The Rodney Dangerfield of Cardiovascular Risk Factors in Diabetes

Some of you may remember the great comedian Rodney Dangerfield who passed away in 2004. While some may remember his roles in Caddy Shack or Back to School (my favorite), he was best known for his catchphrase “I don’t get no respect” which was the basis for many comedy monologues.

When we speak of cardiovascular risk in diabetes, we invoke cholesterol, chronic hyperglycemia, reactive oxygen species (ROS), AGE’s, the presence of kidney disease and perhaps others. But almost no one talks about, measures, or attempts to treat one risk factor that is well recognized and treatable (or at least the effects of it seem to be). Have you guessed it yet?

Haptoglobin (Hp) was first described in 1938. It is an α2-sialoglycoprotein coming mainly from hepatocytes in response to the secretion of cytokines such as IL-6, IL-1 and TNF. Haptoglobin is a tetrameric protein that structurally resembles immunoglobulins because it has two light chains (α) and two heavy chains (β) covalently bound to each other by disulfide bridges (S-S). Its main function is to rapidly bind free hemoglobin from intravascular hemolysis to keep it from oxidatively damaging the vascular endothelium. Although present in all vertebrates, in humans Hp is characterized by molecular heterogeneity caused by genetic polymorphism. In the 1940s and 1950s structural heterogeneity was establish when alleles of different structures and lengths were identified, categorized as Hp 1-1, Hp 2-1, and Hp2-2. While these variants can be found in patients without diabetes, much of the work on their role as risk factors has been done in the context of diabetes (both type 1 and type 2). Biologic functions of Hp include prevention of renal damage from intravascular hemolysis, protection against ‘toxic radicals’, and sparing of nitric oxide when unbound to hemoglobin. It has also been found to have a variety of different effects comprising an immune-modulating action. All of these effects seem to differ with the haptoglobin phenotype, and in general a protective role is seen in patients with the Hp 1-1 variant, and a lack of protective effect or more pathological role is seen with the Hp 2-2 variant. Approximately 40% of patients with diabetes carry the Haptoglobin 2-2 gene variant (1)

Increased oxidative stress in diabetic patients results from oxidation of glucose and the modification of low-density lipoproteins (LDL). These changes may stimulate the production of inflammatory cytokines that have been implicated in the morphological and pathological changes found in macrovascular and microvascular complications, and different degrees of susceptibility to the development of vascular problems have been observed in studies of the antioxidant properties of Hp. In diabetic patients, those with Hp 1-1 show better protection against complications than Hp 2-1 and Hp 2-2 individuals. The Hp 2-2 phenotype has been found more frequently in people developing type 2 diabetes (2). Hp 2-2 has been shown to be a major risk factor in diabetic vascular disease (3), an increased risk of Coronary Heart Disease (4) an increased cardiovascular mortality in type 1 diabetes (5), an increased risk of renal function decline (6), an increased risk of death following stroke (7), retinopathy (8) and many other risks of complications in people with diabetes.

Also, as many of you know, both type 1 and type 2 diabetes are associated with the so called ‘leaky gut’. In type 1 diabetes various antigens are presented to the maturing gut which can stimulate the development of activated T-cells which, over time, destroy pancreatic beta cells. In type 2 diabetes, the ‘leaky gut’ allows lipopolysaccharides into the circulation, releasing cytokines and adipokines causing inflammation, insulin resistance and eventually diabetes with loss of beta cell mass due to glucose and lipid toxicity. A major factor associated with ‘leaky gut’ is zonulin, discovered in 2000 by Fasano. Zonulin is pre-haptoglobin-2. (9) It is fascinating that the haptoglobin 2 allele (especially in those individuals who are homozygous [hp 2-2] would confer risk of diabetes, and risk within diabetes likely due to its role in gut permeability and ongoing inflammation…

The risk associated with the presence of the Hp 2-2 genotype can be mitigated with vitamin E treatment to a striking degree. While vitamin E has not been shown to affect surrogates of risk in individuals with Hp 1-1, its effect is clear for those with Hp 2-2. The summary abstract below speaks for itself:

Clinical trial data from the HOPE, ICARE, and WHS studies is presented showing a pharmacogenomic interaction between the Hp genotype and vitamin E on the development of CVD. Specifically, in individuals with diabetes and the Hp2-2 genotype, vitamin E has been shown to be associated with an approximately 35% reduction in CVD. Cardioprotection by vitamin E in individuals with the Hp2-2 genotype appears to be mediated in part by an improvement in HDL functionality as demonstrated in three independent trials in both type 1 diabetes and type 2 diabetes. (10)

Despite this positive review, and others like it, over 300 articles in PubMed regarding haptoglobin in diabetes, and several presentations at ADA Annual meetings, the current ADA Standards of Medical Care don’t even mention haptoglobin.(11) It truly is the ‘Rodney Dangerfield of risk factors in diabetes’!

