from 55 to 65 experienced a grand total of 17 heart attacks (1.5%) and 15 (1.3%) cardiac deaths. In addition there were 15 (1.3%) cases of stroke.

By far the largest number of "cardiac events" in this group were "revascularizations" ie angioplasty and bypass operations of which there were 75 6.7%. As we know, doctors rush to perform these operations at any hint of heart attack so their prevalence may overstate the seriousness of heart disease in this population.

Total deaths from any cause were 33 or 2.9% of the group. Considering their age, this is encouraging news.

Predictors of Cardiac Events

The most interesting part of this study, to me, was the table that presents "Factors Associated With Primary Events" a.k.a. heart attack or cardiac death.

This table which you can find HERE breaks out those who did and did not get heart attacks by various factors. They give a very good idea of what factors really correlated with heart attack over a period of five years in middle aged people with diabetes.

Factors You Can't Change

Seventy-two percent of the heart attacks occurred in males who made up 53% of the total study population. There were only 9 heart attacks among the 522 women in the study over 5 years. This is not surprising, as heart attack in this age group is always far higher among men.

A family history of premature heart disease was a very strong factor distinguishing between those who did and did not have heart attacks. Thirty-four percent of those who had heart attacks had the family history while only 19% of those who did not have heart attacks had it.

Age also mattered. Those with heart attacks were on average 2 years older than those who did not and had had diabetes for 3.6 years longer. Though you can't change those factors either, all the other factors associated with incidence of heart attack are things you can change.

A1c

To no one's surprise, the average A1c of those who had heart attacks was higher than those of people who did not. Those who had heart attacks had a mean A1c of 7.5%. Those who did not had a mean A1c of 7.0%. That's a significant difference. One would like to see heart attack risk broken out by A1c quartile but there were too few events--32 total--for this number to be statistically significant.

Triglycerides

Triglicerides were far higher in the group that had heart attacks than in those who did not, an average of 203 vs 169. The way you lower triglycerides is by cutting down on your intake of carbohydrates. Cutting carbs always drops triglyceride levels dramatically. The drug metformin also will lower triglycerides to some extent.

LDL Cholesterol was slightly higher in the group with heart attacks (mean 129 vs 114) and HDL was only slightly lower (47 vs 50), but after figuring in the standard deviations the actual difference between the two groups look less impressive to me.

Neuropathy

The incidence and extent of neuropathy appears to be a very significant marker of heart attack potential. 53% of those with heart attacks had neuropathy compared to 34% of those without, but when we look at the severity of what neuropathy was present we find that there was more than twice as much numbness in the group with heart attack as in those without--28% vs 12%. There was also twice as much pain--22% vs 11%.

Autonomic neuropathy, which affects heart beat and blood pressure control, was indicated by another bellwether statistic, erectile dysfunction, though incidence of this was not, oddly, broken out by gender making it difficult to interpret the finding that 61% of those with heart attacks had it as opposed to 48% of those without.

But more importantly Cardiac Autonomic Dysfunction was a major factor: 53% of those who had the heart attacks had this compared to 21% who did not.

Severity of Other Diabetic Complications

The microalbumen:creatinine ratio, a measure of kidney function, also hinted at upcoming heart attack. Seventy-seven percent of those who did not have heart attacks had a ratio <30 while only 59% of those who did have heart attacks did. Seventeen percent of those who had heart attacks had ratios over 300 while only 4% of those who did not have heart attacks had these extremely high ratios indicative of advanced kidney dysfunction.

When they looked at peripheral vascular disease, 28% of the people with heart attacks had PAD but only 9% of those who didn't get heart attacks had it. The story was not as dramatic for retinopathy. Slightly more people with heart attacks had it than those who did not, but not dramatically so (19% compared to 15%)

Insulin Use

A higher percent of those who had heart attacks were taking insulin (34% vs 23%) however, given the higher A1c in the heart attack group and the much higher incidence of diabetic complications, it is possible that insulin use here is a marker for a history of high blood sugars and the existence of the severe complications described above rather than a cause of the heart attack.

Factors that Did Not Correlate with Heart Attack Occurrence

Lipid Lowering Drugs

Forty-seven percent of those who had heart attacks and 47% of those who did not have heart attacks were on lipid lowering drugs, i.e. statins. These drugs apparently made no difference.

Blood Pressure Drugs and Blood Pressure

The measures for these were surprisingly close in both groups. Fifty nine percent of those with heart attacks were taking BP drugs 57% were taking them in the group that did not. The average BP in those who had heart attacks was 134/78. In those who didn't it was 131/79. However, it is worth noting that these are both levels defined as "normal" in the population at large. If your blood pressure is much higher, there is a lot of evidence it can promote stroke and heart attack.

Suprising Findings

Higher BMI Protective?

