Metformin May Prevent Colorectal Cancer

Metformin has been promoted for preventing other cancers, so it is not a surprise that colorectal cancer is prevented to some degree by metformin.

Meta-analysis found metformin therapy was associated with decreased risk for colorectal adenomas and colorectal cancer among type 2 patients.

Studies have suggested that patients with type 2 diabetes may be at an increased risk for developing colorectal cancer (CRC); hyperinsulinemia, hyperglycemia, and chronic inflammation are thought to all contribute to carcinogenesis. Metformin, a biguanide, exerts its antihyperglycemic effects by decreasing hepatic glucose production, decreasing intestinal absorption of glucose, and improving insulin sensitivity by increasing peripheral glucose uptake and utilization.

Since metformin is the most commonly prescribed medication for the treatment of type 2 diabetes, researchers sought to assess whether metformin use has an effect on the incidence of CRC in this patient population. A total of 8,046 study participants were included in the analysis (2,682 in the case group [diabetes patients with incident diagnosis of CRC]; 5364 individuals in the control group [diabetic patients without CRC diagnosis]); each group was 60% male, 40% female. In the case group, 36.6% of patients had metformin exposure, while 38.4% had metformin exposure in the control group. In this study, any metformin use led to a 15% reduction in the odds of CRC; after accounting for healthcare use, the effect was reduced to 12%. Reduction of risk was not significantly associated with metformin dose, duration or total exposure.

Metformin therapy was associated with decreased incidence of colorectal adenomas (P equal to .0002). On adjusted analysis, the summary estimate decreased further to a 25% reduction in colorectal adenoma risk (P equal to .03). Colorectal cancer risk was also significantly reduced among metformin users vs metformin non-users or other treatment users (P equal to .0002).  Adjusted analysis revealed a 22% reduction in colorectal cancer risk for metformin users (P less than .00001).

Recent evidence indicates that metformin therapy may be associated with a decreased colorectal adenoma/colorectal cancer risk in type 2 diabetes patients. However, results are not consistent. So a systematic review and meta-analysis to assess the association between metformin therapy and risk of colorectal adenomas/colorectal cancer in type 2 diabetes mellitus patients was done. They searched the literature published before Aug. 31, 2016 in four databases: PubMed, Embase database, CNKI and VIP Library of Chinese Journal. Summary risk estimates with their 95% confidence interval (95% CI) were obtained using a random effects model.

Twenty studies (including 12 cohort studies, 7 case-control studies and 1 randomized controlled trial study) were selected in terms of data of colorectal adenomas or colorectal cancer incidence. Metformin therapy was found to be associated with a decreased incidence of colorectal adenomas (P equal to 0.0002). When the adjusted data were analyzed, the summary estimate decreased to 25% reduction in colorectal adenomas risk (P equal to 0.03). Besides, a significant reduction of colorectal cancer risk was also observed (P equal to 0.0002). And when the adjusted data were analyzed, colorectal cancer risk for metformin users was decreased with a reduction of 22%, compared with non-metformin users and other treatment users  (P less than 0.00001).

In another study published in Cancer in 2014, it was also concluded that metformin use appears to be associated with a reduced risk of developing CRC among diabetes patients in the United States by 12%. The mean age of the study participants was 55 years and 57 years, respectively, in the control and case groups (P = 1.0). Approximately 60% of the study participants were male and 40% were female in each group. In the multivariable model, any metformin use was associated with a 15% reduction in the odds of CRC. The dose-response analyses demonstrated no significant association with metformin dose, duration, or total exposure.

From the results of multiple studies, it was concluded that the meta-analysis suggested that metformin therapy may be associated with a decreased risk of colorectal adenomas and colorectal cancer in type 2 diabetes mellitus patients.

Metformin Does Cause B12 Deficiency

Allen called me shortly after he read this. I say shortly because he knows I sleep late and he does respect my sleep time. He was surprised that it has taken this long to publish something we have known for a long time. He knew that I would be busy for most of the afternoon and again the following day, but felt this was important enough to remind me of it and ask that I blog about it. Then he asked if I could meet with Ben, Barry, and him on Saturday. I agreed and was happy to do this.

When I arrived, they were waiting for me. Allen had printed a copy for me and asked if I had read it. I told him that I had and would be blogging about it after March 18. Barry said you already have posts that far out and I said yes. Plus, I have three other blogs ready to post and about 18 more topics I want to write in the weeks ahead. Ben said yes, there have been many topics of interest lately. I said I wish I had time to write about all the topics that interest me.

People taking metformin, one of the safest type 2 diabetes medications, for several years may be at heightened risk of vitamin B12 deficiency and anemia, according to a new analysis of long-term data. Allen knows this from first hand experience and others of us know this because our vitamin B12 levels were low and we cannot absorb what we need from the foods rich in B12.

