What follows is my synopsis of the Yearbook in Endocrinology 2002’s review of important articles in endocrinology. As usual, I will add my own "spin," where I think that it is appropriate. I am also please to inform you that I am now accepting patients with Harvard Pilgrim, BCBS, Tufts and most major commercial insurances. Hayward 9/1/2002

Endocrine Review 2002

Intensive insulin therapy, to maintain blood sugars that are below 110 mg per dl reduces morbidity mortality in critically ill patients, who were mechanically ventilated and admitted to a Surgical ICU. Intensive insulin therapy reduces mortality rates from 8% down to 4.6%. The greatest reduction and mortality occurred in-patient's with multi-organ failure with a full septic focus. Intensive insulin therapy was associated if with the reduced duration a mechanical ventilation. The treatment for received intravenous insulin fusion to maintain an average glucose of 103. The results of the study may not be applicable to Medical ICU patient's, however, it has previously been shown, in diabetic patients who have had an acute myocardial infarction, maintaining blood sugars below 215 mg/dl, have improved long-term outcomes. New England Journal of Medicine 345:1359, 2002

Adipose tissue as the found to make a hormone called resistin. Resistin appears to decrease the effectiveness of insulin, and thus may be one explanation as to why obese patients frequently insulin resistant. It should be noted that the study was done in mice. As an aside, the study came from the lab of a high school friend of mine, Mitch Lazar, who was a fellow at MGH three years before me, and is now chairman of the Endocrinology Department at University of Pennsylvania. It is likely that we will see clinical implications of this discovery in the not too distant future. Nature 49:307, 2001.

Patient with adult onset diabetes (DM type 2) will sometimes go on to develop complete islet cell failure. If anti islet cell antibodies are present initially, the likelihood that the patient will developed complete beta cell failure, after five years, is 95%. Journal of Clinical Endocrinology Metabolism 86: 3032, 2001. Screening patient's who have type 2 diabetes, with anti islet cell antibodies (ICA) and/or glutamic acid decarboxylase (GAD) antibody, can help predict whether or not these patients should be classified as type 1 1/2 diabetes. In North America, approximately 30% of patients who have type 2 diabetes, have been found to have either of these antibodies. It was also found that the lower body mass index was more associated with the presence of antibodies; nevertheless, there was sufficient overlap to preclude using a body mass index to predict the presence of antibodies. As 93% of the patient's, who have both of these antibodies, will require insulin after five years, clinicians should consider using the presence of these antibodies, to consider the use of insulin therapy at an earlier point in the patient's disease course. Metabolism 50: 1008, 2001

Starlix, a nonsulfonylurea insulin secretagoue, has been approved for use in type 2 diabetes, both as monotherapy and in conjunction with metformin. As monotherapy, it has not been shown to achieve better hemoglobin A1C control when compared to Prandin. Starlix is less likely to cause hypoglycemia than is Prandin. When Starlix was used in combination with metformin, it was less likely to cause hypoglycemia than the combination of the glyburide and metformin.This may be a combination to be tried in your elderly patients. Yearbook in Endocrinology 2002, page 1

There is no data demonstrating that type 2 diabetics, who monitor their blood sugars, have improved glycemic control. Diabetes Care 24: 979, 2001. As home blood glucose monitoring is expensive and is of no proven benefit in DM-2, I think physicians should not reflexly encourage all type 2 diabetics to monitor blood sugars. As you know, there is an entire industry geared towards encouraging Medicare diabetics to monitor their blood sugars at home. (One of my patients has been told by member of this industry, that the patient should "get another physician" because it was obvious that their physician "did not know what he was doing" because of his refusal to sign the forms the company needed to be able to bill Medicare for the patient's test strips. The company has since written a formal apology. ) Nevertheless, I believe physicians should practice "evidence based medicine" and reconsider the utility of this practice on a case-by-case basis. I have encouraged many of my patients either to discontinue monitoring, or reduce the frequency at which they monitor their blood sugars. I have seen no deterioration in the patient's overall blood sugar control nor an increase in frequency of hypoglycemic events. For those patients who insist that they must monitor blood sugars several times a day, I've told them that there is no medical indication for this monitoring at that it did not seem reasonable to saddle their insurance company (or society) with the cost of the strips. They were, however, free to purchase the test strips at their pharmacy, and that they do not require a prescription to purchase the test strips. Although this may seem harsh, I believe it is imperative, if our health system is to survive, that we all must practice evidence based medicine and that we must educate our patients in this regard.