Those with higher BMIs had fewer heart attacks than those who had lower BMIs. The average BMI among those with heart attacks was 28.7%. Those who did not have heart attacks had average BMI of 31.2. This is interesting, as it suggests the people who did not have heart attacks were technically obese while those who did were merely overweight. The waists of both groups were the same, given as 41 cm. This appears to be an error as it translates to a waist circumference of 16.1 inches. I assume they meant 41 inches or 104 cm. One is a bit concerned to see an error of this type slip through peer review as it makes you wonder about the other figures. The people who did not have heart attacks had slightly larger hips on average (correctly given in cm) but the actual difference was only 4 cm--not even 2 inches, small enough that it probably doesn't mean much.

Aspirin Use

Slightly more of those who had heart attacks were taking low dose aspirin than those who did not have heart attacks. (50% vs 45%)

The Bottom Line

What I take from these statistics is this: To lower your true risk of having a heart attack lower your blood sugars to the level that prevents neuropathy, which we know means keeping blood sugars under 140 mg/dl (7.7 mmol/L) at all times.

Keep your triglyerides down. This means cutting back on carbohydrates.

Do all this and you can reduce the voluntary factors associated with a likelihood of heart attack in people with diabetes.

There is no need to obsess about losing weight if you are mildly obese as long as your blood sugar is under control

Don't trust statin drugs to make an major difference in your heart attack risk.

None of this is new, but it's nice to see some statistics in a population large enough to be worth consideration.

Hypos in the News: More Bad Science

Two studies in this week's issue of JAMA looked at the relationship of hypos with mortality and dementia.

The first study received no play in the medical press, the other got a lot of coverage. The major difference between these studies as far as I can see is that the one that was ignored was much better designed and the one that got all the press is yet another poorly conceptualized study that will be used by insurance companies to deny patients the tools they need to normalize blood sugars.

Let's look at the studies.

The first was:

Relationship Between Spontaneous and Iatrogenic Hypoglycemia and Mortality in Patients Hospitalized With Acute Myocardial Infarction. Mikhail Kosiborod et al. JAMA. 2009;301(15):1556-1564.

What it did was look at

7820 patients were hospitalized with AMI [heart attack] and were hyperglycemic on admission (glucose level ≥140 mg/dL). Patients were stratified based on whether they developed a hypoglycemic event (random glucose level <60 mg/dL) during subsequent hospitalization. Logistic regression models were used to evaluate the association between hypoglycemia and in-hospital mortality within subgroups of patients who were and were not treated with insulin therapy.

What they found was this:

Among patients treated or not treated with insulin, those with hypoglycemia were older and had more comorbidity [i.e. other medical conditions]. Hypoglycemia was associated with increased mortality in patients not treated with insulin (18.4% [25/136] ... but not in those treated with insulin (10.4% [36/346]... Hypoglycemia was a predictor of higher mortality in patients who were not treated with insulin (odds ratio, 2.32 [95% confidence interval, 1.31-4.12] vs patients without hypoglycemia), but not in patients treated with insulin (odds ratio, 0.92 [95% confidence interval, 0.58-1.45] vs patients without hypoglycemia).

In short, this study finds that very sick older people experience serious hypos when hospitalized for heart attacks when not taking insulin. Even more importantly, the study found that though they are more likely to hypo if they are given insulin, these hypos do NOT make them more likely to die unlike the non-insulin-related hypos that do seem associated with higher mortality.

So now we know something new about hypos that most of us didn't know--very sick older people hypo when they're in poor shape.

Now on to the next study, the one that got all the press:

Hypoglycemic Episodes and Risk of Dementia in Older Patients With Type 2 Diabetes Mellitus. Rachel A. Whitmer, et al. JAMA. 2009;301(15):1565-1572.

Researchers in this study tracked hypoglycemic events from 1980-2002 using hospital discharge and emergency department diagnoses. "Cohort members with no prior diagnoses of dementia, mild cognitive impairment, or general memory complaints as of January 1, 2003, were followed up for a dementia diagnosis through January 15, 2007."

The researchers found:

At least 1 episode of hypoglycemia was diagnosed in 1465 patients (8.8%) and dementia was diagnosed in 1822 patients (11%) during follow-up; 250 patients had both dementia and at least 1 episode of hypoglycemia (16.95%).

Compared with patients with no hypoglycemia, patients with single or multiple episodes had a graded increase in risk with fully adjusted hazard ratios (HRs): for 1 episode (HR, 1.26; 95% confidence interval [CI], 1.10-1.49); 2 episodes (HR, 1.80; 95% CI, 1.37-2.36); and 3 or more episodes (HR, 1.94; 95% CI, 1.42-2.64). The attributable risk of dementia between individuals with and without a history of hypoglycemia was 2.39% per year (95% CI, 1.72%-3.01%).

The researchers conclude: Among older patients with type 2 diabetes, a history of severe hypoglycemic episodes was associated with a greater risk of dementia.

