Module 6: Other Populations, Special Situations, and Complications

Multiple studies have been performed that demonstrated LDL level reduction to 50 mg/dL without significant negative results. Prior concerns where that very low LDL cholesterol levels in patients may be associated with an increased risk of death, bleeding, and cancer, and increases in muscle and liver toxicity. The Prove IT trial demonstrated decreased CV events and increased safety in patients who reached LDL levels of <40 mg/dL and 40-60 mg/dL.

1. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010 Nov 13;376(9753):1670-81. Epub 2010 Nov 8.
2. Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E; PROVE IT-TIMI 22 Investigators. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol. 2005 Oct 18;46(8):1411-6. Erratum in: J Am Coll Cardiol. 2006 Jan 17;47(2):472.

Although HDL is protective, the total amount of LDL can still be a problem. The best way to approach the problem is to consider what other risk factors for CAD are present. For a patient with no family history of CAD and who is a nonsmoker, not hypertensive, not diabetic, younger, etc, I would wait until the LDL rose above 130 mg/dL. But if the patient is diabetic and has additional risk factors, a statin and other drugs to reduce LDL would be a wise choice. If the LDL is greater than 100 mg/dL in a patient with diabetes and other risk factors, a statin is recommended no matter the level of HDL.

Medical nutrition therapy is important in the treatment of gestational diabetes. Among the oral antidiabetic agents, metformin and acarbose have US Food and Drug Administration label category B classification (see Table 3).1,2 Although glyburide is classified as category B or C depending on the manufacturer,1 studies have shown that glyburide treatment can provide a relatively safe alternative to insulin therapy. It results in lower mean glucose values with fewer hypoglycemic episodes, but there is still concern for neonatal metabolic morbidity.3 The Metformin in Gestational Diabetes trial randomized 751 women with gestational diabetes to open treatment with metformin (plus insulin, if needed) or insulin alone. Although the trial showed that metformin was not associated with an increase in perinatal complications compared to insulin, 46% of the women receiving metformin also required insulin therapy.4 At present, data are considered insufficient to establish the safety of these agents in pregnancy.
Most of the recommendations regarding insulin in gestational diabetes are from expert opinion, because randomized controlled trials are few. When treatment for gestational diabetes includes insulin, most regimens include intermediate-acting insulins such as isophane (NPH), and short-acting insulins such as regular recombinant (Humulin R) and the insulin analogues aspart (Novolog) and lispro (Humalog). Regular insulin has been the most used form of short-acting insulin. There is some evidence to support the use of short-acting insulin analogues in gestational diabetes.5 The FDA categorizes lispro and aspart as category B (not in guidelines from ACOG6 or ADA). There are not much data on the use of the long-acting insulin analogues glargine (Lantus) and detemir (Levemir) for gestational diabetes. Thus, NPH is the intermediate-acting insulin of choice for women with gestational diabetes who require pharmacologic therapy.

One randomized trial evaluated obstructive sleep apnea as a potential adverse effect of exogenous testosterone and found no significant difference between the mean number of apneic/hypopneic episodes per hour in the placebo and testosterone groups at baseline or after 36 months.¹ Several uncontrolled small studies of hypogonadal men found some evidence of increases in disordered breathing events during testosterone therapy but with wide variability in the extent of sleep disturbances between individuals.^2,3,4 Events included development of obstructive sleep apnea,² increase in apneic and hypopneic events,³ and changes in ventilatory responses.⁴ The development of clinically significant polycythemia happens infrequently from testosterone replacement therapy, but it can occur in men with sleep apnea, heavy smoking history, or chronic obstructive pulmonary disease.⁵

Several mechanisms have been proposed to explain the possible relationship between erectile dysfunction and obstructive sleep apnea. Some investigators have suggested that sleep deprivation might cause significant attenuation of nocturnal testosterone levels.⁶ In the ongoing Law Enforcement Cardiac Screening Program, which is part of the World Trade Center Health Program, study results of 870 middle-age men who were consecutively enrolled showed an independent association between erectile dysfunction and obstructive sleep apnea after controlling for known cardiovascular risk factors.⁷ These results indicate that patients with erectile dysfunction should be evaluated for sleep apnea.