To date, there are no studies, in type 2 diabetics, which demonstrate that tight glycemic control results in a reduction in long term cardiovascular morbidity or mortality.

Diabetic woman who engage in physical activity, including regular, brisk walking, have a substantially reduced risk for cardiovascular events. Annals of Internal Medicine 134: 96, 2001

Leptin is a neuroendocrine peptide that is reduced by adipose tissue. Leptin acts in the hypothalamus to suppress appetite. A small percentage of obese patients have have a genetic abnormality which results in an inability to make a leptin, whereas others obese patients been found to be resistant to leptin (presumably a receptor defect.) In a remarkable study, published in the New England Journal of Medicine, 10 obese patients, who produced no leptin, were given b.i.d. leptin injections. All of the patient's experienced weight loss, decrease caloric intake, improved glycemic control (resulting in a reduction of diabetic therapy) and an improved lipid profile. Undoubtedly, we will hear more about leptin in the future.

American Diabetes Association recommends that aspirin therapy be consider for diabetic adults with cardiovascular disease and for those with 2 cardiovascular disease risk factors (diabetes is a risk factor.)

Avandia is equally effective whether dosed q.d. The 4 mg a day dose results in a reduction in the hemoglobin A1C of about 0.9%, whereas 8 mg q.d. results in a reduction of about 1.1 %. Therapy is associated with an increase in the patient's weight. There is also an increase in both the LDL and HDL level, which appears to be dose related. Diabetes Care 24: 308, 2001. It has been my preference to use Actos instead of Avandia, based on a single, poorly designed study which showed that the Actos had a beneficial effect on lipid profile.

The third report of the National Cholesterol Education Program now recommends target LDL-cholesterol levels that are based on the patient's risk factors and absolute risks for developing coronary artery disease Simplified, the target LDL-Chol is < 100 for patient's with CAD or diabetes, < 130 for patient's with 2 or more risk factors and < 160 for all others. Less well known are the recommendations of the panel to achieve a target "non-HDL cholesterol." The non HDL-Chol is equal to the total cholesterol minus the HDL. Treatment guidelines recommend that the non HDL-cholesterol, for patient's whose TG>200, should be a no higher than 30 points above the target LDL levels. The non HDL-Chol is considered a secondary guideline, after the LDL goal. (The HDL-Chol is a somewhat stronger predictor of cardiovascular mortality then the LDL cholesterol)

The financial burden, arising from the use of statin therapy is not inconsequential therapy. With this in mind, it is important to be aware of the number of patients that must be treated in order to prevent a single event. This is referred to as the number needed to treat or NNT. In the following sub-populations, a physician must treat X number of patients, for one year, to prevent one event:
Primary Prevention Pts without CHD or hyperlipidemia, NNT=256 (AFCAPS/TexCAPS)
Pts with hyperlipidemia and no CHD, NNT=217 (WOSCOPS )
Secondary Prevention Pts with CHD and normal lipids, NNT=167 (CARE)
Pts with CHD and hyperlipidemia, NNT= 63 (4S)
If statin therapy costs $2.50/day, this results in the expenditure of, respectively, $233,600, $198,000, $152,000 and $57,000/year/event prevented. (This excludes the cost associated with the monitoring of therapy.) For low risk patients, total expenditure is between $100,000-$700,000/year of life saved. When looked at from an economic perspective, the use statins is somewhat less appealing in low risk patients while clearly cost effective in other situations.