The press reported this study with headlines like this one from USA Today: Type 2 Diabetics more susceptible to dementia. Or the NYTimes's Study Finds Risk of Dementia Increases After Hypoglycemia.

But what is missed here is that the study found association, not causation. And this is an important point.

Owning a yacht is associated with earning a high income. Studies could easily reveal that yacht owners have a higher "risk" of earning a higher income than people who do not own yachts (HR, 6.94; 95% CI, 5.42-8.64). But buying a yacht will not increase your paycheck. Rich people are more likely to own yachts because being rich means they can afford them.

So when we find an association between severe hypos and dementia we have to ask whether that hypoglycemia causes dementia or whether it is caused by the brain deterioration that occurs as people develop dementia.

As the first study cited above suggests, old, sick people who were more likely to die were prone hypo even without using insulin, which may suggest this is the case. It is possible that very early changes in a brain that is suffering mini-strokes or growing plaques and tangles, changes too subtle to lead to a dementia diagnosis, affect the blood sugar "thermostat" functions of the brain.

In addition, we all know that people in the early stages of the deterioration that leads to dementia are forgetful and likely to a) forget they took their insulin and shoot a second dose or b) confuse their basal and fast acting insulin. Both of these can lead to severe hypos. Because of this, severe hypos may be a very early symptom of dementia not its cause.

But even without that explanation, people who a decade later may develop dementia may also be more prone to hypo long before their diagnosis because the family doctors who treat them (as is the case with most older people with Type 2 diabetes) may put them on "one size fits all" insulin regimens that don't match their fast acting insulin to their carb intake. Typically they will tell the patient to use X units per meal, without any attempt to explain that insulin dose should vary with carbohydrate intake.

These set insulin regimens require no effort on the part of the doctor which makes them attractive to overworked family doctors who do not get reimbursed for helping people with diabetes adjust their insulin. These regimens always prescribe intentionally low insulin doses to avoid hypo risk since insulin isn't matched to meals. As a result, patients using these inadequate insulin regimens usually run very high blood sugars--many studies show their A1cs ranging from 8-10%. So their long term exposure to high blood sugars may be contributing to the progress of their dementia. Even with the too-low doses, they are prone to hypo if they become sick, can't eat, and continue to inject their set insulin doses as doctors often do not explain to them that they should not use insulin if they can't eat. So it is possible that some of the hypos in this study are a marker of poor insulin prescribing practices leading to poor blood sugar control, and that this poor control is causing the dementia, not the hypos.

This isn't just my conclusion. It's the conclusion of Dr. Nir Barzilai, a distinguished endocrinologist from Albert Einstein Medical School (Dr. Bernstein's Alma Mater) who was quoted in Forbes' coverage of this story:

... the study looks at association only, and doesn't actually prove any cause-and-effect link between the two conditions, cautioned Dr. Nir Barzilai, director of the Institute for Aging Research at Albert Einstein College of Medicine and the Montefiore Hospital Diabetes Clinic in New York City.

"It could be fluctuation of glucose. We know that hyperglycemia [high blood sugar] is also very toxic to the cells. All those things cannot be dissected on a study like this," he said.

Further on Dr. Barzilai added:

But the whole picture is likely to be much more complicated, Barzilai said.

"The glucose concentrations in the brain are much, much lower than in the [rest of the body], and it takes it a long time to actually adjust if you change the peripheral glucose for the brain to have lower glucose," he explained. "Not only that, but the neurons in the brain are really not fed by glucose but by other metabolites. The rest of the body, when glucose goes down, will feel it. The brain is totally different story.

More Ammo for Those Who Don't Want to Pay for Insulin?

The worrisome thing about this study is that it comes hard on the heels of several other poorly designed and badly reported studies which are being interpreted (erroneously) as "proving" that tight control achieved using insulin is dangerous for people with Type 2 diabetes.

Most notably, too, all the studies showing problems with insulin are studies done in populations of elderly Type 2s with years of poor control behind them and advanced cardiovascular disease resulting from those years of poor control, but the results in this population are being extrapolated to apply to the huge and growing population of young people with Type 2 whose ages range from their teens on up.

Armed with these studies, insurers can argue that "evidence based medicine" suggests people with Type 2 should not use insulin. They are already arguing that it is "dangerous" to strive for an A1c lower than 7.0%, even though there are almost two decades of research showing that lowering blood sugar prevents the classic, horrifying diabetic complications: amputation, blindness and kidney failure.

Now the opponents of tight control can claim that "using insulin leads to hypos and we 'know' hypos cause dementia." And they will. Because insulin is expensive and insurers could boost their bottom line enormously by refusing to supply insulin to people with Type 2.

