A Case of the Sugars

Case #355: Glucose-driven atherosclerotic risk in the well-controlled patient

Michael” is a 65-year-old male with a history of dyslipidemia and hypertension. When I saw him in early 2007, he had two of five NCEP risk factors and a Framingham Risk Score over 10 percent. Michael weighed in at 245 lbs with a BMI above 30 and had quit smoking in 2000.

His blood pressure and lipids have been very well controlled on a beta blocker, calcium channel blocker, thiazide and aspirin since 2003. In the past he had been on statin and fibrate therapy, but was currently on FDC statin/ER niacin.

Michael’s family history includes a grandmother who had a stroke in her 60s, his father with MI in his 60s who lived into his 70s, plus late onset DM2 with his mother and other family members in their 80s. His health, lifestyle and family history were cause for concern regarding diabetes as well as risk of stroke and heart attack.

Imaging
We had obtained a carotid ultrasound with atheroma measures and CIMT some years back, which was abnormal. CUS/CIMT in July 2010 showed significant plaque, with mean composite of 0.811 mm with right bulb plaque 3.1 mm heterogeneous (het) plaque and left bulb plaque of 1.4 mm and 2.2 mm het. Repeat testing in July 2011 showed mean composite CIMT of 0.878, which we noted was increasing on excellent BP and lipid therapy. Michael’s right bulb showed 3.8 mm of het plaque (atheroma and growing) and left bulb 1.6 mm and 2.9 mm het (growing) and LICA 1.4 mm het plaque. The growing plaque burden was of major concern.

VAP
Cholesterol Test

March 2007
August 2007
March 2008
TC 122 96 124
TG 195 (high) 122 93
Direct LDL 54 44 63
NHDLc 85 65 79
IDLc 10 8 8
VLDLc 31 (high) 21 16
VLDL3 16 (very high) 12 (high) 10 (high)
IDLc+VLDL3 (RLPs) 26 (near high) 20 18
HDLc 36 (low, it has been lower) 31 43
HDL2 10 (large, buoyant, protective; low) 6 (low) 7 (still low, should be > 10)
HDL3 26 (low) 25 (low) 36
LDL Density Pattern A/B pattern A/B pattern B pattern
LpPLA2 121

Labs
Click here to view Michael’s VAP Test results and appropriate reference ranges from Atherotech:

Lab Results
Michael has been on statin therapy since the early 2000s and on rosuvastatin 10 mg since the mid 2000s. His VAP lipid results from March 2007 are shown in the chart at right.

The patient’s comparative VAP lipids in Aug 2007 on rosuvastatin 10 and fenofibrate 145 are shown in the chart at right.

Note the improvements, but also note the persistent defects. ER niacin was then added.

Michael’s VAP lipids in March 2008 on rosuvastatin 10, fenofibrate 145, and ER niacin 1000 are shown in the chart at right.

Again, note the improvements, but I was still concerned with low HDL2, remnant VLDL3 and persistent dense LDL pattern. Was Michael diabetic? Fasting glucose was 125 mg/dL; the rest of his CMP and thyroid testing were normal. His HgbA1c was 5.8%. In 2008, this measure was not considered at-risk for DM2, and we chose not to obtain 2 hour OGTT testing. The American Diabetes Association revised its recommendations in 2009 to encourage the use of HbA1c as a diagnostic — as well as management — tool in clinical practice.

Note again the transition of lipid changes with treatment. He needed to maintain LDLc < 100 and NHDLc < 130 based on NCEP and FRS. Considering his low HDLc and cardiometabolic risk, we chose more aggressive targets.

Repeat CUS/CIMT testing in July 2011 showed continued increasing atheroma on excellent BP and lipid therapy, which caused me significant concern. Concurrent with carotid ultrasound, his July 2010 Atherotech labs showed glucose and CMP were normal. The VAP on FDC statin/ER niacin showed findings in the chart at right.

VAP
Cholesterol Test

July 2010
July 2011
TC 113 113
TG 102 126
Direct LDL 53 54
NHDLc 69 74
IDLc 6 7
VLDLc 16 20
VLDL3 10 (high) 11 (high)
IDLc+VLDL3 (RLPs) 16 19
HDLc 43 39
HDL2 9 (low) 8 (low)
HDL3 35 32
LDL Density Pattern B pattern A/B pattern
LpPLA2 121 119
A1c 5.4%
NTproBNP 66
Vitamin D 33
ApoB 57 57
ApoA1 134 128
Apo B/A1 Ratio 0.43 0.45

The July 2010 VAP showed that Michael was persisting with TG, remnant VLDL3, low HDL2 and dense LDLc.

We repeated Atherotech labs in July 2011 with carotid ultrasound on FDC statin/ER niacin. A1c was now back up to 5.8% and glucose was 109. VAP results revealed:

The numbers show that he continued with the same defects. I ordered the GlycoMark 1,5-anhydroglucitol (1,5- AG) test to measure postprandial glucose. His GlycoMark was markedly abnormal at 9.6 ug/mL; we therefore ordered two-hour OGTT testing at the hospital. His fasting glucose in December was 56 mg/dL on no glucose medications and only a family history of late onset DM2 in family members on his Mom’s side (in their late 80s).