Metformin helps to control the amount of sugar, or glucose, in the blood by reducing how much glucose is absorbed from food and produced by the liver, and by increasing the body’s response to the hormone insulin, according to the National Institutes of Health.

The study used blood samples and the researchers found that at year five, average B12 levels were lower in the metformin group than the placebo group, and B12 deficiency was more common, affecting 4 percent of those on metformin compared to 2 percent of those not taking the drug.

Borderline low B12 levels affected almost 20 percent of those on metformin and 10 percent of those taking placebo.

Average vitamin B12 levels were higher by year 13 than in year five, but B12 deficiency was also more common in both the metformin and placebo groups, as reported in the Journal of Clinical Endocrinology and Metabolism. The down side of being vitamin B12 deficient can mean nerve damage that is severe and may be irreversible. Severe and prolonged B12 deficiency has also been linked to impaired cognition and dementia. It can also cause anemia (low red blood cell count), but fortunately, this condition is reversible with treatment. Another finding of the study was more people in the metformin group were also anemic at year five than in the placebo group.

Humans do not make vitamin B12 and need to consume it from animal sources or supplements. Vegetarians may get enough from eating eggs and dairy products, but vegans need to rely on supplements or fortified grains.

Doctors who prescribe metformin to patients long-term for type 2 diabetes, gestational diabetes, polycystic ovarian syndrome or other indications should consider routine measurement of vitamin B12 levels, the authors conclude.

People who are taking metformin should ask their doctor about measuring their B12 level. Restoring healthy B12 levels is easy to accomplish with pills or monthly injections.

Finally, the study authors say, “The risk of B12 deficiency should not be considered a reason to avoid taking metformin.”

Is Metformin Losing Its Luster?

The current black box warning may be overstating the kidney risk. Yet, we need to use some caution. Metformin has a reputation of being a real blockbuster drug and is the primary drug in the treatment of type 2 diabetes. This may be a potential problem due the FDA and the limit placed on it usage. The current label carries a contraindication against the use of metformin when serum creatinine levels exceed 1.4 mg/dl in women or 1.5 mg/dl in men.

Despite its establishment as the first-line therapy for type 2 diabetes, about one-half of the patients currently in the United States do not take it. A major proponent of this is its current labeling, which expresses, for some, unjustifiable concerns about its use for treatment in those with mild to moderate renal insufficiency.

In the last few years, clinicians in the USA have developed an overwhelming consensus that the US Food and Drug Administration (FDA) labeling for metformin could be more lenient and also that it can be expressed in more precise estimated glomerular filtration rates (eGFRs), rather than serum creatinine.

The FDA's initial rationale behind the label was due to resilient evidence that phenformin caused lactic acidosis (another biguanide which has been removed from the US market). Metformin is cleared from the body via the kidneys and for patients with significant renal failure, there were increasing concerns that metformin could potentially build up to relatively high levels that could leave patients to have lactic acidosis. There is now an overwhelming two decades’ worth of research and evidence showing no serious increased risks for lactic acidosis in patients with mild-to-moderately impaired renal function.

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have furthermore supported the removal of restrictions on metformin, propagating the notion that practitioners “would continue to prescribe metformin even when the eGFR falls to less than 45 to 60 mL/min/1.73m2, perhaps with dose adjustments to account for reduced renal clearance of the compound. One criterion for stopping the drug is an eGFR of less than 30 ml/min/1.73m2.” It is important to note that patients with chronic kidney disease would require stringent follow-up of renal function.

One of the most recent studies published on the potential impact of metformin eligibility for adults in the United States assessed 3,902 patients with diabetes who partook in the 1999-2010 National Health and Nutrition Examination Surveys. These patients were eligible if the serum creatinine levels met the eligibility markers “of less than 1.4 mg/dl for women and less than 1.5 mg/dl for men along with eGFR categories (likely safe, greater than or equal to 45 mL/min/1.73 m2; contraindicated, less than 30 mL/min/1.73 m2; and indeterminate, 30–44 mL/min/1.73 m2).” Different equations were used to measure eGFR, including: four-variable MDRD, CKD-EPI, CKD-EPI cystain C and Cockroft-Gault with diabetes itself being self-reported or for patients with an A1C greater than 6.5%.