I don't know what we people with diabetes can do to stem the tide of poor research being used to deny us lifesaving treatment. It's getting worse with each passing week, and with the emphasis on "cost cutting" in medicine rising world-wide, it is quite possible that society will just let older Type 2s deteriorate "safely" because of the imagined risks of tight control.

But I do have to wonder what's wrong with JAMA and NEJM that their "peers" are reviewing and recommending publication of studies like these without demanding that the summaries make it clear--and that the media report--the real findings of these studies, rather than the misrepresentations that may cause family doctors to provide "care" that will blind and cripple their patients.

The same doctors who find no fault with the oral drugs that can promote cancer (Januvia) and blindness (Actos) are knocking themselves out to find problems with insulin that can only be demonstrated in studies with significant methodological flaws.

One thing is for certain: hypos attributable to insulin are far less likely to cause life-ruining damage than are prolonged exposure to high blood sugars.

Research That's Been Ignored: C-Peptide May Cause Thickened Arteries

I was rooting around looking for studies addressing the question of whether or not high insulin levels including those caused by injecting insulin causes heart attack when I stumbled on a very interesting article published in 2007 the journal Circulation Research that raised the possibility that it is not insulin, but the C-peptide which is produced as a byproduct of natural insulin production that causes cardiovascular disease.

C-Peptide in Insulin Resistance and Vascular Complications: Teaching an Old Dog New Tricks Dennis Bruemmer. Circ Res 2006 November 24; 99(11): 1149–1151. doi: 10.1161/01.RES.0000251785.83860.3b.

This article points to several other studies including:

C-Peptide induces vascular smooth muscle cell proliferation: involvement of SRC-kinase, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinase 1/2.
Walcher D et al. Circ Res 2006;99:1181.

In this study they examined

"postmortem thoracic artery specimens ... As previously described, C-peptide deposition was detectable in the intima of all diabetic subjects included in this recent study. In addition, 8 of these 21 individuals with diabetes exhibited C-peptide deposition in the media, where C-peptide colocalized with VSMCs [vascular smooth muscle cells].

This shows that C-peptide is deposited in early vascular lesions and appears to stimulate the overgrowth that leads to clogged arteries.

The researchers then went on to examine whether C-peptide could cause smooth muscle proliferation:

To assess the effect of C-peptide on VSMC proliferation, thymidine incorporation assays were performed. Twenty-four hour stimulation of human aortic smooth muscle cells (HASMCs) with human C-peptide increased cell proliferation in a concentration-dependent manner with a maximal 2.6±0.8-fold induction at 10 nmol/L C-peptide (P<0.05 compared with unstimulated cells; n=9). The extent of C-peptide induced HASMC proliferation was similar to the effect of the well established VSMC mitogen platelet-derived growth factor (PDGF) at 10 ng/mL. Scrambled C-peptide (at 10 nmol/L), containing similar amino acids in a random order, had no such effect, underscoring the specificity of C-peptide’s mitogenic action (Figure 1A). In addition, heat-inactived C-peptide did not induce cell proliferation, thus ruling out endotoxin contamination

They found that it did and double checked that it was the C-peptide causing the proliferation not something else.

If this is true, it is is an extremely interesting finding that may answer the question that all of us have who inject insulin: are we raising our heart attack risk by using insulin to lower our blood sugar?

The reason that this is so important is that most studies which have linked insulin levels to cardiovascular risk have not distinguished between the effects of high levels of naturally secreted insulin and the effects of high levels of injected insulin. If C-peptide rather than circulating insulin is the problem, injected insulin may be much safer than high levels of naturally secreted insulin because injected insulin does not contain C-peptide.

People with Type 2 diabetes may be producing a lot of insulin because severe insulin resistance multiplies by a factor of ten how much insulin they need. For example, a young person with Type 1 who produces no insulin at all might need only 20 units a day of insulin to attain a 6% A1c while a person with Type 2 might need 200 units to achieve the same blood sugar level. I have heard from people with extreme forms of diabetes who are injecting as much as 500 units a day.

Because insulin is a growth hormone, it is a valid concern to ask whether injecting huge quantities of insulin might be promoting heart disease even as it lowers blood sugar in people with Type 2. It is the fear that this is the case that has driven the latest retreat from the idea that people with Type 2 should strive for lower A1cs.

But if it turns out that it is C-peptide causing the thickening of arteries, not insulin, things get very interesting indeed, because injected insulin contains no C-peptide.

This lack of C-peptide has become a huge issue to some members of the Type 1 community because there is other research that suggests that C-peptide might help counteract the nerve damage seen with diabetes. So some people with Type 1 diabetes have launched a campaign to demand that insulin manufacturers add C-peptide to injected insulin to make it more "natural."

But if it turns out that "natural" C-peptide is what causes clogged arteries, this might not be such a good idea.

And if that is true, it might also explain why sulfonylurea drugs that stimulate beta cells to produce even more insulin are associated with a higher risk of heart attack. It might also suggest that using drugs to sensitize Type 2s to their own very high levels of secreted insulin (with the accompanying high levels of C-peptide) might be more dangerous than using Metformin with injected insulin.

