I saw an 82-year-old man last week with an HbA1c of 6.1%. His basal insulin had been continued to be increased because of fasting morning hyperglycemia. His fasting blood glucose was often in the 200 mg/dL to 300 mg/dL range. Because of this, his primary care provider raised his dose of bedtime basal insulin. He was not on scheduled pre-meal insulin but had a correction scale of fast-acting insulin, which he rarely used because whenever he did, he became hypoglycemic.

Scenarios such as this are common. The first question I ask when I see a frail elderly individual with such a low HbA1c while treated with insulin or oral hypoglycemic medications is: Where is the hypoglycemia that we are missing?

Although lower HbA1c has been shown to correlate with lower-risk of microvascular complications in studies such as theUnited Kingdom Prospective Diabetes Study and others, recently the benefits of lowering HbA1c have been questioned. Intensive blood pressure and glycemic control reduced microvascular complications in ADVANCE but not macrovascular events. The ACCORD and VADT trials raised concerns about the safety of intensive glycemic control.

In a retrospective cohort study recently published on line in Lancet, Currie et al found that an HbA1c of 7.5% was associated with the lowest mortality. Both high-and-low HbA1c were associated with increased all-cause mortality and cardiovascular events. This U-shaped curve was true for patients on oral combination vs. insulin based regimens but more prominent for those on insulin. The authors suggested that if results are confirmed, guidelines may need to include a minimum HbA1c recommendation.

In my patient, I strongly suspected nocturnal hypoglycemia with rebound hyperglycemia the following morning. I advised decreasing his basal insulin and requested middle of the night fingerstick blood glucose measurements so we could be sure that the problem had been addressed. However, at first his family was hesitant to reduce his insulin. They had been told that his target was an HbA1c of <6.5%. They were under the impression that with HbA1c, lower is better.

I explained that an HbA1c of <6.5% without hypoglycemia may indeed be the target for many people. However, in an 82-year-old man who lives alone and has other comorbidities, the consequences of hypoglycemia would be more serious than the benefits of preventing microvascular complications decades in the future. In someone such as this patient, an HbA1c of between 7% and 8% without hypoglycemia is reasonable.

Many diabetologists would also have decreased his insulin as I did, even before the recent studies raising questions about intensive glycemic control. HbA1c and other therapeutic targets must always be individualized to the patient. Our question now is what are and how do we determine the ideal goals for our patients across the spectrum of presentations we see in clinical practice? Further research is clearly needed. However, until the results of such research are available, we must not forget to use simple common sense and clinical experience when managing our patients.

Treat the patient, not just the numbers!

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I recently encountered three men with poorly controlled type 2 diabetes complicated by severe hypertriglyceridemia and I was faced with some difficult decisions to make.

• Case 1: 43-year-old with type 2 diabetes for about five years; BMI of 32, HbA1c 10.2 %and triglyceride level was 7,254 mg/dL (yes, it was that high).
• Case 2: 37-year-old with type 2 diabetes for seven years. BMI of 29, HbA1c 8.6% and triglyceride level of 3,682 mg/dL .
• Case 3: 38-year-old with type 2 diabetes for only three years. BMI of 35, HbA1c 9.6% and triglyceride level of 4,943 mg/dL .

These men shared several other clinical characteristics. Each had a positive family history of type 2 diabetes; each had been treated with oral agents only until quite recently when either prandial insulin (two patients) or glargine insulin at night had been started. Each patient was asymptomatic and only one had a few eruptive xanthomas.

My problems started when I looked at their lab data, which were five to 10 days old when they came to the clinic. Not only was their triglyceride significantly high, but many other analyses in the printout were abnormal and essentially meaningless. Two of them had hyponatremia with serum sodium of 125 mEq/L and 126 mEq/L, and one patient had a reported estimated GFR of 1,273 – I did not make this up. The GFR was reported as >60 in one and 251 in the third. The total cholesterol, LDL, and HDL were also meaningless.

That they were reported at all with these obvious measurement errors and without any effort to notify the requesting physician of critical values is a major concern. In desperation I called the first of the three labs where these measurements had been made and reported. I was advised that none of the lab results from that report could be trusted. Really!! A fasting specimen should be collected and ultra-centrifuged before any measurements were made and the measurements should be made with ion-specific electrode (ISE) methods.