The results of this particular study demonstrated that by replacing the serum creatinine threshold with eGFR thresholds, practitioners were able to expand metformin’s utilization for patients without any significant safety concerns. Findings noted that metformin use amongst patients with an eGFR of 90 ml/min or higher was 90% with a slight drop to 80% with an eGFR of 60 to 90 ml/min. Even with patients with an eGFR below 30 ml/min were found continuing use of metformin; based off of the collected results, an estimation could be made on how many additional people may have benefited from starting therapy (approximately 425,000 patients if the data was from the 60 to 90 ml/min group and almost 560,000 patients if expanded to the 30 to 60 ml/min group). The key main findings of the study include: metformin use has increased in the past decade or so for treatment of type 2 diabetes and implementing eGFR or CrCl rather than serum creatinine thresholds for eligibility of use could considerably expand the utilization of the drug. With greater use of metformin, there is consequently tighter glycemic control, resulting in improvement of healthcare.

Looking forward to the future, additional research is imperative, including prospective randomized trials of metformin at multiple stages of renal injury and a much closer examination of archives of CKD patients taking metformin.

Treat Prediabetes as Diabetes

What can we as people with type 2 diabetes do to encourage our doctors and other professionals to help people with prediabetes? This is a difficult question and David Mendosa tackles prediabetes from a different perspective that is interesting to read.

David says, “If you have prediabetes, taking the diabetes drug metformin might stop you from getting diabetes and could also help you in other ways. But persuading your doctor to prescribe it could be a challenge.” Yes, many doctors will not prescribe metformin “off label” and probably because they do not feel this is the correct thing to do.

Lifestyle intervention is not working because most doctors and certified diabetes educators refuse to work with people with prediabetes. Without education and reinforcement, most people will fail here because of the term prediabetes and the lack of seriousness by doctors and CDEs.

The biggest factor hurting people with prediabetes is the American Diabetes Association. The ADA only gives prediabetes a casual mention and even ignores many people with type 2 diabetes when Dr. Robert Ratner, chief scientific and medical officer for the ADA that says, “Many people with type 2 diabetes who are on medications don't need to do home glucose monitoring at all," in talking about oral medications.

It is this attitude that discourages doctors and especially patients when they know that people inside the ADA are not on their side and working to make management of diabetes work for them. Dr. Ratner wants people with type 2 diabetes to manage diabetes in the dark and make diabetes progressive.

Fortunately, many people are learning to buy the testing supplies on their own, are reading on their own to manage prediabetes and type 2 diabetes, and are ignoring the ADA. I have many people that ask me why I cover some of the ADA guidelines when they don't care about people with prediabetes and diabetes. I have to tell them that we still need to be aware of what they are saying and if there is any hope for change. The ADA has changed some in recent years, but still done very little for helping people with prediabetes, which is a group of people they created in 2003 with their experts.

David does cover some of the known side effects of metformin and gives some of the proper warnings. You should take the time to read his blog.

Metformin Has Link to Neuropathy, B12 Deficiency

Called me puzzled! I have never understood why the American Diabetes Association had never called for testing of vitamin B12 deficiency for people taking metformin for any length of time. Even this article shows a lack of this testing and only calls for more research. This is why I am reversing the situation and listing what Diabetes-in-Control lists as practice pearls first.

Practice Pearls:

1. Metformin has been linked with vitamin B12 deficiency.
2. A randomized placebo-controlled trial showed that metformin use is associated with an increase in neuropathy scores for patients.
3. Current guidelines do not offer specific instructions on metformin and B12 deficiency, but future research is warranted.

Yes, one of the most common and beneficial T2DM drugs may contribute to neuropathy and vitamin deficiency – metformin.

The link between metformin and vitamin B12 lowering is well-known and mentioned in American Diabetes Association guidelines as a disadvantage of the drug. However, the ADA gives no recommendations for monitoring and prevention of vitamin B12 deficiency for patients taking metformin. Vitamin B12 deficiency is associated with adverse effects such as anemia, fatigue, mental status changes, and neuropathy. Given the prevalence of neuropathy in diabetic patients, metformin-induced vitamin B12 deficiency is clinically relevant.

The relationship between vitamin B12 deficiency and metformin was studied in a recent randomized placebo-controlled trial. The trial lasted 52 months and included 390 type 2 diabetes patients. They were treated with 850 mg metformin at doses up to three times a day or a placebo. Patients with baseline vitamin B12 deficiency or patients taking vitamin B12 supplements were excluded from the trial.

Metformin is prescribed around the world, so this relationship warrants more investigation according to the study authors. Future studies may clarify the relationship and will help the authors of guidelines decide whether to recommend testing or supplementation.

Doctors Ignore Guidelines for Prediabetes Patients

Many of the diabetes news sources are carrying this news item. The titles vary by what each source wants to emphasize. Basically, the consensus is disparaging about doctors that are under using metformin to treat prediabetes. Considering that the drug is generic and cheap, I can agree that this is an inexpensive therapy to help manage and possibly prevent the full onset of type 2 diabetes.