A more recent review of the research on C-peptide--available in full text and worth reading in its entirety--also cites findings that:

"C-peptide has been shown to induce pro-inflammatory mediators, such as nuclear factor kappa B, inducible nitric oxide synthase, and cyclooxygenase-2, indicating that C-peptide treatment could be associated with side-effects that may accelerate the development of diabetes-associated complications.

Proinsulin C-peptide: Friend or foe in the development of diabetes-associated complications? Lina Nordquist and M Johansson. Vasc Health Risk Manag. 2008 December; 4(6): 1283–1288.

Yet another recent discussion of the relationship of C-peptide and clogged arteries is found here:

C-Peptide and Atherogenesis: C-Peptide as a Mediator of Lesion Development in Patients with Type 2 Diabetes Mellitus? Nikolaus Marx and Daniel Walcher, Exp Diabetes Res 2008; 2008: 385108. Published online 2008 April 1. doi: 10.1155/2008/385108.

There's a lot more to the diabetes-heart disease story than C-peptide of course, including the fact that people with Type 1 diabetes who have no circulating C-peptide at all still develop heart disease after long-term exposure to high blood sugars.

And because we know of the oft-demonstrated straight line relationship between A1c and heart attack in everyone, not just people with diabetes or who are using diabetic medications, it is very likely that high glucose levels themselves, rather than insulin, may play just as important a role in producing cardiovascular disease.

But this finding about C-peptide may point to why insulin resistance is such a problem for people with Type 2 diabetes. It may also encourage you to follow strategies that not only lower blood sugar but ower the amount of insulin your body produces and along with that the amount of C-peptide that might be deposited in your arteries.

The best way to cut down on your native insulin production is to cut down on the amount of carbohydrate you eat. Metformin also has been shown to lower native insulin production without sacrificing blood sugar control, as I blogged a few days ago. This C-peptide factor may explain why Metformin has often been found to have a positive effect on cardiovascular disease.

If your insulin production is dropping and you are insulin resistant, this data suggests you might better off injecting insulin rather than using a drug like Glyburide, Amaryl, or Prandin to stimulate more native insulin--and C-peptide-- production. The explanation for why these insulin stimulating drugs appear to raise the incidence of heart attack has focused on their ability to stimulate receptors on the heart. And since newer drugs in these families don't target the heart receptor, it has been argued they are safer. But this new finding about C-peptide makes me wonder if it is the C-peptide they stimulate causing heart problems too.

Back from the Endo

Here's a report on my latest doctor visit.

The good news is that my High Sensitivity C-Reactive Protein, a measure of cardiac disease was .56 mg/L. This is extremely good. Under 1 is "low."

The not so good news is my A1c was 6.0%. I had stopped taking Levemir six weeks ago because I was not seeing consistent results and the fasting bgs I was getting without it didn't seem to be significantly elevated over those I'd been getting with it. My impression had been that the last vial of Levemir I got from the pharmacy was weak, but they wouldn't replace it and my copays are high. So my not using Levemir might explain the slight rise, though the difference in my fasting blood sugars was only about 10 mg/dl. My post-meal numbers have been testing in range and had even been a bit lower than usual as I was experimenting with Prandin which was giving me quite a few hypo readings in the 60s.

Everything else was fine. My total cholesterol was, as usual, very high, since I have that "large fluffy LDL" genetic variant. My dad also had this gene. He tested with a total cholesterol of 340 in the 1970s and lived to be 100 without any meds until his late 90s. As soon as he started a statin in his 90s, he became depressed and experienced a steep cognitive decline. My HDL was 72 and TGs were 110, which is a bit higher than usual for me but still fine.

My biggest problem has been that I have been gaining weight like crazy, even eating mostly low carb without insulin for 2 of the last 3 months and still eating a lot of low carb meals. I've only been using insulin or prandin for one meal a day. Even so, after dieting carefully for 8 weeks--eating only 1350 calories a day, weighted and logged with software--and losing 7 lbs, I managed gained back every pound I'd lost in four weeks of eating more normally, but more than 100 g a day and 1700 calories.

So I'm going to give Metformin ER another try. It doesn't so much of anything for my blood sugar, but through the years as I was taking it, I didn't gain weight. So I'll give it another try.

I had stopped taking Metformin as it was giving me burning pains in my upper gastric area. Testing found no sign of ulcer, but the burning pain was quite unpleasant. I hope whatever it was causing this has cleared up, as I had taken Metformin without problems for 3 years before that and it had made it very easy to maintain my weight even after I started insulin. In fact, I lost weight the first year I was using fast acting insulin with my meals, even though I was using twice as many units as I have been using during the past month.