Now the problem is what to do with these asymptomatic patients while waiting for correct laboratory values. After discussing the clinical situation with each patient and making changes to the management of their uncontrolled diabetes I collected a blood sample from each and had it spun down in the clinic centrifuge. Even without letting it sit in the refrigerator overnight as we were taught during residency, it was abundantly evident (I was about to say abundantly clear but it was abundantly cloudy) that each of them had very lipemic serum. I am kicking myself for not doing a fundoscopic exam to look for lipemia retinalis, but I was far more concerned about lipid management.

There are options for less severe increases in triglyceride which can be classified as: Normal <150 mg/dL; Borderline 150 mg/dL to 199 mg/dL; High 200 mg/dL to 499 mg/dL; and Very high >500mg/dL.

Diet counseling is essential, but values >200 should be treated with fibric acid derivatives, niacin, or omega-3 fatty acids. With higher triglyceride levels, consideration should be given to adding a statin or increasing the dose of statin if that is already being used.

Aggressive measures including withholding food, maintaining hydration with IV fluids, and sometimes plasmaphoresis are called for in the setting of acute pancreatitis or unstable cardiac disease, but my patients were asymptomatic and such approaches did not seem justified. At the same time one has to be cognizant that an acute clinical problem could arise at any time.

Each patient was instructed to limit his food intake (unlikely to happen) and maintain more than adequate hydration. One patient already on a statin had his dose increased and I added omega-3 fatty acid therapy. For the other two I recommended extended release niacin and omega-3 fatty acid.

To date, my patients have been doing remarkably well with glycemic control on their minimalist diets and that of itself is an important lesson with long-term benefit for them. They remain symptom free from their hypertriglyceridemia but I am not sure how often it should be repeated given the complexity of the processing.

As with each of these blogs in which I report unusual/extreme abnormalities, comment and advice from readers will be a big help.

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I chose this controversial topic because I am interested in hearing others’ thoughts on the matter.

Recently, a series of studies were published raising the question of possible increased risk for malignancy with insulin glargine (Lantus, Sanofi-Aventis) compared to other insulins. Although the literature remains inconclusive, this controversy reminded me of earlier concerns regarding the use of insulin glargine in pregnancy. Soon after its release, questions were raised regarding increased affinity of glargine for the insulin-like growth factor I receptor compared with other insulins. Could this be clinically significant?

Initial teratogenic reproductive studies were performed in rats and rabbits. There were five rabbit fetuses from two litters in the high-dose group (approximately twice the recommended human starting dose) which exhibited dilation of cerebral ventricles. Fertility and embryonic development were normal. However, retrospective/observational studies have not seen increased adverse maternal or neonatal outcomes in humans treated with insulin glargine during pregnancy compared to other insulins.

Insulin therapy is standard of care in patients with diabetes who are pregnant. Insulin glargine is not approved by the FDA for use in pregnancy; however, there is currently no insulin with a formal on-label indication for use in pregnancy. Some insulins, including aspart, lispro, regular and NPH, are generally regarded as safe and are pregnancy category “B.” Insulin glargine as well as detemir, however, are pregnancy category “C,” which means these agents should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

There are widely differing opinions regarding the use of insulin glargine in pregnancy. When I ask colleagues whether they use insulin glargine in pregnancy, responses range from: “We do it all the time, is there a problem?” to “Oh no! We would never do that! You don’t use insulin glargine in pregnancy — do you?” What I find curious is how some obstetricians who avoid insulin glargine in pregnancy have absolutely no problem using oral agents such as glyburide and/or metformin. This is also off-label prescribing with unknown effects.

When insulin glargine was first released, I switched many of my pregnant patients with diabetes over to multiple doses of NPH for basal insulin coverage. This regimen worked reasonably well. In an ideal situation, however, patients who require intensive insulin during pregnancy are best managed with a continuous subcutaneous insulin infusion pump (preferably initiated before pregnancy).

Nevertheless, there are many who cannot go on an insulin pump because of insurance limitations or personal preference. In these patients, particularly those who are already on insulin glargine with excellent control, I am hesitant to switch to another basal insulin purely because of theoretical concerns. It is not that I do not think such concerns are valid. Indeed, the issue of basal insulin analogs in pregnancy must be investigated further.

I am hesitant to switch because of the real harm that can occur from poorly controlled diabetes during pregnancy. It is difficult for me to put the fetus at risk by changing to another regimen that may or may not be as effective without stronger rationale to do so.

I am interested in hearing your thoughts on this issue. Is this a concern for you? What are you telling your patients? What are you doing in your own practices?

Gallen IW. Diabet Med. 2008;25:165-169.

Fang YMV. Journal Matern Fetal Neonatal Med. 2009;22:249-253.

Henderson CE. Reprod Med. 2009;54:208-210.

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