The best predictor of the development of peripheral vascular disease is the total cholesterol:HDL cholesterol ratio. C-reactive protein was also found to be predictive of peripheral arterial disease. The level of the C-reactive protein is felt to correlate with the inflammatory component of the atherosclerotic lesion. It is felt to identify patient's who may have inflammatory, and thus, unstable lesions. Statins have been found to reduce the C-reactive protein level. All the studies of C-reactive protein use a high sensitivity CRP which has a normal level less than 1.5 mg/dl. Patients who have values in/above the upper normal distribution are at increased risk. It should be noted that C-reactive protein is elevated by DM-2, infection, obesity and trauma. Yearbook of Endocrinology page 73

At this time, there is no substantive data to suggest that the vitamin E or vitamin C are protective against coronary artery disease. On the other hand, there is increasing data that folate 0.8 mg a day will help lower homocysteine levels 20%-25%. Given the relationship between homocysteine and CAD, folate and vitamin B12 may be effective in both primary and secondary to prevention of coronary artery disease, this remains to be proven.

Coffee appears to increase both homocysteine and cholesterol. Avoiding coffee will reduce your homocysteine level, proximally 1.0 mcmoles/L (10% decrease risk of CAD) and decrease cholesterol 10 mg/dl (another 10% decrease risk of CAD). Life would be awfully dull without coffee. I guess we all must make choices.

The use of statin therapy immediately after myocardial infarction:
Treatment with the Lipitor 80 mg q.h.s., initiated 24-96 hours after either a non Q-wave myocardial infarction or the development of unstable angina diminished recurrent ischemic events (16%) in the first 16 weeks. JAMA 285: 1711, 2001. The use of statin therapy at/or before discharge, after myocardial infarction, was associated with a 25% reduction in one year mortality. JAMA 285: 430, 2001. However, is felt that many of these studies using statins to treat acute coronary syndrome, are poorly designed. In addition, other studies have shown no benefit with the use of statins, immediately after a myocardial infarction. Yearbook in Endocrinology 2001, page 107.

Lescol 80 mg /day was not found to reduce major cardiac events or myocardial ischemia. There was a 28% reduction in mortality, however, this was not statistically significant. Yearbook in Medicine 2002 page 107. Circulation 102: 2672, 2001.

For patient's with a history of coronary artery disease and a low HDL cholesterol, the addition of gemfibrozil (Lopid) 600 mg b.i.d., results in a reduction of coronary events. (NNT= 20 man for 18 months.) Changes in the HDL cholesterol cannot completely explained to the reduction of coronary events. In this same population, the use of gemfibrozil results in a 30% reduction in the risk of stroke. (NNT= 56 man for five years.) In the year 2001, 2 studies demonstrated that increased levels of HDL-Chol were associated with a reduced risk of CVA.

There have been several studies which have demonstrated that the use of vitamin E supplementation, either alone or in conjunction with statin therapy is not effective coronary events. Further, the use of vitamin E concomitantly with the use of Zocor and niacin, can increase the incidence of coronary events, when compared to Zocor and niacin alone. At this time, the preponderance of data suggest Vitamin E should not be used at all as a treatment to prevent coronary events. Yearbook in Endocrinology 2001 page 113.

The use of protease inhibitors, in HIV patient, predisposes to the development of insulin resistance, obesity, dyslipidemia and type 2 diabetes. Although there is data to suggest that the use of fibrates can reduce hypertriglyceridemia, the lack of knowledge concerning drug interactions (statins, fibric, Proteus inhibitors,) should give one pause before prescribing such therapy. Yearbook in Endocrinology 2001 page 117

Women taking hormone replacement therapy have reduced levels of total body fat and lower levels of intra-abdominal fat. Metabolism 50: 835, 2001

Obesity is associated with insulin resistance. However, it has been found that there is a subgroup of obese women, with a body mass index > 30, who are not predispose to obesity related comorbidities. A lower level of visceral fat (despite high level told total body fat) and a longer duration of diabetes, was found to be protective against obesity related comorbidities. This raises a question regarding the medical urgency to treat obese post-menopausal women, in order to protect them from the comorbidities associated with obesity. Yearbook in Endocrinology 2001 page 135.

In young women, obesity is associated with increased rate of anxiety disorders.