Before I continue, I will make some observations. First, I am not surprised at the lack of prescriptions for metformin because many doctors are not screening for prediabetes. Second, many doctors believe prediabetes and diabetes are a lifestyle disease and want patients to suffer and will not prescribe any medications until full diabetes is present and sometimes even then will delay medications. These doctors want to see improvement in weight and other lifestyle changes that prove the patient will follow a medication regimen. Many patients often surprise these doctors by making the lifestyle changes and not needing the medications the doctors were planning to make them take because the doctors believe that prediabetes and diabetes are progressive and people will not be able to manage their prediabetes or diabetes.

Metformin was prescribed for only 3.7% of patients with prediabetes, even though it can help prevent the onset of type 2 diabetes, according to a new retrospective cohort analysis. Lead author Tannaz Moin, MD, from the David Geffen School of Medicine at University of California, Los Angeles, says, “We were surprised to see just how low the [prescription] rates were, particularly among the highest-risk individuals, where evidence for metformin use is strongest."

"Despite inclusion in national guidelines for more than 6 years and proven long-term tolerability, safety, and cost-effectiveness, the prescription of metformin in the real-world clinical approach to diabetes prevention remains unclear," Dr Moin and colleagues write.

Their findings are published in the April 21 issue of the Annals of Internal Medicine.

Among those with a BMI equal to or greater than 35 kg/m2 (n= 391) or gestational diabetes (n = 121) the prevalence of metformin prescription was 7.8%. This is "the group for which the ADA guideline places the most emphasis on treating prediabetes with metformin," the authors write.

In their study, Dr Moin and colleagues analyzed data from a national sample of 17,352 adults aged 19 to 58 years with prediabetes between 2010 and 2012 who were insured for 3 continuous years to determine the percentage who were prescribed metformin.

In 2008, the American Diabetes Association (ADA) updated its "Standards for Medical Care in Diabetes" guidelines to include metformin use in patients aged less than 60 years who are at very high risk [of diabetes], are very obese (body mass index [BMI] greater than 35 kg/m2), or have a history of gestational diabetes.

The guidelines also say clinicians can consider metformin in those with impaired glucose tolerance, impaired fasting glucose, or an HbA1c of 5.7% to 6.4%.

Again, this study is interesting and would be more valuable if doctors were taking prediabetes seriously and screening for it.

Two other articles can be read. The first is from Science Daily, titled “Drug that can prevent onset of diabetes is rarely used.” The second is from Diabetes-in-Control and is titled “Metformin Reported in Use with Only 3.7% of Those with Prediabetes.”

Help in Diabetes Management Education – Part 10

Part 10 of 12

Goals and how to set them is up to you. Beware of doctors that set the goals for you and will not discuss the reasons or why they are what they are. These paternalistic doctors need to be in control, but do not want you in charge of anything. Never mind that you only see them at most about one hour per year. If you don't make their goals, be prepared for a tongue-lashing. If you want to find out how bad they are, tell them that your goals are different short-term and you will consider their goals long-term. Be prepared to be told to find another doctor.

No, a doctor should suggest goals and give you the reasons, but if you have other ideas, they should listen. If they feel you are not setting the correct goal, they may encourage you to try for a different goal. This means that they are trying to help you, and will listen to you. Suggestions are always appropriate from doctors, until they know you and how hard you work or don't work to attain goals.

I have supplied you with reading to help you set your own goals in the last nine blogs.

Depending on the progress of your diabetes at the time of diagnosis, you might want to consider a goal of getting off medication. This will depend on many factors; the first is whether you have a doctor that will accept this. Second, you will need a plan of action that your doctor approves. Then you will need a food plan that will help keep your blood glucose levels in acceptable range.

Next, make sure that you have an exercise regimen that you will enjoy and are capable of accomplishing. Many fail when it comes to the last two items. You will need to keep testing and seeing the doctor for appointments. The next thing will be whether you are succeeding or having problems. Testing will let you know as will the A1c that the doctor sees. The important thing to realize is if you are having trouble keep your blood glucose levels down that you don't stay off medication for too long.

One of our new members tried three times before giving up when his blood glucose levels kept rising each time. The third time his doctor told him not to try again until he had kept his blood glucose levels below a set level for at least six months on medication and then for another six months at a lower level of medication. His doctor is supporting him and this makes him want to keep trying until he knows it is no longer possible.

Besides goals, people need to understand that as they age, their bodies can stop being efficient enough in obtaining the vitamins and minerals necessary for health from many foods. Most of the time the correct foods will supply everything you need.

