Sugar turns LDL cholesterol “ultra-bad”

Posted on June 19, 2011 by Dr. Jonathan

That serving of french toast may be doing more to contribute to cardiovascular disease than promoting insulin resistance and dyslipidemia. A paper just published in the journal Diabetes details how excess blood sugar causes LDL cholesterol to stick more readily to arterial plaque. Inflamed vulnerable plaque on arterial walls is the main precipitating factor for heart attacks and strokes. The authors set out to…

“…study whether modification of LDL by methylglyoxal (MG), a potent arginine-directed glycating agent that is increased in diabetes, is associated with increased atherogenicity.”

Glycation is the damaging process by which sugar binds to substances in the body that it shouldn’t do normally. As the practitioners reading this know, hemoglobin A1c (HbgA1c, produced by glycation of hemoglobin) is an important laboratory metric for determining how high a person’s blood sugar has been on average over the previous few months. People with pre-diabetes (metabolic syndrome) and type 2 diabetes have higher levels. By modifying human LDL by methylglyoxal to reproduce what happens in vivo, the authors were able to measure the effect on LDL particle characteristics and its tendency to deposit in the arterial wall. What did they find?

“MGmin-LDL [glycated LDL] had decreased particle size, increased binding to proteoglycans, and increased aggregation in vitro. Cell culture studies showed that MGmin-LDL was bound by the LDL receptor but not by the scavenger receptor and had increased binding affinity for cell surface heparan sulfate–containing proteoglycan. Radiotracer studies in rats showed that MGmin-LDL had a similar fractional clearance rate in plasma to unmodified LDL but increased partitioning onto the aortal wall…A computed structural model predicted that MG modification of apoB100 induces distortion, increasing exposure of the N-terminal proteoglycan–binding domain on the surface of LDL. This likely mediates particle remodeling and increases proteoglycan binding.”

In other words, glycated LDL is a nasty compound that is less likely to be scavenged from the bloodstream; and it is smaller, denser and stickier than normal LDL so that it has a higher tendency to adhere to the blood vessel well. Glycated LDL has been called the “ultra-bad cholesterol“. It also shows part of the reason why blood sugar lowering therapies reduce cardiovascular disease. The authors conclude:

“MG modification of LDL forms small, dense LDL with increased atherogenicity that provides a new route to atherogenic LDL and may explain the escalation of cardiovascular risk in diabetes and the cardioprotective effect of metformin.”

Less mortality and cardiovascular risk with metformin than other diabetes drugs

Posted on April 11, 2011 by Dr. Jonathan

It’s by far best to prevent type 2 diabetes by acting on the earliest signs of metabolic syndrome with appropriate lifestyle changes and evidence-based support for genetic and epigenetic needs based on objective laboratory data. All too often, however, this isn’t accomplished and the case advances to type 2 diabetes as insulin resistance mounts and insulin production can no longer compensate. When we enter the realm of pharmaceuticals for T2DM there are choices. A huge study just published in the European Heart Journal offers valuable evidence that metformin is associated with much less risk of cardiovascular disease and all-cause mortality. The authors state:

“The impact of insulin secretagogues (ISs) on long-term major clinical outcomes in type 2 diabetes remains unclear. We examined mortality and cardiovascular risk associated with all available ISs compared with metformin in a nationwide study.”

The authors examined the data for all Danish residents over 20 years old who starting taking an a single-agent insulin secretagogue (medication that provokes the secretion of insulin, ISs) or metformin between 1997 and 2006, a total of 107,806 subjects. They were followed for up to 9 years (3.3 years on average) for all-cause mortality, cardiovascular mortality, and the combination of myocardial infarction (MI), stroke, and cardiovascular mortality. This was correlated with the use of individual ISs. What did their data show?

“Compared with metformin, glimepiride: 1.32, glibenclamide: 1.19, glipizide: 1.27, and tolbutamide: 1.28 were associated with increased all-cause mortality in patients without previous MI. The corresponding results for patients with previous MI were as follows: glimepiride: 1.30, glibenclamide: 1.47, glipizide: 1.53 (1.23–1.89), and tolbutamide: 1.47. Results for gliclazide and repaglinide and were not statistically different from metformin in both patients without and with previous MI, respectively. Results were similar for cardiovascular mortality and for the composite endpoint.”

In other words, for example, patients (who had never had a heart attack) taking glimepiride had a 32% increased chance of dying compared with taking metformin. The authors conclude by stating:

“Monotherapy with the most used ISs, including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than other ISs.”

This outcome is not unexpected when we consider that, in addition to suppressing hepatic glucose production, metformin acts to increase insulin receptor sensitivity. The authors of an editorial published in the same journal comment on the gravity of this study:

“While this is not the first study to evaluate outcomes with these drug classes comparatively, the observations are among the most robust published based on the very large sample of patients with drug choices largely free of selection bias, sufficient numbers of events ascertained to yield substantial statistical power to analyse outcomes for each insulin secretagogue individually, with additional stratification by history of previous myocardial infarction.”