So my question to all of you is: With the clear role of haptoglobin genotype 2-2 in the risk of micro and macrovascular complications AND with the clear indication that treatment with Vitamin E can substantially reduce that risk…when was the last time you suggested obtaining a haptoglobin genotype for your patient with diabetes?

1) Changing the Face of Diabetic Care with Haptoglobin Genotype Selection and Vitamin E Nina S. Levy, Ph.D. and Andrew P. Levy, M.D., Ph.D. Rambam Maimonides Med J. 2011 Apr; 2(2): e0047

2) Shi X, et al. Haptoglobin 2-2 Genotype Is Associated with Increased Risk of Type 2 Diabetes Mellitus in Northern Chinese. Genetic Testing and Molecular Biomarkers 2012;16:563-568

3) Asleh R. and Levy AP. In vivo and in vitro studies establishing haptoglobin as a major susceptibility gene for diabetic vascular disease. Vascular Health and Risk Management 2005;1:19–28

4) Cahill LE, et al. The Risk of Coronary Heart Disease Associated With Glycosylated Hemoglobin of 6.5% or Greater Is Pronounced in the Haptoglobin 2-2 Genotype. Journal of the American College of Cardiology 2015;66:1791-9

5) Costacou T. and Orchard TJ. The Haptoglobin genotype predicts cardio-renal mortality in type 1 diabetes. J. Diabetes Complications. 2016;30:221-6

6) Costacou, T, et al. Haptoglobin Genotype and Renal Function Decline in Type 1 Diabetes. Diabetes 58:2904–2909, 2009

7) Ijas P, et al. Haptoglobin Hp2 Variant Promotes Premature Cardiovascular Death in Stroke Survivors. Stroke. 2017;48:1463-1469

8) Mukund R, et al. Haptoglobin2-2 phenotype is an additional risk factor of retinopathy in type 2 diabetes mellitus. Indian Journal of Human Genetic. 2013 Apr-Jun; 19(2): 154–8.

9) Fasano A., Physiological, Pathological, and Therapeutic Implications of Zonulin-Mediated Intestinal Barrier Modulation. The American Journal of Pathology 2008;173:1243-1252

10) Hochberg I, et al. Interaction Between the Haptoglobin Genotype and Vitamin E on Cardiovascular Disease in Diabetes. Current Diabetes Reports 2017_online Jun 17

11) American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care 2017; 40: Supplement 1

Rectifying 2013 ACC/AHA Lipid Guidelines in patients with Diabetes

Since the release of the 2013 ACC/AHA Guidelines on the Treatment of Blood Cholesterol to Reduce Atherosclerotic  Cardiovascular Risk in Adults, much attention has been placed on potential overtreatment of patients with statins and overuse of higher doses of statins. In our patients with diabetes, these guidelines recommend a moderate intensity statin for those with LDL-C between 70-189mg/dL aged 40-75 yrs without atherosclerotic cardiovascular disease (ASCVD) and a high intensity statin in those with LDL-C between 70-189mg/dL aged 40-75 yrs with an estimated 10 year ASCVD risk of ≥7.5%.1  There is substantial evidence of major benefit to support the use of moderate intensity statin therapy in patients with diabetes.  This evidence is from 2 major trials which showed compelling evidence of decreasing the risk of first major coronary events, coronary revascularization or stroke with atorvastatin 10mg compared to placebo or simvastatin 40mg compared to placebo.2-3

Controversy comes with the recommendation of high intensity statins in patients with estimated 10 year ASCVD risk of ≥7.5%. Little to no evidence exists in this specific population, however the recommendation is made based on extrapolation from those at increased risk without diabetes.  Given the concerns regarding the validity of the new ASCVD risk calculator and possibility of it overestimating the true ASCVD risk of our patients, this recommendation could lead to over treatment with high intensity statins.4  If one were to input the baseline characteristics of our key primary prevention studies in the ASCVD risk calculator, the results indicate that population would have needed high intensity statin therapy based on their risk being >20% considering the trials mostly included men. This is concerning given the potential link between statins and increased risk of diabetes and worsening glycemic control.5-6 Adverse effects of statins are known to be dose related, more frequent in females and possibly greater in the Asian population.7 Additionally, risk calculators were not used to determine eligibility in any of landmark trials investigating the effect of statin therapy on the prevention of cardiovascular disease. Risk calculators are only as good as the population from which they have been derived and there are limitations with each.

Clearly, all patients with diabetes would benefit from statin therapy.  The question is, what dose is necessary to best prevent first cardiovascular events in our patients while minimizing the potential adverse effects? How do you address this in your clinical practice? What risk calculator do you use to assess your patient’s risk?