Subclinical hyperthyroidism occurs in 6% of the elderly population. It is defined as a low TSH with a normal T4, a normal T3 and the absence of symptoms of hyperthyroidism. In one study, of patients over 60 years of age, subclinical hyperthyroidism is associated with about a 2 fold increase risk of mortality occurring as a result of (predominantly) cardiovascular and circulatory diseases. Nevertheless, there is still controversy among endocrinologists as to the definition of subclinical hyperthyroidism (TSH off<0.001, TSH<0.01, TSH <0.1 or TSH<0.5). For example, a TSH < 0.1 is associated with an increased 10 year risk of atrial fibrillation, however a low TSH in the range of 0.1-0.4 is not associated with increased risk of atrial fibrillation. It also remains to be determine whether the normalization of the TSH, in patients with subclinical hyperthyroidism, results in a reduction of all cause mortality. Women > 65, with a TSH < 0.1, have a 3-4 fold increase risk of fracture. Thus, treatment of subclinical hyperthyroidism must be individualized given the lack of definitive data demonstrating that treatment results in a reduction of long term risks and then failure to treat subclinical hyperthyroidism is associated with an increase morbidity and mortality. The Yearbook in Medicine 151 Yearbook in Endocrinology page 152.

One cannot predict which patients, with Graves' disease, are likely to achieve a long-term remission. Optimum initial therapy, for Graves' disease, would be methimazole 15-30 mg a day. After maintaining a euthyroid status for 1-2 years, a weaning trial should be initiated. Remission are more likely in women, patients < 40 with small goiters, mild hyperthyroidism, those with high serum antithyroid peroxidase antibodies and those with undetectable TSI, measured by using the newer and more sensitive TSI assays. The published remission rates are 20% for men and 40% for women, however my anecdotal experience would suggest that these numbers are high. Yearbook in Endocrinology 2002, page 157

Postpartum thyroid dysfunction can occur anytime up to one or more years after delivery. It effects approximately 5-10% of women and may present as hypothyroidism (49%), hyperthyroidism followed by hypothyroidism (32%) or as hyperthyroidism (19%). hyperthyroidism will sometimes resolves spontaneously, with hypothyroidism has a more variable course. It probably should be treated with LT4 for least 6 to 12 months, before a weaning trial was initiated.

Conditions associated with elevations in the estrogen level may necessitate an increased dose of LT4 in hypothyroid patients. This is frequently occurs in hypothyroid patient's who are started on birth pills or become pregnant. Although there is limited data, it appears that the same need for high dose of LT4 therapy may occur in patients who are treated with SERMS such as raloxifene or Evista.

Patients who have thyroid cancer, with a positive thyroglobulin level but a negative total-body scan showed probably be treated with a large dose of 131 iodine if the thyroglobulin level is greater than 5 (during thyroid hormone withdrawal) or greater than two (after Thyrogen). Yearbook page 201 . (At this time, there is no data to suggest treatment with iodine ablation, in patients with negative total-body scan and positive thyroglobulin level, prolongs life.)

Palpable thyroid nodules occur in approximately 20% of the population and 70% are found to have thyroid nodules by ultrasound. On the other hand, only about 5-8% of thyroid nodules are malignant. Additionally, fine needle aspiration is the first line diagnostic studies ordered to necessitate a thyroid nodule. Unfortunately, FNA is nondiagnostic about 10-15% of the time. In addition, a “benign” FNA has an accuracy rate of about 95 to 97%. Recently, it is been found that a tumor marker can be measured on the FNA specimen. (ret/PTC gene rearrangement) if the FNA is positive for the ret/PTC gene rearrangement, the nodule is malignant. Unfortunately, if the ret/PTC gene rearrangement is negative, the nodule may still be malignant (sampling error), and thus needs to be excised. Yearbook page 227. Although some physicians still use thyroid hormone suppression to assess whether or not a nodule is benign or malignant, I do not advocated such a diagnostic trial. If the nodule does not undergo more than 50% reduction in size, and if the nodule subsequently turns out to be malignant, the delay in having removed, in excess of 1 year, is associated with increased mortality.