People that are on metformin need to be concerned that they are not becoming deficient in vitamin B12. Folic acid (vitamin B9), especially when taken in high doses, can mask the symptoms of a vitamin B12 deficiency. Older and even a few middle age people with type 2 diabetes can become unable to absorb or manufacture vitamin B12 from animal foods. Vitamin B12 is found only in animal foods. Liver, sardines, and salmon rank highest, with liver running away with it. Kidney, eggs, beef, and pork are also good sources. There are no vegetarian sources.

If you develop neuropathy – a tingling or burning in your feet, and especially the toes may indicate that you may have a vitamin B12 deficiency. The quicker you have the test the more likely you will be able to prevent the neuropathy from spreading. Some of our members have had vitamin B12 shots and then prescribed a supplement and a few others have been told to start a vitamin B12 supplement.

The final bit of information on this is your blood glucose levels need to be managed to keep them below 140 mg/dl. With about 60 percent of the people with diabetes developing neuropathy, this tells us that many people are not managing diabetes and may vitamin B12 deficient.

Metformin Not First-Line Treatment

Even though this is interesting, it still does not tell us why many doctors are not using metformin as the first-line treatment for type 2 diabetes. The results of a new US study show that only 58% of individuals with type 2 diabetes were started on metformin as their first oral glucose-lowering medication. This is despite the fact that this drug is widely recommended as the initial therapy of choice in numerous diabetes guidelines.

I can say that insulin can be an excellent choice when the doctors have waited too long to diagnose type 2 diabetes, but this isn't even mentioned in the people receiving other medications. All were other oral medications - sulfonylureas, thiazolidinediones, and dipeptidyl peptidase 4 (DPP-4) inhibitors. The Study period was from July 2009 to end of June 2013 and who filled a second prescription for a medication in the same class within 90 days of the first.

Senior author Dr Niteesh K Choudhry, from the division of pharmacoepidemiology at Harvard Medical School, Boston, MA explained it this way, "These findings have significant implications for quality of life and medication costs."

In an accompanying commentary, Drs Jodi B Segal and Nisa M Maruther (Johns Hopkins University School of Medicine, Baltimore, Maryland) agree with these conclusions. "This meticulously conducted study… adds modestly to what is already known on this topic. First-line therapy should be metformin in patients without contraindications."

“Without contraindications” is the key and this, along with quality of life and medication costs are the reasons for metformin being considered in first-line therapy. Occasionally some doctors are persuaded by drug representatives to use other medications and money may be the reason these doctors start with the more expensive drugs.

Dr. Choudhry stated, “Although the study did not examine the specific prescribers involved, with this type of national insurer the "vast majority" of physicians would have been primary-care providers (general internists) seeing patients in routine care settings.”

A total of 15 516 patients were said to have met the inclusion criteria, of whom 8964 (57.8%) started therapy with metformin. Sulfonylurea treatment was the first drug in 23% of cases, 6.1% began treatment with thiazolidinediones, and 13.1% with DPP-4 inhibitors.

“Patients prescribed metformin were less likely to require treatment intensification compared with those who used the other medications: 24.5% who started on metformin required a second oral medication, compared with 37.1% of patients prescribed a sulfonylurea, 39.6% who began with a thiazolidinedione, and 36.2% given a DPP-4 inhibitor first. Sulfonylureas, in particular, were associated with more adverse cardiovascular events and hypoglycemia.”

I am aware of many patients that are started on metformin, extended release (ER), that have been doing well because they followed directions and consumed it with food or at meal time and had few of the gastrointestinal problems. Others have started on regular metformin and have encountered the gastrointestinal discomfort. Most are okay in a few weeks and a few have been unable to tolerate this. I don't know anyone using the liquid metformin, but it is available.

In addition to the above link, this topic has received wide press. One more link if you are interested is this by Healio Endocrine Today.

Metformin Without Vitamin B12 May Impair Cognition

I am a little surprised at this study, as I have been aware of this for some time and knew that metformin caused Vitamin B12 deficiency. I also knew that Vitamin-B12 deficiency could cause cognition problems in patients. Now a new study from Australia suggests, repeat, suggests this may be true. Yes, there have been some conflicting studies previously, but apparently, this study can only suggest this being the case. This tells me this study missed some important points or was incomplete in the data collected.

Lead author Eileen M. Moore, PhD, a medical research scientist in the department of surgery, Deakin University, Geelong Hospital, Barwon Health, Geelong, Australia, says, “Up to 30% of patients taking metformin may be deficient in B12, and this is thought to be due to an interaction between metformin and a receptor in the distal ileum, leading to some inhibition in the uptake of the vitamin.”

She continued, "Metformin remains a very effective first-line antidiabetic drug and may reduce cardiovascular risk in patients with diabetes. Clinicians and patients should not be alarmed by these findings, but the need to monitor and correct vitamin-B12 levels is highlighted."