One last interesting note. I discovered (on my own, not from the doctor visit) that the reason I was seeing those Prandin lows may be because I was eating fresh grapefruit to fight off a nasty cold. Turns out Prandin is one of those drugs metabolized with cytochrome P450 enzymes which get blocked by grapefruit. So when you take Prandin with grapefruit the body can't remove it from the blood stream.

This is probably why I saw the lowest blood sugar I've ever seen--in the 50s--last week. Usually my body just counterregulates lows right back up, but with the grapefruit Prandin affected me like a sulf which meant I was chugging carbs and still dropping low. Usually Prandin only works for an hour or so, but with the grapefruit it had my poor old betas pouring out insulin for about 3 hours.

That's enough about me. Now back to discussing topics of interest to everyone!

Rise in Toddler Obesity Points to Genetic Damage from Pollutants

There has been a huge increase in obesity among toddlers and young children. No one disputes this, especially not me.

But what is disturbing is that the blame for this phenomenon has been placed on the children's parents not where it belongs: on the industrial polluters who have filled our air, water, and food supply with chemicals that we know disrupt the genes of developing fetuses.

Pregnant women drink tap water that contains detectable amounts of SSRI antidepressants, which are well known to cause endocrine disruptions leading to obesity. They eat food from cans lined in bisphenol A, known to cause obesity in animals exposed to it as fetuses. They breathe air filled with chemical breakdown products from factories. They eat vegetables imported from third world countries grown with endocrine disrupting pesticides.

The poorer you are, the more likely you are to live in a neighborhood contaminated with industrial runoff. Look at this study for just one example of how blood levels of PCBs and pesticides predicted diabetes in an upstate New York population of Native Americans.

When I raised my children in the early 1980s parenting books cited numerous studies that proved quite conclusively that children under 6 with normal metabolisms will not overeat no matter how much food you expose them to. The studies found in case after case that young children who overate at one meal would under eat at another and that over time even if allowed to eat whenever they wanted and whatever they chose from a wide selection of foods including desserts, their nutritional intake stayed surprisingly constant and surprisingly well balanced.

But as so many of us with diabetes have learned, when metabolic regulatory systems are not working properly, one of the first symptoms is abnormal appetite. And this kind of metabolic dysregulation, apparently from birth onward, is exactly which is what we are seeing in the 20% of four year old children found to be obese. It is also why were are seeing an increasing number of young children being diagnosed with Type 2 diabetes before age 6 though we know that it takes a decade or more for adults to develop the kind of diabetes associated with obesity. These children are not getting diabetes because they are making poor choices. They are developing diabetes (and the obesity that comes along with the rampant hunger associated with metabolic failure) because they are being born with genetic damage.

It's time to start being honest about what is going on in these children that has dysregulated their metabolisms. There are thousands of studies already in print linking maternal exposure to air pollution with negative outcomes in newborns, such as low birth weight (which in turn has been linked with a higher risk of obesity and type 2 diabetes later on.

Just this week the public learned of a two year old study that found perchlorate--rocket fuel--in water supplies all over the country and, more importantly, in the blood of all 3,000 people tested for it. Perchlorate is known to damage the thyroid and cause brain abnormalities in children and it appears to be getting into our bodies even if we don't live near chemical plants via vegetables and fruits grown in regions where the ground water supply has been contaminated with it. The EPA has fought against doing anything about this problem, even after it was identified, because the rocket fuel was put into our environment by huge, powerful, politically connected corporations.

Still, there are encouraging signs that now that the EPA is no longer a wholly owned subsidiary of the chemical companies this may change. Besides the recent hearings about rocket fuel in our water, new EPA studies are also looking at some of the worst environments like Schools down wind of factories. NIH is funding The National Children's Study a huge long term study underway now that will measure air and water exposure of a large number of 100,000 children from birth onward.

But the fact is we don't need more studies, and we certainly don't have time to wait for those 100,000 recently conceived children to grow into adults to confirm that their exposure to environmental toxins, from birth, will disturb or destroy their metabolisms. There have been thousands of studies conducted already linking air, water, and food pollution to metabolic problems in children and adults. There are whole journals devoted to research on pollution and its effects on living things ranging from microbes to babies.

What we really need is for the media to start telling the public the truth--that the so-called "obesity epidemic" is a symptom of the widespread, decades long pollution of our environment by biologically active organic compounds that are disrupting the metabolisms of adults and damaging the bodies of our babies while they are still in the womb. And we must face the fact that some of this genetic damage may not be fully reversible.

It will take billions or even trillions to halt the damage. We'll need to develop water treatment plants capable of removing pharmaceuticals from our water supply. These drugs are getting into it in the first place because everyone who takes a pill excretes significant amounts of the pharamceuticals it contains into our sewer system or ground water and current water treatment strategies are unable to remove these organic pharmaceutical molecules from the treated water.

