Hayward Zwerling, M.D.

Endocrine review for the year 2003

Before proceeding with this year's endocrine review, I would like to comment on 3 endocrine issues and one general issue.

First, the most efficient workup for a thyroid nodule that is picked up on physical exam is to obtain a baseline TSH. If the TSH is normal, the patient should be referred to an endocrinologist or otolaryngologist for biopsy. It is not necessary to get the thyroid ultrasound, scan or any other imaging studies, prior to the referral. If the TSH comes back suppressed, then the patient should have a 123 iodine scan and uptake to determine if it is a hot nodule. Hot nodules are very unlikely to be malignant.

The second issue that I would like to mention is the use of Fosamax, Actonel and Evista to osteopenia and osteoporosis. In our medical community, it has become very common to treat osteopenic post-menopausal women. Although this is technically acceptable, there no data demonstrating that treating osteopenic women prevent fractures. When treating women who have osteoporotic (not osteopenic) women with a bisphosphonate, the fracture rate is reduced from about 25% over the course of 3 years. This means that 30 women must be treated for three years in order to prevent one fracture. If/when we get fracture data from the treatment of osteopenic women, it is likely that we will find that maybe 100 women must be treated for three years to prevent one fracture. When look that from this perspective, I believe the enthusiasim for treating osteopenia (both from the patient's perspective and a public health perspective) is considerably less.

Third, prior to the initiation of therapy for erectile dysfunction using Viagra or Levitra, the physician needs to determine whether or not there is evidence of hypogonadism. Obviously pituitary tumors and primary testicular failure will result in erectile dysfunction. Thus, before either of these agents are initiated, patients should have an FSH and a total testosterone level. If either of these tests is abnormal, the patient should be referred to an endocrinologist.

Finally, I believe physicians and the public need to understand that the treatment with a drug does not ensure that the patient's outcome will be better. Drug representatives encourage the use of a drug if it has been shown to reduce the risk of disease. If a five years study shows a reduction in the risk of an event from, say, 4% down to 2%, the drug representative will rightfully tell you that their drug reduces the risk of disease by 50%. Although this sounds very impressive, one should remember that, given that data, a physician would need to treat 50 patients for five years to prevent one event. When looked at from the perspective of the number needed to treat (NNT), the drug does not look nearly as impressive. Given the financial collapse of today's health care system, I think it is imperative that all physicians consider the cost effectiveness of all medical therapies. A recent statement by the American College of Physicians has endorsed this philosophy. I also believe that all physicians should routinely ask their drug rep to disclose the NNT.

I hope you find the below summary useful. I appreciate your referrals. If you are considering acquiring an electronic medical record for your office, please stop by and look at ComChart EMR (www.comchart.com) before you make a commitment. You will find that ComChart is better designed than the other EMRs and it can file labs from Lowell General, PathLab and Quest.

Sincerely,

Hayward Zwerling, M.D., FACP


OBESITY
As everybody is aware, the American public is getting heavier. Data has been collected which demonstrates that this increased in size is due to an as increase in portion sizes. Activity patterns over the last decade have not changed. This trend towards increased portion size began in the 1970's and accelerated 1980's. I have begun to encourage my patients to begin the "lose a third diet." I have suggested to them that they should reduce their portion sizes of anything they eat by 1/3. If they are going to eat an apple, doughnut, muffin, salad, steak, bag of chips, or glass of juice, they should discard/remove one-third of the portion, before the begin eating.

Structured exercise program are not successful in helping patients maintain weight loss. Despite frequent reminders, patients become noncompliant with the prescribed exercise regime. In order to maintain weight loss, patient's need to exercise 4 or 5 times a week for about 45-60 minutes. (Hardly realistic for most patients.) Metabolism 51:1003, 2002

In a meta-analysis, the incremental benefit of using anti-obesity medications is relatively small.

DIABETES
Zyprexa (olanzapine) is associated with a clinically significant increased risk of developing diabetes. Risperdal (risperidone) is associated with a nonsignificant increased risk of developing diabetes. Patients treated with these drugs should be monitored more closely for the development of diabetes (BMJ 325: 243, 2002) On rare occasions, Zyprexa can cause DKA.

The use of ramipril (Altace), over the course of five years is associated with about a 34% decrease risk of developing diabetes. This is likely class effect of all ACE inhibitors. (One would need to treat approximately 55 patients for five years to prevent one case of diabetes.) JAMA 286: 1882, 2001

In poorly controlled diabetics on a sulfonylurea and metformin, the addition of a thiazolidinedione (Actos or Avandia) can further reduce the hemoglobin A1C. However, this comes that a significant cost. Three drug therapy costs approximately $10 a day whereas the use of insulin with metformin is about $3 a day and, the use of insulin alone is substantially less expensive. It has been my practice to avoid the use of a three drug therapy because of the cost issue and because it has been shown that the side effect profile is much higher when compared with insulin alone.