At least she understands how important her last statement above is and that doctors with patients on metformin need to be tested for vitamin B12 deficiency. Dr. Moore recommends "Clinicians should consider monitoring cognition in [all] patients over the age of 50 years who use metformin, especially when there are other risk factors for dementia present. Because current treatments for dementia are palliative only, intervention in the early stages of cognitive decline remains the best option.”

This is important in the United States because many doctors do not and will not test for vitamin deficiencies as they believe in the medication route only and that we should obtain our vitamins and minerals from a well balanced diet only. What these doctors do not understand is that with metformin, even patients on a well-balanced diet have malabsorption of vitamin B12 and this leads to the deficiency.

Even with this problem, people with diabetes have a link to dementia without metformin, so it would be wise to test all patients for vitamin B12 deficiency and to be concerned about dementia.

Diabetes Experts versus Diabetes Patients

When a couple members from the support group saw this title, one made the comment, “Here we go again!” I asked what he saw in the title and he said that it was another blog about oral medications. I had to agree, as that is my intent. I must declare I am on insulin (long acting and short acting) plus a minimal dosage of metformin.

I do believe it is time for patients to declare their intentions, especially if they are on some of the medications that are being reported with serious side effects. I have nothing against metformin in the extended release version, as the gastrointestinal side effects are often minimal when taking it. Many people have no side effects with the extended release version. And the fact that it is generic and the cost is affordable and makes this an economical treatment for type 2 patients.

Yet, our diabetes experts want to stack one oral medication on top of another oral medication for several medications. I complain that this is not good and this practice by physicians needs to stop, the AACE Diabetes Algorithms not withstanding. The American Diabetes Association and the American Association of Clinical Endocrinologists don't want this to happen and advise keeping patients on oral medications. The sad part of this advice is the corporate sponsors of these two organizations are the beneficiaries and the officers of the ADA and AACE receive fees from these same sponsors.

It is convenient for me that one of the studies reported out of the ADA 2103 Scientific Sessions June 22, is about stacking three medications and the author reports starting people newly diagnosed with type 2 on triple drug therapy. You may read about this ongoing study here at Medscape. This has to make the ADA and AACE very happy.  I hope this becomes fully tested as the side effects may be great and dangerous.

This relationship with the pharmaceutical companies has to end for any trust in the ADA and AACE to be restored. How can we place trust in the guidelines issued and the recommendations of their officers when we know that they are influenced heavily by the fees they receive from the pharmaceutical companies? Then in addition, they are well paid as officers from the contributions or sponsorships of these same pharmaceutical companies to their respective organizations.

Yes, I will continue to blog about the guidelines issued by the ADA and AACE, but everyone needs to be aware of the biases built in and the underlying motives for some of their misdirected guidelines. Comprehensive the guidelines are not and with the built in discrimination by researchers when they exclude the elderly and the young from participating in research, the people that are using the majority of the medications have not had the medications tested on them. This adds more reason to take a jaundiced view of the guidelines. Insulin anyone?

And before I forget, I salute the people with type 2 diabetes that are able to manage diabetes without medications. Some have been able to manage without medications from the start while others have been able to wean themselves off medications and continue to manage without further medications.

Sulfonylureas Cause Higher Mortality Risk

Alvin Powers, MD, of Vanderbilt University in Nashville, TN, who was not involved in the study, was brave enough to make this statement, "We don't know enough about those drugs [sulfonylureas]." I thought as long as these had been around, they should have had more than enough information, but when it comes to oral diabetes medications, apparently there is still a lot to learn even when they are now in generic.

The study compared data from a large retrospective cohort study of metformin to three commonly prescribed sulfonylurea drugs. The three drugs were glipizide, glyburide, and glimepiride. The discovery was a little shocking when diabetes patients had a 50 percent higher risk of death compared to patients on metformin. The study, which was funded by drug company Astra Zeneca shows that apparently the sulfonylureas are more a cause for concern.

This is speculation on my part, but I feel that doctors just don't cover the side effects in sufficient detail. They don't emphasize the warning that these drugs cause low blood glucose by themselves (hypoglycemia) and if you skip a meal, skip the medication. This alone could be causing part if not much of the increase in mortality. Patients that do not understand the dangers of hypoglycemia will not take the care that needs to be taken. This is also an area that the certified diabetes educators seem to gloss over.

I also hope this will give researchers cause for concern and not to stack so many oral medications. Many researchers that think the larger the oral diabetes medications cocktail, the greater glycemic control there should be. Some researchers may continue to stack oral medications and fail to report adverse medication events until the adverse events become so great like they did on the ACCORD study.