We'll need to get aggressive about eliminating dangerous smokestack emissions. We'll need to investigate the plastics that surround us and ban those, like bisphenol A which are being found in our blood streams in detectible amounts. We'll need to find alternative ways of protecting crops that don't depend on the pesticides that kill insects fast and people slowly.

And most importantly, we'll have to realize that this is a problem that transcends national borders. The pollutants that go into the air in China or India are carried around the world and will eventually fill the air and water all of us breathe. The peppers grown in South America ends up on tables in Vermont.

If we don't do what we need to do, the problem will in fact go away on its own, along with the human and animal population of the earth: because when genetic damage reaches a certain point human (and animal) fertility will begin to drop at the same time as the rate of disturbing mutations will rise. There are suggestions this is already happening. Infertility and the need for assisted reproduction has become a much bigger issue over the past 50 years while the horrifying rise in the rate of autism over the past 20 years hints of the kinds of pregnancy outcomes we may all have to deal with if the current pace of planetary pollution continues.

These obese toddlers are just the canaries in the coal mine, poor little things. But it is time to stop blaming their parents--most likely to be those living in poverty so that they are more exposed to pesticides (if they are agricultural workers) or smokestack and factory water discharges, since there is a strong poverty-incidence connection in childhood obesity. Blame instead those who have profited mightily from hiding the truth about pollution from us and blaming the victims for what is becoming clearer every day is an "epidemic" of environmentally caused genetic damage.

Latest Metformin Study Really Shows Impact of Improperly Dosed Insulin

I've had a chance to read the full text of the latest study to examine the impact of metformin on cardiac health and complications over a five year period. The study is:

Long-term Effects of Metformin on Metabolism and Microvascular and Macrovascular Disease in Patients With Type 2 Diabetes Mellitus. Adriaan Kooy et al., Arch Intern Med. 2009;169(6):616-625.

This is one of those studies where if you read the abstract rather than look at the actual statistics you come away with a very different idea of what the study really found.

This study involved 390 Dutch subjects with Type 2 diabetes. All were using Insulin. Half were given metformin and half were given a placebo. They were followed for a median 4.3 years.

The crucial information about this study does not appear in the abstract. It is this:

All subjects monitored their glucose levels at home every 2 weeks (ie, just before and roughly 90 minutes after breakfast, lunch, and dinner, and at bedtime) using the same monitoring device (Glucotouch; Lifescan, Beerse, Belgium).

You immediately notice that with subjects testing blood sugar once every two weeks, there could be no attempt to match insulin dose to carbs-eaten-per-meal. This is probably why the participants in both arms of this study never achieved A1cs close to even the ADA's anemic target 7%.

Another problem is that it is not clear how much metformin people were given. The only statement regarding this is this one:

Patients with a creatinine clearance in the range of 40 to 60 mL/min/1.73 m2 were allowed a maximum of two 850-mg tablets per day; those with a range of 30 to 40 mL/min/1.73 m2 were allowed one 850-mg tablet per day; and those below 30mL/min/1.73m2 were withdrawn from the study.

As many people will require a dose of 2550 mg a day to see the full effect of metformin, it sounds like quite a few people in the "metformin" arm were not taking an effective dose.

Cardiac Outcomes

So knowing that both groups had A1cs of at least 7.5% and knowing further that both groups ended up with fasting blood sugars higher than 140 mg/dl it should come as no surprise that whether or not they took metformin made almost no difference in their outcomes both for heart attack or complications.

At the outset of the study 21 people in the placebo group had had heart attacks (11% of all in the group) and at the end 25 or 13% of the placebo group had had heart attacks. In the group who took metformin 24 started out having had heart attacks (12% of the group) and at the end 28 had had heart attacks (14% of all)

Since the incidence of heart attack skyrockets as A1c rises from the 5% to 7% and both groups had A1cs well over 7%, this should be no surprise. The blood sugars in both groups, despite insulin use were terrible. In the placebo group the mean fasting blood sugar at the end of the study was 144 mg/dl. In the metformin group it was 146 mg/dl.

Post meal blood sugars (90 minutes after eating) in the placebo group at the end of the study averaged 162 mg/dl in the placebo group and 160 mg/dl in the metformin group but with those fasting blood sugars so high, these people were spending most of their day well over the blood sugar level (140 mg/dl) known to correlate with the development of complications.

The summary of this study while admitting that metformin "...did not improve the primary end point," adds, "Metformin did, however, reduce the risk of macrovascular disease." This makes it sound like metformin had a significant impact on macrovascular disease, but examining the actual event numbers provided in the study shows the "significance" here is statistical and very small.

The actual differences in the incidence of events like stroke and heart attack were tiny--in the range of 1 or 2% and because there were problems with the way the groups were randomized, it is hard to trust these statistics.

