PARHOFER K.

Management of Dyslipidemia and Hypertension in Diabetic Patients KLAUS PARHOFER Professor of Endocrinology and Metabolism / Medical Department II - Grosshadern, University of Munich, Germany

Numerous studies have shown that diabetic patients have an increased risk for cardiovascular diseases. In fact, the diagnosis of diabetes confers an equivalent risk to aging 15 years [1]. Since the rate of cardiovascular events is related to HbA1c a number of studies have tested the hypothesis that lowering HbA1c will prevent cardiovascular disease. As it is well known these studies (ACCORD, ADVANCE, VADT) have failed to reach this result. [2, 3, 4]. Since obviously lowering HbA1c is not sufficient to prevent cardiovascular disease in diabetic patients other factors must be addressed. Since many patients with diabetes are also characterized by an abnormal lipid profile and an elevated blood pressure, these factors are obvious targets. During this presentation I will discuss the management of dyslipidemia and hypertension in type 2 diabetes.

Dyslipidemia Patients with type 2 diabetes are characterized by an elevated total cholesterol, elevated triglycerides, low HDL-cholesterol and a moderately elevated LDL-cholesterol level. However, this LDL-cholesterol level represents predominantly small-dense LDL-particles and therefore represents a higher risk than the same LDL-cholesterol level observed in nondiabetic patients [5].

The pathophysiology behind this lipid abnormality is closely linked to an increased secretion of triglyceride-rich lipoproteins from the liver. This, in turn is related to an increased flux of substrate (free fatty acids, glucose, etc.) to the liver. An increased concentration of triglyceride-rich lipoproteins results in lower levels of HDL-cholesterol and the predominance of small-dense LDL-particles (both mediated trough the action of CETP).

While lowering HbA1c has overall failed to prevent cardiovascular disease, lowering LDLcholesterol has been highly successful in this situation [6, 7]. However, it should also be noted that lipid lowering therapy only results in a risk reduction of approximately 35%. Thus, the majority of events can not be prevented. Further strategies to improve this rate are either to 55

further lower LDL-cholesterol (i.e. <70 mg/dl) or to also address HDL-cholesterol and triglycerides. Both strategies are currently used.

In patients at very high risk (for example patients with diabetes and established cardiovascular disease) LDL-cholesterol should be <70 mg and HDL and triglycerides should be normalized. Therefore, in many patients statin therapy by itself is not sufficient. In these patients additional drugs may be used.

One such drug would be a fibrate. However, 2 recent trials have been disappointing in this respect [8, 9]. In both studies diabetic patients as a group did not benefit from fenofibrate (either in monotherapy or in combination with simvastatin). Another possibility is the use of nicotinic acid (niacin), but few data are available in diabetic patients. Nevertheless, a number of studies indicate that the additional use of nicotinic acid may be beneficial in high risk patients [10]. Therefore the current strategy with respect to dyslipidemia in diabetic patients is outlined in figure 1. First line therapy should be statins. If lipid goals are not achieved, then additional drugs may be necessary. This may include ezetimibe to further lower LDLcholesterol or niacin to also address HDL-cholesterol and triglycerides. In rare occasions fibrates and/or omega 3 fish oils may be used.

Hypertension Several studies have shown that lowering blood pressure in diabetic patients can reduce cardiovascular events and even mortality. In the hot trial [11] it was even shown that diabetic patients benefit particularly from lowering blood pressure. However, in a more recent trial it was shown that lowering systolic blood pressure below 120 mmHg (compared to <140 mmHg) did not confer any additional benefit [12]. However, it must be acknowledged that even the control group had an average blood pressure value of 133 mmHg. Thus, it seems wise to try to achieve a systolic blood pressure below 135 mmHg or even below 130 mmHg. There are currently a number of different drugs available which can decrease blood pressure in diabetic patients. These drugs differ in their metabolic effects. A meta-analysis indicates that ARBs and ACE inhibitors are metabolically beneficial, calcium channel blockers are neutral, and beta blockers and diuretics may worsen glucose and lipid metabolism [13]. However, in a more recent study directly comparing the metabolic effect of irbesartan vs. hydrochlorothiazide we did not observe such an effect [14]. It should be noted that in the same study we observed that irbesartan decreased hs-CRP and albuminuria compared to hydrochlorothiazide. This is in good agreement with previous study showing that ACE inhibitors or ARBs can improve renal function [15].

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Therefore, it is recommended that the primary antihypertensive medication consists of an ARB or ACE inhibitor. If this is not sufficient then either of these drugs can be combined with hydrochlorothiazide or a calcium channel blocker. Beta blockers are primarily indicated in patients with established coronary heart disease. Beta 1-selective beta blockers should be preferred. In many patients with diabetes and hypertension several drugs are necessary to successfully decrease blood pressure to target values.

In summary, it currently seems wise to address HbA1c, lipid values and hypertension.

While earlier studies achieving less strict target values have shown benefits the recent studies trying to achieve very strict target values have been disappointing. This may relate to the fact that such strict target values are often only achievable by very aggressive drug therapy. This aggressive therapy may be associated with side effects which may balance the beneficial effects. Thus, therapy must be individualized especially with respect to very strict targets.

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References 1. Booth GL et al. Lancet 2006 (366):29-36 2. ACCORD Study Group. N. Engl. J. Med. 2008 (358):2545-2559 3. ADVANCE Collaborative Group N. Engl. J. Med. 2008 (358):2560-2572 4. Duckworth W. et al. N. Engl. J. Med. 2009 (360):129-139 5. Geiss HC et al. Metabolism 2001 (50):983-988 6. Colhoun HM et al. Lancet 2004 (364):685-696 7. CCT Collaborators Lancet 2008 (371):117-125 8. Keech A. et al. Lancet 2005 (366) :1849-1961 9. ACCORD Study Group N. Engl. J. Med. 2010 (362): 1563-1574) 10. Bruckert E. et al. Atherosclerosis 2010: In Press 11. Hansson et al. Lancet 1998 (351):1755-1762 12. ACCORD Study Trial N. Engl. J. Med. 2010 (362): 1575-1585 13. Elliott WJ et al. Lancet 2007 (369):201-211 14. Parhofer K. et al. Int J. Clin. Pract. 2010 (64):160-168 15. Parving HH et al. N. Engl. J. Med. 2001 (345): 870-878

Treatment of Dyslipidemias Define lipid goals Life Style Modification Drug Therapy Hypertriglyceridemia

Combined dyslipidemia LDL-hypercholesterolemia

Fibrate/ ω3FS/ Niacin

(

Statin

)

Statin + Fibrate

Statin + ω3FS

Statin + Niacin

Parhofer K Vasc Health Risk Man. 2009 (5): 901-8

Statin + Statin + Ezetimibe Colesev. end

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