Important: metformin is known to interfere with vitamin B12 absorption (see previous posts). Patients should be followed carefully for indications of suboptimal vitamin B12 levels, preferably by urine or serum methylmalonic acid assays.

More evidence that metformin can cause vitamin B12 deficiency

Posted on July 4, 2010 by Dr. Jonathan

British Medical Journal Patients with advanced diabetes whose insulin receptors have sustained years of damaging insult sometimes require the medication metformin. Clinicians and patients alike need to bear in mind that metformin tends to cause a deficiency of the critical nutrient cofactor vitamin B12. Research just published in the British Medical Journal reminds us that this is not in question or a matter of opinion. The authors set out to…

“…study the effects of metformin on the incidence of vitamin B-12 deficiency (<150 pmol/l), low concentrations of vitamin B-12 (150-220 pmol/l), and folate and homocysteine concentrations in patients with type 2 diabetes receiving treatment with insulin.”

Incidentally, this reference for vitamin B-12 is extremely low and far from optimal. After following 390 patients with type 2 diabetes who were treated with 850 mg metformin or placebo three times a day for 4.3 years, what did they conclude from their data?

“Long term treatment with metformin increases the risk of vitamin B-12 deficiency, which results in raised homocysteine concentrations. Vitamin B-12 deficiency is preventable; therefore, our findings suggest that regular measurement of vitamin B-12 concentrations during long term metformin treatment should be strongly considered.”

Do remember that serum B12 is not a reliable indicator. To ascertain that your genetic and circumstantial needs for this critical cofactor are actually being methylmalonic acid, measured in serum or urine, is much more reliable.

Another warning about metformin for diabetes and Vitamin B12

Posted on March 16, 2010 by Dr. Jonathan

Diabetes Care 0210 Judging from the tone of this paper just published in the journal Diabetes Care, there are still too few professionals and lay people alike who are not aware that Vitamin B12 must be attended to when taking the type 2 diabetes drug metformin. The authors focus on the varying severity of diabetic neuropathy and observe:

“Long-term use of metformin is associated with malabsorption of vitamin B12 (cobalamin [Cbl]) and elevated homocysteine (Hcy) and methylmalonic acid (MMA) levels, which may have deleterious effects on peripheral nerves.”

It won’t surprise any readers of these posts that their data showed…

“Metformin-treated patients had depressed Cbl levels and elevated fasting MMA and Hcy levels. Clinical and electrophysiological measures identified more severe peripheral neuropathy in these patients; the cumulative metformin dose correlated strongly with these clinical and paraclinical group differences.”

Their conclusion:

“Metformin exposure may be an iatrogenic cause for exacerbation of peripheral neuropathy in patients with type 2 diabetes. Interval screening for Cbl deficiency and systemic Cbl therapy should be considered upon initiation of, as well as during, metformin therapy to detect potential secondary causes of worsening peripheral neuropathy.”

Remember, when taking metformin you need to check your B12 levels, not by measuring it in the serum (blood) which is unreliable, but with methylmalonic acid in the blood or urine (not perfect but better) and keeping an eye on homocysteine.

Lifestyle beats metformin for diabetes prevention

Posted on January 4, 2010 by Dr. Jonathan

The 10-year follow-up of diabetes and weight loss in the Diabetes Prevention Program Outcomes Study was reported in a paper published recently in The Lancet. The authors state that “Diabetes incidence in the 10 years since DPP randomisation was reduced by 34%…in the lifestyle group and 18%…in the metformin group compared with placebo.” It has been my experience that, although evidence-based nutraceuticals and medications have an important role, lifestyle factors including diet and exercise carry the greatest weight. Also hear this story on the impact of lifestyle changes reported on NPR.

Taking Metformin? Make sure you have Vitamin B12

Posted on November 2, 2009 by Dr. Jonathan

There is abundant evidence that metformin, a medication commonly used for type 2 diabetes, impairs the absorption of Vitamin B12 (even by broad pathological reference standards, not to mention the more sensitive functional reference ranges). Few patients seem to be told about this even though it has been well known for a long time:

For vitamin B12 I recommend the sublingual methylcobalamin form.

(Metformin is a type of biguanide. Homocysteine and methylmalonic acid levels go up with B12 deficiency.)

Diabetes Drugs Do Not Reduce Inflammation

Posted on October 8, 2009 by Dr. Jonathan

This Harvard study shows evidence that although metformin (a commonly used diabetes medication) and insulin lower blood glucose, they do not reduce key inflammatory biomarkers. With these medications the blood sugar goes down, but the inflammation continues. These inflammatory biomarkers are associated with a host of chronic diseases: cardiovascular, cancer, autoimmune, etc. Moreover, “recent-onset type 2″ diabetics were assessed. The damage starts before the diagnosis.