Findings, like this study, presented at medical meetings are typically considered preliminary until published in a peer-reviewed journal. However, this could still cause "enormous clinical implications." Apparently, sulfonylureas have been considered safe and effective. Now we will need to see if the FDA will require a label warning.

Cost cannot be a distinguishing factor, as all three sulfonylurea drugs are available in inexpensive generic forms. Metformin offers an alternative to sulfonylureas as first-line oral therapy for diabetes and also is available as a generic.

An enterprise-wide electronic health record (EHR) system was used to conduct the retrospective study of diabetic patients who started treatment with one of the sulfonylureas or metformin from Oct. 24, 1998 to Oct. 12, 2006. The search produced records for 23,915 patients. About half (12,774) started treatment with metformin, followed by glipizide (4,325), glyburide (4,279), and glimepiride (2,537). All patients were adults treated in outpatient clinics. Investigators excluded patients using insulin, other injectable diabetes medications, or multiple oral drugs for diabetes.

The patients had a median follow-up of 2.2 years and 2,546 patients died. This was verified by the EHR or Social Security Death Index. This is how patients treated with a sulfonylurea had a mortality hazard ratio of 1.50 compared with metformin.

Because recent reports suggested sulfonylurea risk varied in patients with coronary artery disease (CAD), investigators conducted a separate analysis of 2,721 patients with a history of CAD. As compared with metformin, patients who started treatment with glyburide had a 38% increase in the mortality hazard (HR 1.38), and there was a 41% increased risk in patients started on glipizide (HR 1.41). Only glimepiride was not associated with an increased mortality hazard versus metformin.

Dr. Minisha Sood, also an endocrinologist at Lenox Hill, said that sulfonylureas may fare worse than metformin because they may "interfere" with cardiovascular processes that strengthen and protect heart tissue making it more resilient should a cardiac event occur.

"What's interesting about this study is that all three sulfonylureas examined led to increased mortality rates vs. metformin in the entire cohort study, which included patients without coronary artery disease," Sood added. "Does this mean that we shouldn't be prescribing sulfonylureas at all? I think prospective trials are needed to answer that question, so the jury is still out."

Metformin and B12 Deficiency

This is something my endocrinologist tests for and tells patients taking Metformin to take a Vitamin B12 supplement. Yet there are many doctors that do not tell their patients to add Vitamin B12 to their supplement regimen. One of the members of our group (Allen) is taking Metformin and was surprised when we told him to take Vitamin B12. After his last appointment, he said his doctor told him not to be taking supplements and said there was no reason to be on supplements if he was eating the right foods.

We decided to use this blog to discuss this with Allen. After reading this and following the links, he was still hesitant to go against his doctor. We did take time to explain that doctor or not, Metformin would cause the Vitamin B12 deficiency and that he should add this to his regimen. He did state that he had been on Metformin for almost eight years and we suggested strongly that he have the test to determine the level of B12. A call to his regular doctor confirmed that they would not do the test. We then suggested he go to the doctor that I see and he agreed

I was able to get him in the following day and went with him. After a quick talk with the doctor, he wanted to do several tests that his doctor was not doing. We waited for the lab to be available and he had a blood draw. Next, we sat for about 20 minutes and Allen asked if they will have the results that quickly. I said this was normal and depending on the tests ordered, he should receive most of them in another 10 to 15 minutes. He did ask me to accompany him when he saw the doctor and I agreed.

After updating and reviewing his medications, the nurse left and the doctor came in. He sat down, asked a couple of questions about allergies, and said he was going to get two shots. The first shot would be a Vitamin B12 injection. Then he surprised both of us by saying he would also have a large dose injection of Vitamin D. I stepped out for a few minutes and then was invited back in.

Allen was asking why the two shots. The doctor said that his Vitamin B12 was very low and required another test already ordered from the blood sample. The Vitamin D level was below minimum guidelines and he was given the shot just to prevent something that the doctor feared might happen. He did not say what it was, but for three days, Allen would need to return for the two shots. Or he said he could be admitted to the hospital. Allen said he could drive back and forth and the doctor said no driving until after two weeks or the tests were at or above minimum guidelines.

Then the doctor said he was also prescribing both B12 and D3 for him to start on the fifth day. He was to return in seven days for another round to tests and then in 14 days for repeat of tests to see if he could then drive. We asked why and he would only say that he was the first person they had seen with deficiencies that low and he and the head of the department did not want him to drive. He then asked for his license stating he could surrender it temporarily to them, or possibly a lot longer to the highway patrol. Allen looked at me and gave it up.

The doctor did say that the remainder of the tests would be available the next day and the head of the department was requesting two additional tests that would also be available. On the way home with me driving, Allen was somewhat surprised at the thoroughness and was wondering if he should consider changing doctors. I did suggest that he wait until the two weeks were done and see what he thought then. He agreed, but commented this had raised some serious issues in his mind and I had to agree.

