Lipid-Lowering Intervention in Diabetes

It is now well established that hyperlipidemia is a risk factor for CVD in the diabetic population. In type 2 diabetes, lipoprotein abnormalities are manifested during the largely asymptomatic diabetic prodrome and contribute substantially to the increased risk of macrovascular disease. On the other hand, it has been demonstrated that lipid-lowering therapy in type 2 diabetes is effective in decreasing the number of cardiac events. However, it should be stressed that the rationale for treatment of lipid disorders in diabetes mellitus It is now well established that hyperlipidemia is a risk factor for CVD in the diabetic population. In type 2 diabetes, lipoprotein abnormalities are manifested during the largely asymptomatic diabetic prodrome and contribute substantially to the increased risk of macrovascular disease. On the other hand, it has been demonstrated that lipid-lowering therapy in type 2 diabetes is effective in decreasing the number of cardiac events. However, it should be stressed that the rationale for treatment of lipid disorders in diabetes mellitus

American Diabetes Association guidelines call for aggressive treatment of high TG and LDL-C. TG should be =200 mg/dl, are considered borderline high between 200 and 400 mg/dl, and high when ?400 mg/dl. Low HDL is defined as =35 mg/dl. Control of obesity with diet and exercise and reduced intake of saturated fat and C are important first steps. If needed, drug therapy is appropriate to lower TG and, specifically, to reduce LDL-C to levels = 130 mg/dl in all adult diabetics and =100 mg/dl in those with CVD. The lipid profile should be monitored at beginning and during treatment, including TG and total and LDL-C.

The therapeutic interventions to reduce body weight, increase physical activity and control the glycemic condition are described in chapters II–VI. Here we recall that the National Cholesterol Education Program guidelines suggested a dietary two-step approach. Step 1 consists of reduction of % calorie assumption to =10% from saturated fat, =10% from polyunsaturated fats and 10–15% from monounsaturated fats, while C assumption should be = 300 mg/day. If the therapeutical goals are not reached, then step 2 should

be adopted, which consists in further reduction of saturated fat to =5% of total calories and C intake to =200 mg/day. When dietary measures (plus exercise) and hypoglycemic agents have failed to achieve acceptable lipid levels, drug therapy should be prescribed. Drugs currently in clinical use for the treatment of hyperlipidemias are listed in table 1, in which the distinction is made between drugs mainly lowering C, represented by the HMG-CoA reductase inhibitors statins (besides bile acid- binding resins and niacin) and drugs primarly lowering TG, consisting of the group of fibrate derivatives (besides niacin and fish oil). As a rule, the treatment in the diabetic patients should be based on the use of statins or fibrates (ciprofibrate and fenofibrate appearing more effective than bezafibrate), whereas other drugs are in general not recommended, unless severe hyperlypid- emia or intolerance to statins or fibrates is present.

Intensive treatment with lipid-regulating agents is often necessary to nor- malize diabetes-associated dyslipidemias. HMG-CoA reductase inhibitors are the only agents thus far shown in prospective multicenter trials to reduce the risk of coronary events in diabetic patients. Long-term statin treatment of coronary patients significantly lowers the recurrence of coronary events, in addition to improving the lipid disorder. However, no information is available concerning the preventive effect of long-term improvement of lipid disorders

Table 1. Lipid-lowering drugs Drug

Effects Hypercholesterolemia

Mechanism

Bile acid (BA) binding resins 1 B BA reabsorption; CBA synthesis;

B LDL-C; CHDL-C; BTG

C LDL receptors

(Cholestyramine, 8–12 g b.i.d. or t.i.d.) (Cholestipol, 10–15 g b.i.d. or t.i.d.)

Niacin 2 B VLDL synthesis

B TG; BVLDL- & LDL-C; C HDL

(Niacin, starting; 100 mg t.i.d., then up to 1–2 g t.i.d.) (Niacin (extended release) 0.5–3 g/day)

HMG-CoA reductase inhibitors 3 B Cholesterol synthesis; CLDL receptors

B LDL-C; BVLDL secretion; B TG

(Lovastatin, 10–80 mg/day) (Pravastatin, 10–40 mg/day) (Simvastatin, 5–40 mg/day) (Fluvastatin, 20–40 mg/day) (Atorvastatin, 10–80 mg/day) (Cerivastatin, 0.1–0.3 mg/day)

Probucol 4 (500 mg b.i.d.)