A Finnish study has demonstrated that the risk of death in type 2 diabetics who have a first coronary event coronary is the same as non-diabetics who have establish cardiac disease. Thus, the recommendation that all diabetic should have an LDL cholesterol less than 100. A recent study from Scotland refutes (BMJ 325:939,2002) this claim by demonstrating that patients with type 2 diabetes are at lower risk of death than patients with establish heart disease. At this time, it is still my goal to get the LDL cholesterol of all diabetics are under 100. In Circulation 105:1424, 2002, it has been demonstrated that diabetics, with an LDL cholesterol of less than 125, benefit from Pravastatin therapy.

Blood glucose testing in the forearm may not registered acute changes in the blood sugar as quickly as blood glucose testing in the fingertips. Thus, postprandial blood sugar testing in the forearm may not be accurate. Also, testing the blood sugar in the proximal nail bed tends to be less painful than on the tip of the finger.

Although Medicare will pay for special diabetic shoes, a recent study has shown that therapeutic shoes and inserts do not significantly reduce the incidence of ulcerations in those patients who have no severe foot deformity. 2 previous studies have shown a benefit. JAMA 287: 2552, 2002

Good glycemic control (hemoglobin A1C less than 7.5%) is predictive of improve survival of diabetic patients who were starting hemodialysis. Although dialysis is associated with an abysmal prognosis, patient should still be treated to keep the hemoglobin A1C less than 7.5 Diabetes Care 24: 909, 2001

Surgical ICU patient's who are on mechanically ventilation will have a reduction in mortality (8% down to 4.6%) if their diabetes is treated aggressively to maintain a blood sugar less than 110. In this study (NEJM 345: 1359, 2002), IV insulin infusion was used. Results may not be applicable to Medical ICU patient's. In patients who have had acute myocardial infarction treated with insulin glucose infusion to maintain blood sugars below 215, followed by multiple dose insulin regime, long term outcome is improved. Lancet 99: 2626, 1999

CABG reduces cardiac morbidity and mortality to a greater extent than PTCA in diabetic patients. Diabetic patients with severe LV dysfunction may not benefit from CABG. JACC 36: 1166, 2000

As of yet, there is no data that type 2 diabetics have better control if they monitor their blood sugars. Although it may be desirable to have diabetics occasionally monitor their blood sugars, evidence based medicine suggested that should not be considered an essential part of the treatment plan. Home blood glucose testing is also very expensive.

LIPIDS
In a study of more than 20,000 adults with coronary artery disease, neither vitamin C, vitamin E or beta-carotene reduced the 5 year mortality from a cardiovascular disease, cancer or other major outcomes. In addition, it has previously been demonstrated the beta-carotene supplementation, in smokers increases the risk of lung cancer. At this time, there is no justification for the use of anti-oxidant therapy to reduce the risk of cardiac disease in patients with establish coronary artery disease. Lancet 306: 23, 2002, NEJM 345:1583, 2001

In a meta-analysis of almost 20,000 patients, there was no different in non-cardiovascular serious adverse events when comparing those treated with Pravastatin 40 mg versus the control group. The percentage of patients who had LFTs more than three times the upper limit of normal was the same as the control group. Pravastatin was discontinued in three patients and seven placebo patients had their medications discontinued because of elevated CPK. No cases of mild or severe myopathy were observed. Thus, Pravastatin is extremely safe. Circulation 105: 2341, 2002

There is no objective data (randomized control) to unequivocally demonstrate starting a statin at the time of a cardiac event or within two or three days of a myocardial event is to the patient's advantage. Further, one article suggested that early the initiation of statin therapy, in acute coronary patients whose baseline LDL cholesterol is less than 130, may result in a worse prognosis. (JAMA 287: 3087, 2002) On other hand, the cessation of statin therapy, in the setting of an acute cardiac event, is associated with a worse outcome when compared to patient's who remained on their statin and when compared to patients were never treated with a statin. (Circulation 105: 146, 2002,) Thus, patient's who have an acute cardiac event and are already on a statin should remain on their statin during and after their hospitalization.