In regard to the contraindication of testosterone replacement therapy and obstructive sleep apnea, the recommendation is that patients should be evaluated for signs or risk factors for obstructive sleep apnea, and testosterone replacement therapy could be used if there are no risk factors or if the obstructive sleep apnea is appropriately treated.⁷

1. Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Holmes JH, Dlewati A, Staley J, Santanna J, Kapoor SC, Attie MF, Haddad JG Jr, Strom BL. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab. 1999 Jun;84(6):1966-72.
2. Matsumoto AM, Sandblom RE, Schoene RB, Lee KA, Giblin EC, Pierson DJ, Bremner WJ. Testosterone replacement in hypogonadal men: effects on obstructive sleep apnoea, respiratory drives, and sleep. Clin Endocrinol (Oxf). 1985 Jun;22(6):713-21.
3. Schneider BK, Pickett CK, Zwillich CW, Weil JV, McDermott MT, Santen RJ, Varano LA, White DP. Influence of testosterone on breathing during sleep. J Appl Physiol. 1986 Aug;61(2):618-23.
4. White DP, Schneider BK, Santen RJ, McDermott M, Pickett CK, Zwillich CW, Weil JV. Influence of testosterone on ventilation and chemosensitivity in male subjects. J Appl Physiol. 1985 Nov;59(5):1452-7.
5. Wald M, Meacham RB, Ross LS, Niederberger CS. Testosterone replacement therapy for older men. J Androl. 2006 Mar-Apr;27(2):126-32. Review.
6. Budweiser S, Enderlein S, Jörres RA, Hitzl AP, Wieland WF, Pfeifer M, Arzt M. Sleep apnea is an independent correlate of erectile and sexual dysfunction. J Sex Med. 2009 Nov;6(11):3147-57. Epub 2009 Jun 29.
7.Erectile dysfunction is independently associated with sleep apnea in a large population of middle aged men. Poster May 16, 2011. American Urological Association 2011 Annual Scientific Meeting. http://www.aua2011.org/abstracts/printpdf.cfm?ID=1325

One recent report on mathematical models of observational data regarding the impact of seasonal sun exposure yielded results that agreed closely with measured data from a large population-based study. Advice to get 10-20 min of daily sun exposure during the summer months did little to increase overall 25-hydroxyvitamin D levels, but longer exposure would compromise skin health.¹
The Institute of Medicine 2010 report Dietary Reference Intakes for Calcium and Vitamin D2 did not offer any recommendation for sun exposure and instead assumed minimal sun exposure. There is little information about what levels of sun exposure can occur without increased risk of cancer and whether that level would contribute a significant amount of vitamin D to the body. In addition, studies of populations at different latitudes show inconsistent relationships between sun exposure and 25-hydroxyvitamin D levels.³

The amount of Vitamin D supplementation should take into account the baseline level and the patient population. Obese patients and patients undergoing bariatric surgery are at high risk for vitamin D deficiency and will need a higher dose for replacement. For recommended daily required intake for vitamin D by gender and age, see the Institute of Medicine 2010 report, Dietary Reference Intakes for Calcium and Vitamin D.²

1. Diffey BL. Modelling the seasonal variation of vitamin D due to sun exposure. Br J Dermatol. 2010 Jun;162(6):1342-8. Epub 2010 Feb 15.
IOM. 2010. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. http://www.nap.edu/catalog.php?record_id=13050, accessed August 1, 2011.
2. Lamberg-Allardt C, Kirjarinta M, Dessypris AG. Serum 25-hydroxy-vitamin D, parathyroid hormone and calcium levels in adult inhabitants above the arctic circle in Northern Finland. Ann Clin Res. 1983 Aug;15(4):142-5.