Patient who have sporadic, nontoxic multinodular goiters have been found to have a slow, gradual increase in the size of the goiter, with the development of nodules and autonomy. After 12 years, about 10% of the patient will be hyperthyroid. The main problem is substernal thyroid extension. The best treatment is probably total or near total thyroidectomy. LT4 suppression runs the risk of the development of atrial fibrillation, and is not very effective. It is also associated with the development of osteoporosis in women. Radioactive iodine is effective but can require large doses to be effective if the goiter is large and/or has some degree of autonomous function. Radioactive iodine treatment is also associated with the development of hypothyroidism in about 45% of the patient's. Recently, the use of very small doses of recombinant human TSH (Thyrogen 0.01 mg) in combination with 131 iodine has been shown to be effective. Early treatment with 131 iodine (± Thyrogen) may be a better treatment option than surgery. Yearbook in Endocrinology page 244

In elderly women (over age 75 and with an average age of 82) conjugated estrogens have been found to increase bone mineral density at nine months. The study did not have the power to assess fracture rate. JAMA 286:1815, 2001

Patient who have hyperaldosteronism usually have either an aldosterone producing adenoma for bilateral adrenal hyperplasia. The former is treated surgically and the latter is treated medically. The presence of a unilateral adrenal mass, along with an elevated aldosterone/renin ratio may not be sufficient to prove that the hyperaldosteronism is the result of a aldosterone producing adenoma. Further testing, measuring changes in the aldosterone or 18-hydroxycortisone concentrations, may be necessary, before proceeding to surgery. In some cases, adrenal vein sampling maybe needed. Yearbook in Endocrinology, page 270-27., JCEM 85: 4526, 2000. It should be noted that adrenal incidentalomas occur in between 0.5% and 5% of the population.

Oral contraceptives are commonly used to treat her such as some in women with polycystic ovary syndrome. One study suggests that this form of therapy is less effective in obese rather than in lean women. Yearbook, page 309

Raloxifene, (Evista) can be used to treat uterine leiomyomas in post menopausal women. Yearbook in Endocrinology page 313

The incidence of hypogonadism, in healthy men, increases with age. For men and less than 50, 12% were hypogonadal. For men 50-59, 19% were hypogonadal. In the 60-69 age group, 20% were hypogonadal and in men 70 to 71 49% were hypogonadal. The study did not address whether or not men who were defined as hypogonadal, would benefit from medical therapy or whether, in fact, the "normal" range needs to be age adjusted. Yearbook page 321. It should also be noted that testosterone levels are highly variable, and the variability is even greater than measuring free testosterone levels. Usually, I attempt to measure two or three samples, before I draw any conclusions about testosterone levels, in a given patient.

Recently I came upon patient, on Androgel, whose testosterone level was markedly higher than all his prior testosterone levels. The dose of the Androgel had not been changed. In questioning the patient, it ultimately turned out that it was rubbing the Androgel in his antecubital fossa, and that the blood draw was taking place directly through an area of skin on which Androgel had been applied Once he discontinued doing this, his testosterone levels became much more consistent.

Panhypopituitarism appears to be associate with increased mortality. Some have argued that this increased mortality is a result of untreated growth, resulting in increasing cardiovascular mortality. As of yet, there is no data to prove treating patients with growth hormone deficiency prove the morbidity and mortality statistics. Yearbook in Endocrinology page 344. At this time, it remains my practice not to treat growth hormone deficiency. Once there is data demonstrating, unequivocally, that treating patients with growth hormone improves morbidity and mortality, and that other, less expensive treatment option do not achieve the same result, I will begin prescribing growth hormone replacement therapy, where indicated.

Low testosterone levels can be demonstrated in women with panhypopituitarism. It remains to be determined if testosterone therapy, in this subgroup, is beneficial to this subset of women. It has been demonstrated. DHEA 50 mg po qd, can improve a patient's sense of well-being, decrease depression and improved sexual function in those women who have a diagnosis of either primary was secondary adrenal insufficiency. Yearbook in Endocrinology page 374.