  1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA Guidelines on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. J Am Coll Cardiol. 2014;63:2889-2934
  2. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the collaborative atorvastatin diabetes study (CARDS):multicenter randomized placebo-controlled trial. Lancet 2004;364:685-96
  3. Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial. Lancet 2003;361:2005-16
  4. Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease. Lancet 2013;382:1762-65
  5. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011;305:2556-64
  6. Ergou S, Lee CC, Adler Al. Statins and glycemic control in individuals with diabetes: a systematic review and meta-analysis. Diabetologia 2014;57:2444-52.
  7. Chatzizisis YS, Koskinas KC, Misirli G, et al. Risk Factors and Drug Interactions Presidposing to Statin-Induced Myopathy: Implications for Risk Assessment, Prevention and Treatment. Drug Saf 2010;33:171-187.

Aspirin: My Wonder Drug

Aspirin is a “Wonder Drug” (I know that because it says so on my bottle). In my case the wonder is why we don’t use more of it for people with diabetes (not only more often, but more drug in each dose).

We know that people with diabetes are ‘hypercoagulable’ having increased platelet reactivity as well as increases in several coagulation factors likely due to constant low-grade damage to vascular endothelium by ‘glucose toxicity’. Aspirin therapy has been a topic of a multitude of studies over many years. There are meta-analyses and even mega-aggregation meta-analyses, and unfortunately they often come to different conclusions (!) Several things tend to stand out. Studies have suggested that low dose aspirin works in secondary prevention, and there are mixed results in primary prevention studies. In most of these studies, individuals with diabetes are mixed in the overall patient population, and thus their results in primary and secondary prevention are obfuscated to some extent when the collective results are published.


Several studies have suggested that people with diabetes have ‘aspirin resistance’ which may be a combination of hypercoagulability and lack of effect of lower doses in some patients. A recent study in patients with diabetes without known cardiovascular disease (Bethel, Diabetic Medicine 2016;33:224) suggest that doses greater than 100 mg/day (either 200 mg in one dose or 100 mg twice daily) have a greater effect on platelet reactivity than 100 mg/day, and there other some evidence supporting a rough dose response relationship for the antiplatelet effect, the degree depending on the assay you use (Gurbel, et al. Circulation. 2007 115:3156).

Some meta-analyses will conclude that larger doses of aspirin are associated with more significant rates of major bleeding. One of the references often cited (Yu, et al. JACC Intervention 2012;5:1231) points out the importance of digging deeper into the data, since the authors concluded: “In patients with ST-segment elevation myocardial infarction undergoing primary PCI, discharge on high-dose rather than low-dose aspirin may increase the rate of major bleeding without providing additional ischemic benefit” despite the fact that twice as many individuals in the ‘high dose’ aspirin group (>200 mg/da) were taking a concomitant thienopyridine compared with the ‘low dose’ group (<200 mg/da). Many studies related to bleeding complications have other methodological issues as well. Clearly aspirin has a tendency to reduce blood coagulation, which is why we give it in the first place. There are studies that found increased major bleeding that was (kind of) dose related, other studies that did not find that, and yet more studies where only minor bleeding episodes were increased with increasing dosage. Were some of these folks individuals who shouldn’t have been given it in the first place? Are the differences in these studies clinically significant? Try wading through some of them, and you will quickly get frustrated by what information is NOT in the studies.

As you know, current aspirin recommendations are 75-162 mg/da (ADA) in subgroups for secondary prevention and for primary prevention only if your CV Risk is >10%…but with all the disagreements on which risk engine is the best, and clear differences between them…what’s a pharmacist to do? Our knowledge base is hostage to a dosage no-mans land where studies have suggested that 100 mg /day or more may be better and more predictable vis-à-vis risk reduction, but if you only have access to the 81 mg tablets, then you give two tablets per day at least. If 200 mg/day works better than 100 mg per day (see Bethel, above) then you are potentially stuck with giving either three tablets of 81 mg or a full 325 mg tablet. The cost differences alone are significant for diabetes patients. What is sorely needed is a study on only patients with diabetes, with multiple dosages of aspirin, with concomitant measures of coagulability [there are several and none seems preferable], stratified by risk such as the stratification used in ACCORD, and using the ‘best’ risk engine…whatever that one is! Then and only then will the multitude of heterogeneous recommendations, negative and positive findings related to effectiveness and side effects be put to rest. In the meantime, a lot of people take aspirin (Williams, et al. Journal of Gen Intern Med 2015;48:501) despite their use being classified as “inappropriate” (Hira, et al. JACC 2015;65:111).

There are other benefits to taking aspirin regularly including lower rates of colorectal cancer (Cao, et al JAMA Oncology 2016 _online Mar 3), and those occur more commonly in patients with type 2 diabetes (Guraya, World J Gastroenterol. 2015;21:6026). Of course you should not give aspirin to someone with a bleeding disorder…we all know that. Me, I’m taking a full aspirin every day, inappropriate or not, and I tell my diabetes patients to do the same!