Combination therapy of statin-fibrates or statin-niacin is safe and effective in high risk patients. This combination should be considered for all patients who have persistent dyslipidemia, after they reached the LDL goal. CPK should be monitored when using statin-fibrates and glucose, uric acid should be monitored when using niacin. One may also want to occasionally monitor SGOT. Yearbook of Endocrinology 2003, page 78

60% of all patients with acute MI have preexisting diabetes, newly discovered diabetes or impaired glucose tolerance. Fasting and post challenge hyperglycemia in the early phases of an acute myocardial infarction may be considered early markers of high risk patients. Lancet 359: 2040, 2002

Hormone replacement therapy results in an increased risk of thromboembolic disease, CVA, breast cancer, coronary artery disease and a decrease risk for fractures and colon cancer. Overall 5 year mortality is not effected. During the first one or two years of therapy, the risk of coronary disease is increased. During the subsequent three to five years of therapy, the risk is decreased. At this time, there is little justification for using hormone replacement therapy except to treat menopausal symptoms, transiently. JAMA 288: 321, 2002

THYROID
The use of LT4 therapy to reduce the size of a nontoxic multinodular goiter is not efficacious whereas 131 iodine can be effective.

Subclinical hypothyroidism during pregnancy should be treated aggressively to prevent abortion and premature delivery. Thyroid 12:63, 2002. In patients who are on LT4 therapy prior to pregnancy, 70% will need their LT4 dose increased by 46 mcg per day in order to maintain a euthyroid status. After the deliver, they should immediately be returned to their pre-pregnancy dose.

The clinical course of thyroid cancer is more aggressive in patients who have Graves' disease and thus, these patients should be treated more aggressively.

Subclinical hyperthyroidism (undetectable TSH with normal FTI and T3) is a risk factor for atrial fibrillation. It is not yet known whether the treatment with an anti-thyroid regime prevents the development of atrial fibrillation. In patients with atrial fibrillation, 19% who have subclinical hyperthyroidism and 24% to have overt hyperthyroidism, who will revert to sinus rhythm after their rendered euthyroid.

The current normal range of TSH (approx 0.3 - 5) is probably derived from a population that included some patients who have subclinical hypothyroidism. The normal TSH range should probably be considered closer to 1-2. In patients who are on LT4 therapy, I usually attempt to get the TSH into 0.5 - 2.0 range.

At this time, methimazole should be the preferred drug for treating hyperthyroidism, with the exception of pregnant women.

Patients over 60 years of age, who have had a low TSH with normal thyroid levels (subclinical hyperthyroidism) have a significantly increased mortality from cardiovascular disease and should be treated aggressively. Lancet 358: 861, 2001

OSTEOPOROSIS
Patients who were diagnosed with osteoporosis should probably have, at a minimum the following studies in order to rule out secondary causes: 24 urine for calcium and creatinine, serum calcium, serum parathyroid hormone level and probably a 25-hydroxy-vitamin D level. Patients on LT4 therapy should also have a TSH. This panel of tests will diagnosed 98% of all secondary causes of osteoporosis. JCEM 87 4431,2002. The same group of tests should be considered for all women were admitted to the hospital with hip fractures, and in whom osteoporosis has been diagnosed.

The use of Zometa, an intravenous bisphosphonate, given once a year has been shown to improve bone density to about the same degree as the oral bisphosphonates such Fosamax and Actonel. NEJM 346: 653, 2002

Combination therapy of a bisphosphonate in conjunction with either Premarin or Evista is as or more effective at improving bone mineral density and/or reducing markers of bone turnover, when compared to either agent alone. We did not know if combination therapy reduces the fracture rate to a greater extent than single agent therapy alone. When comparing Fosamax versus Evista versus combination therapy, combination therapy is the most effective in the hip. Combination theray is not significantly better in the spine, when compared to Fosamax alone but it is better than Evista alone. JCEM 87: 985, 2002. The combination of Actonel and Premarin is more effective at improving bone mineral density in the hip then estrogen alone. JCEM 86: 1890, 2001. I do not believe one should begin using combination therapy until the patient has had at least a 2-3 year trial of a single agent and also had secondary causes of osteoporosis excluded: Hypercalcuria (9.8%), malabsorption (8.1%), primary or secondary hyperparathyroidism (6.9%), vitamin D deficiency (4.1%), exogenous hyperthyroidism (2.3%). It should also be noted that the lower limit of the "normal" vitamin D is probably higher than that currently reported, thus patients may have Vitamin D deficiency if ther 25-PH Vitamin D level is at the lower end of normal.

The newest agent to treat osteoporosis is Forteo teriparatide)20 mcg sc qd, is the amino terminal end of the parathyroid hormone molecule. This drug is about $20 a day and can improved bone density to a much greater extent than the bisphosphonate and is also more effective in reducing the non-vertebral fracture rate. It is the only agent that actually helped build a bone. It is not yet clear whether this agent is safe in the long run. It is recommended that it be used for no more than 6 months at a time or a maximum of two years. The drug is contraindicated in patients with osteogenic sarcoma, Paget's disease, children in young adults with growing skeletons. I have not starting using Forteo.

In patients who have primary hyperparathyroidism and osteoporosis, Fosamax therapy can improve bone mineral density. However, parathyroid surgery should remain the first treatment option. JCEM 87: 4482, 2002