B LDL

B LDL-C

Antioxidant

B Atherosclerosis

See below Hypertriglyceridemia

Fibric acid derivatives 5 See below

Fibric acid derivatives 5 C LPL; CHPL; BVLDL production;

B TG; CHDL; KCLDL-C a

B ApoC-III synthesis; CLDL clearance

(Gemfibrozil 600 mg b.i.d.) b, c (Fenofibrate, 100 t.i.d. or q.i.d.) (Fenofibrate, micronized 200–250 mg/day)

(Bezafibrate 6 , 400 mg/day or 200 mg t.i.d.) (Ciprofibrate, 100 mg/day)

See above Fish oil 6 (4 g t.i.d. or q.i.d.)

Niacin 2 See above

B TG a Fenofibrate may be an exception, producing a decrease in LDL-C.

B VLDL product

b Long-acting formulations of these fibrates are also available. c This fibrate increases LDL particle size. 1 Resins may cause gastrointestinal symptoms (nausea, constipation, hemorrhoidal bleeding); contraindicated in biliary

obstruction and in hypertriglyceridemia. 2 May cause various symptoms: cutaneous (flushing, dry skin), cardiac (tachycardia, arrhythmias), gastrointestinal

(nausea, diarrhea, peptic ulcer, hepatic dysfunction), metabolic (insulin resistance, glucose intolerance, hyperuricemia); contraindicated in peptic ulcer, cardiac arrhythmias, liver diseases, hyperuricemia, diabetes mellitus.

3 May cause abnormal liver function tests and myopathy; contraindicated in myopathies, renal failure, or in association with fibrates or niacin.

4 May reduce HDL-C. 5 May favor bile stone or cause nausea, abnormal liver function tests or myopathy; contraindicated in hepatobiliary disease. 6 Usually a mixture of eicosapentaenoic acid (D58-64%) and docosahexaenoic acid (D36–42%); may be associated with

a slight increase in LDL-C.

in type 2 diabetic patients without CHD, or in patients with the ‘classical’ type of diabetic lipid disorder (hypertriglyceridemia with low HDL and normal LDL-C levels). In these latter patients, beneficial lipid effects can be obtained (although perhaps not normalization) with fibrates alone or, especially, in combination with current statins. Recent data showed that the risk reduction was 22–50% with statins and approximately 65% with fibrates (relative to placebo). Preliminary results indicate that fenofibrate treatment in type 2 diabetes under optimized metabolic control improves not only fasting lipid levels but also postprandial lipemia and associated abnormalites in lipoprotein levels and composition. However, it was pointed out that the statins should

be regarded as the current lipid-lowering drugs of choice because the change in LDL-C to HDL-C ratio is better than with fibrates (gemfibrozil). According to the IDF guidelines (1999) to type 2 diabetes, drugs for lowering lipids should be prescribed according to the following scheme. A statin should be used when LDL-C ?115 mg/dl (q3.0 mmol/l) or, in subjects at low risk (including the thin elderly), when LDL-C ?155 mg/dl (4.0 mmol/l).

A fibrate should be used when TG are ?200 mg/dl (?2.2 mmol/l) and LDL-C = 115 mg/dl (=3.0 mmol/l). Atorvastatin should be used when TG are 200–400 mg/dl (2.3–4.5 mmol/l) and LDL-C q115 mg/dl (q3.0 mmol/l). When TG are markedly elevated, i.e. ?600 mg/dl (?6/8 mmol/l), a fibrate should be first used, and thyroid, renal, and liver function, and ApoE fenotype should be checked; if LDL-C levels remain elevated, combined fibrate-statin therapy should be advised. Combined therapy (beginning with a statin) is also suggested when both LDL-C and TG are markedly elevated.

Finally, it is noteworthy that antiproteinuric and lipid-lowering therapy can be expected to reduce vascular damage and the progression of diabetic nephropathy.

Lipid-Lowering Intervention in Diabetes