Allen wanted to meet with Tim when we returned so he called him and Tim was there when we arrived. Tim was surprised at what had transpired, but agreed with the tests and asked if he was needed to drive. I said yes, to get me home, and for at least one or two trips. Allen asked about their taking his drivers license, and Tim said no, it was probably not legal, but that it was preferable to giving it up to the highway patrol where it would become part of his records, and that they could enforce it longer. Tim asked about which doctor he would keep and I said that Allen should not make a decision until at least this was done. Tim said that was probably best, but should be seriously considered. I agreed and said this should be discussed along with other possibilities.

Allen did want some reading and Tim said he would stop back after he took me home. We did discuss some reading and search words for him to leave Allen. Tim said he would take Allen the next day and we could alternate. I said that would work, but we should let Allen decide if he had preferences. Tim said he would, but that he could not go every time.

The next day, Allen asked me to come by when he returned home. So with Tim and me present, Allen asked what was he to do. He had all the test results now and he was really frightened. All the tests had been out of range on the low to extreme low side and the doctor had suggested he see another doctor for more tests. I agreed with Tim when he said that he should see the second doctor and get his health checked out. Tim did state that it was time to decide on making a change in doctors. He said he felt from what had been discussed today, that Allen was being given a second chance and he should take full advantage of it by switching doctors now and having his records transferred.

I could see some fear in Allen, so I asked him when his VA appointment would be. He said in about five months and I said that would be good. Therefore, if he ended up with some expensive medications and the VA had them or ones in the same drug family, the doctors would synchronize with the VA and he would be ready. I could see Allen relax visibly and he asked if the doctors would work with the VA? I said not the way he was thinking, but that he would give the doctors the name of his VA doctor and they would send a fax or call them with what they were suggesting for medications and see if the VA could get them started coming to him. The doctors would also forward copies of the tests and the reasons for the drug request.

Tim did say that the doctor had suggested that with his A1c and creatinine level that Allen should consider changing oral medications or start on insulin. He also said he would make a referral to the endocrinologist. Allen did say he would like to stay on oral medications if possible, but he was going to pay more attention to our discussions about insulins and not leave it as a medication of last resort. We said that was okay. I suggested that he should ask for the test for determining how much insulin he was still producing before he made that decision. Tim said that was another test they had done and his own insulin production was still okay, but on the low side. He said to Allen that just the fact he wanted to learn about insulin was a good sign and would make him ready when the change was right.

The following two days I drove Allen and we had some interesting discussions about the different oral medications and insulin. He did say that since the doctor had given him some time to read about the different oral medications and their side effects, he was thinking seriously about insulin. I did suggest that he ask which oral medications they would be recommending and Allen said that would give him a better idea instead of learning about all the oral medications.

One the fourth day, Allen said doctor (after conferring with the endocrinologist) would have a recommendation for him when he came in for the blood draw the following Tuesday, and that he should seriously consider insulin. So we asked several others to meet with us on Saturday and we would research and discuss oral medications in more detail and insulin. Even Brenda asked to be included so we would be only short one person as Sue had another commitment.

Are Physicians Correct in Not Following ADA Guidelines?

This is one article that gave me a different message than I was expecting. When I read the headline “Many Physicians Do Not Follow ADA-recommended Prescribing Guidelines,”  I actually thought this may be a good thing. However, the article did not give me any of what I was thinking.

I had hoped that the discussion may have been about starting newly diagnosed patients with type 2 on insulin to gain maximum management quickly. No, the article was about prescribing oral medications only and not the use of cheaper, generic medications, but the more expensive oral medications. When doctors force patients to use oral medications that are more expensive by $1,120 (or more) per year, this is the wrong way to proceed.

These doctors do need to be called on the carpet and asked to explain their reasons.  There is one very effective generic that these doctors were not prescribing. It is the drug metformin that is recommended as the first line of treatment by the American Diabetes Association (ADA) and another Professional Group for persons newly diagnosed with type 2 diabetes.

This study was the work of researchers from CVS Caremark, Harvard University, and Brigham and Women's Hospital. It looked at data from pharmacy claims for 254,000 patients started on diabetes medications between January 1, 2006, and December 31, 2008. You know that insurance companies will review their records to see what the doctors are prescribing and whether they should revise their formulary.

After reading this blog and the linked article, you may wish to review your medications with your doctor to determine if you are using the correct medication and not one that is overly expensive. If your doctor has you on one of the brand medications and refuses to change to a generic, you may want to have a pointed discussion with the doctor or consider a second opinion.