Most notably, 30% of the placebo group were smokers while only 19% of the metformin group were smokers. This alone would be likely to skew cardiovascular outcomes. The metformin group, conversely was on average 5 years older than the placebo group, but this is offset by the fact that the people put on metformin at the start of the study had lower serum insulin, slightly better blood sugars, and were using less insulin than the placebo group at the beginning of the study.

These tiny differences between the group taking metformin and those not, to me, suggest that the tiny 1 or 2% differences in the incidence of the cardiac outcomes were probably not as significant as the statistics might make them seem. Yes, you can adjust for smoking, etc, but with such tiny differences between the groups, such adjustments are suspect.

Impact on Weight

Over the 4.3 years were these: People in the placebo group, who started out heavier than those in the placebo group gained an average of 4 lbs. Those taking metformin gained an average of 2 lbs. These people had an average weight of 190 lbs, so the two pound difference in average final weight is not exactly miracle weight loss.

Impact on Blood Sugar

Over the 4.3 years the average A1c of the placebo group stayed unchanged at 7.9%. That of the metformin group dropped .5% from 7.9% to 7.5% but interestingly, the difference between mean fasting and postprandial blood sugars were only on the order of 2 mg/dl each and the metformin group had higher average fasting blood sugars (by 2 mg/dl) than the placebo group.

Impact on Insulin

There was a major difference between the two groups in the amount of insulin circulating in their blood streams and in the amount of insulin they were injecting--though obviously, given the very high blood sugars, the amount of insulin being injected was not anywhere near the amount needed to get real control.

The placebo group started out with average serum insulin level of 43.3 μIU/mL and ended up with a average levels of 75.2 μIU/mL. The metformin group started out with average serum insulin levels of 35.7 μIU/mL and ended up with average serum insulin levels of 46.5 μIU/mL.

The daily dose of insulin in the placebo group was 64 units a day at outset and 100 at the end of the study. In the metformin group it was 62 at outset and 75 at the end of the study.

No Effect on BP, LIpids, or Microvascular Outcomes

The researchers point out that there were no difference in the two groups in terms of lowering blood pressure or improving microvascular outcomes. With blood sugars as high as these people were running, microvascular damage was certain. We know you have to lower post meal blood sugars below 140 mg/dl to eliminate neuropathy, retinopathy and kidney failure. Since average fasting blood sugar in both groups was over 140 mg/dl and almost identical, it is no surprise they developed the same amount of microvascular complications.

What This Study Really Shows

This study is being interpreted as showing that metformin fights weight gain in people who take insulin and that it has a positive effect on some cardiovascular endpoints.

It does indeed show that using metformin makes a tiny difference in weight gain and that it reduces both the amount of circulating insulin and how much insulin need be injected to achieve the same blood sugar level.

But what this study really proves, if you read it carefully, is that if you dose insulin without regard to how many grams of carbohydrates people are eating at each meal, you will not be able to get anything approaching good control and that without good control you will end up with patients whose blood sugar is so high they are guaranteed outcomes--cardiovascular "events" and classic diabetic complications.

Until people with Type 2 are taught to use insulin in a way that matches insulin dose to the amount of carbohydrate they eat, per meal, people with advanced Type 2 requiring insulin will never be able to attain the lower blood sugars that have been associated with better outcomes, no matter what oral drugs they take.

Did These Patients Deteriorate Because Type 2 is a Degenerative Condition Or Because of Those High Blood Sugars?

The researchers as is usual, plot graphs showing that their patients needed more and more insulin as the study continued and use this to conclude that people with Type 2 always deteriorate because Type 2 diabetes is a degenerative condition.

However, all they have really proven is that people maintaining blood sugars that have been shown to be high enough to kill beta cells are likely to lose beta cells and see their blood sugar deteriorate. If the subject's blood sugars had been kept in the range advocated by the American Association of Clinical Endocrinologists, using modern insulin dosing techniques that match dose to carb intake, the outcome probably would have been quite different.

But don't expect your busy family doctor to understand that. Or, for that matter, your busy endo who doesn't have time to read anything but the abstract and who may not realize just how poorly insulin was dosed in this study.

A Silver Lining?

One last thing this data suggests to me that total insulin dose does not have a lot of impact on cardiac or complications outcome, which is probably good news. Since the metformin group was using significantly less insulin with almost identical outcomes in terms of heart attack and mortality, it seems we can stop worrying about whether high doses of insulin itself are promoting heart disease. The tiny differences in heart disease outcomes between the two groups suggest it doesn't.

The final point I must make here is this: in people who use metformin along with low carb diets with or without insulin, we usually do see improved lipids and slightly better blood sugars with the same level of dietary carbohydrate intake. Metformin is very helpful when you use it to cover a small amount of carbohydrate. This study suggests, as do so many studies, that metformin isn't able to counteract the impact of putting 300 grams of carbohydrates a day in your system with inadequate amounts of insulin. No oral drug will do that.