On the basis of evidence from animal and human studies, vitamin D has emerged as a potential risk modifier for T1DM and T2DM.¹ Observational case-control studies have shown that vitamin D supplementation in pregnancy^2,3,4 or early childhood^5,6,7 is associated with reduced risk of incident T1DM, but there are no trials on the effect of vitamin D on T1DM.

A systematic review of 8 observational longitudinal cohort studies reporting associations between vitamin D status and incidentT2DM, and 11 randomized controlled trials of vitamin D supplementation, were performed.⁸ The results of the meta-analyses of the observational studies showed a decreased risk of T2DM of 13% with vitamin D intake of >500 international units a day with the lowest risk in individuals with 25-hydroxyvitamin D levels of >25 ng/mL. But in several of the other included trials among participants with normal glucose tolerance at baseline, there was no effect of vitamin D supplementation on glycemic outcomes.

Therefore, the hypothesis that vitamin D may modify diabetes risk needs to be confirmed in research specifically designed for that purpose using better observational studies and randomized controlled trials that measure blood 25-hydroxyvitamin D concentration and clinically relevant glycemic outcomes.^1,8

1. Pittas AG, Dawson-Hughes B. Vitamin D and diabetes. J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):425-9. Epub 2010 Mar 18.
2. Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. 2001 Nov 3;358(9292):1500-3.
3. Fronczak CM, Barón AE, Chase HP, Ross C, Brady HL, Hoffman M, Eisenbarth GS, Rewers M, Norris JM. In utero dietary exposures and risk of islet autoimmunity in children. Diabetes Care. 2003 Dec;26(12):3237-42.
4. Marjamäki L, Niinistö S, Kenward MG, Uusitalo L, Uusitalo U, Ovaskainen ML, Kronberg-Kippilä C, Simell O, Veijola R, Ilonen J, Knip M, Virtanen SM. Maternal intake of vitamin D during pregnancy and risk of advanced beta cell autoimmunity and type 1 diabetes in offspring. Diabetologia. 2010 Aug;53(8):1599-607. Epub 2010 Apr 6.
5. Vitamin D supplement in early childhood and risk for Type I (insulin-dependent) diabetes mellitus. The EURODIAB Substudy 2 Study Group. Diabetologia. 1999 Jan;42(1):51-4.
6. Zipitis CS, Akobeng AK. Vitamin D supplementation in early childhood and risk of type 1 diabetes: a systematic review and meta-analysis. Arch Dis Child. 2008 Jun;93(6):512-7. Epub 2008 Mar 13. Review.
7. Mohr SB, Garland FC, Garland CF, Gorham ED, Ricordi C. Is there a role of vitamin D deficiency in type 1 diabetes of children? Am J Prev Med. 2010 Aug;39(2):189-90.
8. Mitri J, Muraru MD, Pittas AG. Vitamin D and type 2 diabetes: a systematic review. Eur J Clin Nutr. 2011 Jul 6. doi: 10.1038/ejcn.2011.118. [Epub ahead of print]

For triglycerides 200-499 mg/dL (2.3-5.6 mmol/L), 1 of 3 drugs may be used if needed to achieve non-HDL cholesterol targets. Statins are the first-line drug choice for reducing LDL cholesterol (or non-HDL cholesterol). Fibrates may reduce risk for coronary events (Level 2 Evidence), and then niacin may be used. A combination of a statin plus a triglyceride-lowering drug (fibrate or niacin) may be more effective for improving lipid profile than monotherapy (Level 3 Evidence) but is associated with increased risk for myopathy (Level 2 Evidence).

National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002 Dec 17;106(25):3143-421.

Obesity and increased Hgb A1c levels are associated with suboptimal 25-hydroxyvitamin D levels. Serum 25-hydroxyvitamin D levels decrease and Hgb A1c increase with increasing BMI. A 10% increase in Hgb A1c is associated with a decrease in 25-hydroxyvitamin D levels.

Hyppönen E, Power C. Vitamin D status and glucose homeostasis in the 1958 British birth cohort: the role of obesity. Diabetes Care. 2006 Oct;29(10):2244-6.