Michael’s subsequent two-hour OGTT in August 2011 showed:

  • Fasting glucose = 138, no urine glucose (they did not perform insulin levels as I had ordered)
  • 30 minute urine = no glucose
  • 60 minute and 120 minute urine = 3+ glucose
  • 30 minute, 60 minute and 120 minute serum glucose = 225, 275, 229 respectively (pretty impressive! Especially with A1c of 5.8%)

We added FDC saxagliptan 5 mg/glucophage 1000 mg qd and repeated the two-hour OGTT in January 2012. A1c again is 5.8%. Michael’s fasting insulin was 25 and fasting glucose was 115. His 60 minute glucose was markedly better at 165; 120 minute glucose was also much improved at 155 mg/dL.

Discussion
From the beginning, I was concerned about Metabolic Syndrome, family history, heart disease risk and diabetes risk. In addition to my clinical experience, published research has also given us insight into these clinical challenges. In 2000, Alexander, Landsman and Teutsch reported in the American Journal of Cardiology that that patients with diabetes mellitus — both diagnosed and undiagnosed (by fasting glucose only), as well as impaired FG — have an increased risk of heart disease, compared with those with normal FG.

Again, my general philosophy is to assess risk through NCEP, Met Syn and FRS plus VAP lipid testing and non-invasive imaging:

  • Two of five NCEP factors equate with moderate risk
  • Met Syn/prediabetes is indicated with three of five positive cardiometabolic risk factors
  • FRS 10-year risk prediction

In Michael’s situation, we have a very interesting case where a simple GlycoMark Test encouraged us to perform a two-hour OGTT and confirm diabetes type 2 in well-controlled HTN and lipids on multiple agents. The importance of lifestyle changes was emphasized, as his weight problems were definitely a factor.

However, the patient’s atheroma growth and persistent lipoprotein abnormalities led me to believe his problems were glucose driven. Adding GlycoMark postprandial glucose testing and blood glucose testing to VAP advanced lipid testing helped me resolve this challenging presentation.

In my experience, insulin and insulin resistance results in overexposure to long-term insulin, which may be “toxic” and pro-atherogenic. Michael was definitely insulin resistant. He likely had insulin resistance for more than a decade and postpriandial glucose (PPG) problems nearly as long. I also see patients who aren’t insulin resistant, yet have a PPG problem. I think in those cases, after-meal, sugar-prolonged elevations are also endotoxic and atherogenic. They appear to be two different issues but often coexist in most obese patients.

In the Patient’s Terms
Quitting smoking in 2000 was obviously a major, positive move. However, with all the other issues going on, I emphasized to Michael that it was imperative he work on therapeutic lifestyle changes and lower his waist and weight. This would lower his risk and keep his diabetes under control. With proper monitoring and testing along with lifestyle modification, I assured Michael we could manage his risks, avoid the early MI and stroke that affected other members of his family and help him live a much healthier life.

His blood pressure, lipids and diabetes are now well controlled. We will repeat imaging and labs, including GlycoMark and two-hour OGTT. As a final note, I do think that thiazolidinedione therapy or other incretin-based options would also have been suitable for his new onset diabetes along with lifestyle changes.

Abbreviations
BMI = Body Mass Index
BP = Blood Pressure
CIMT = Carotid Intimal-Medial Thickness
CMP = Cardiometabolic Metabolic Panel
CUS/CIMT = Carotid Intimal-Media Thickness/Carotid Ultrasound
DM2 = Diabetes Mellitus Type 2
FDC = Fixed Dose Combination
FRS = Framingham Risk Score
GlycoMark = monitors intermediate glycemic control by measuring the levels of the monosaccharide 1,5-anhydroglucitol (1,5- AG) in blood
HDLc = High Density Lipoprotein Cholesterol
HgbA1c = Glycosylated Hemoglobin A1c, (also A1c) for diagnosing diabetes and managing glucose levels post diagnosis.
HTN = Hypertension (high blood pressure)
IDLc = Intermediate Density Lipoprotein Cholesterol
LICA = Left Internal Carotid Artery
LDLc = Low Density Lipoprotein Cholesterol
Lp-PLA2 = Lipoprotein-associated phospholipase A2, The PLAC Test.
Met Syn = Metabolic Syndrome, or The Cardiometabolic Syndrome
MI = Myocardioal Infarction (Heart Attack)
NCEP = National Cholesterol Education Program
NHDLc = Non-HDL Cholesterol
NTproBNP = N-terminal Prohormone BNP
OGTT = Oral Glucose Tolerance Test
PPG = Postprandial Glucose
Qd = Daily
RLP = Remnant Lipoprotein
TC = Total Cholesterol
TG = Triglycerides
TSH = Thyroid Stimulating Hormone
VAP = Vertical Auto Profile (VAP) Test
VAP UC = VAP Ultracentrifugation = VAP Test
VLDLc = Very Low Density Lipoprotein Cholesterol


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