Abstract
Diabetes mellitus, specifically type 2, is often associated with disorders in lipid metabolism. Elevated levels of plasma free fatty acids play a pivotal role by contributing significantly to insulin resistance. In addition free fatty acids promote diabetic dyslipidemia through increasing VLDL synthesis in the liver, and by virtue of cholesterylester transfer protein, modifying LDL to increase small-dense LDL subfractions and to decrease HDL cholesterol. This atherogenic lipoprotein profile (elevated triglycerides, increased small-dense low-density lipoproteins, and decreased high-density lipoproteins), contributes to the development of atherosclerosis and increases the risk of experiencing cardiovascular events, the most common cause of death in type 2 diabetes. To decrease the risk of cardiovascular disease events in diabetics, dyslipidemia needs to be treated, as evidenced from epidemiology, from intervention trials, and from subgroup analyses of large intervention trials initiated to evaluate effects of lipid lowering treatment that also included patients with type 2 diabetes.
Most measures used to counteract hyperglycemia, are also prone to ameliorate dyslipidemia: dietary intervention (medical nutrition) including ω-3 fatty acids as part of lifestyle changes that also comprise cessation of smoking, increases in physical activity and reduction in body weight. In addition insulin, biguanides, acarbose and glitazones applied for glycemic control also improve diabetic dyslipidemia.
Additional pharmacological treatment of dyslipidemia if persisting after glycemic control relies on different drug classes. Fibrates effectively reduce free fatty acids, fasting and postprandial lipemia, shift the distribution of LDL particles towards less dense subfractions and increase HDL cholesterol, thus particularly addressing key components of diabetic dyslipidemia. For LDL cholesterol lowering statins are mainly used that decrease LDL cholesterol levels by competitive inhibition of the HMG-CoA reductase. As type 2 diabetes is found to be associated with a two- to fourfold increase in coronary heart disease risk and as the degree of glycemia is more related to microvascular complications, correcting dyslipidemia appears to be a major task in order to reduce macrovascular events in patients with type 2 diabetes.
Key words
Diabetes mellitus - dyslipidemia - weight loss - medical nutrition - drug therapy - fibrates - statins
References
-
1
Albert C M, Campos H, Stampfer M J, Ridker P M, Manson J E, Willett W C, Ma J.
Blood levels of long-chain n-3 fatty acids and the risk of sudden death.
N Engl J Med.
2002;
346
1113-1118
-
2
American Diabetes Association .
Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications.
Diabetes Care.
2002 a;
25 (Suppl 1)
S50-S60
-
3
American Diabetes Association .
Management of dyslipidemia in adults with diabetes.
Diabetes Care.
2002 b;
25 (Suppl 1)
S74-S77
-
4
Austin M A, Breslow J L, Hennekens C H, Curing J E, Willett W C, Krauss R M.
LDL subclass patterns and risk of myocardial infarction.
JAMA.
1988;
260
1917-1921
-
5
Austin M A, Hokansen J E, Edwards K L.
Hypertriglyceridemia as a cardiovascular risk factor.
Am J Cardiol.
1998;
81
7B-12B
-
6
Austin M A.
Triglyceride, small, dense low-density lipoprotein, and the atherogenic lipoprotein phenotype.
Curr Atheroscl Reports.
2000;
2
200-207
-
7
Boden G.
Effects of free fatty acids on glucose metabolism: Significance for insulin resistance and type 2 diabetes.
Exp Clin Endocrinol Diabetes.
2003;
111
121-124
-
8
Boyle P J, King A B, Olansky L, Marchetti A, Lau H, Magar R, Martin J.
Effects of pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus: A retrospective review of randomly selected medical records.
Clin Therapeutics.
2002;
24
378-396
-
9
Brown B G, Hilger L, Zhao X Q, Poulin D, Albers J J.
Types of change in coronary stenosis severity and their relative importance in overall progression and regression of coronary disease.
Ann NY Acad Sci.
1995;
748
407-417
-
10
Brown B G, Zambon A, Poulin D, Rocha A, Mahler V MG, Davis J W, Albers J J, Brunzell J D.
Use of niacin, statins, and resins in patients with combined hyperlipidemia.
Am J Cardiol.
1998;
81
52B-59B
-
11
Canner P L, Berge K G, Wenger N K, Stamler J, Friedman L, Prineas R J, Friewald W.
Fifteen year mortality in coronary drug project patients: long-term benefit with niacin.
J Am Coll Cardiol.
1986;
8
1245-1255
-
12
Coronary Drug Project Research Group .
Clofibrate and niacin in coronary heart disease.
JAMA.
1975;
231
360-381
-
13
Davies M J, Baer D J, Judd J T, Brown E D, Campbell W S, Taylor P R.
Effects of moderate alcohol intake on fasting insulin and glucose concentrations and insulin sensitivity in postmenopausal women. A randomized controlled trial.
JAMA.
2002;
287
2559-2562
-
14
Davignon J, Montigny M, Dufour R.
HMG-CoA reductase inhibitors: a look back and a look ahead.
Can J Cardiol.
1992;
8
843-864
-
15
Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD) 2000 .
Recommendations for the nutritional management of patients with diabetes mellitus.
Eur J Clin Nutr.
2000;
54
353-355
-
16
Diabetes and Nutrition Study Group of the European Association for the Study of Diabetes .
Recommendations for the nutritional management of patients with diabetes mellitus.
Diabetes Nutr Metab.
1995;
8
186-189
-
17
Diabetes Atherosclerosis Intervention Study Investigators .
Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study.
Lancet.
2001;
357
905-910
-
18
Dunn C J, Peter D H.
Metformin. A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus.
Drugs.
1995;
49
721-749
-
19
Elam M B, Hunninghake D B, Davis K B, Garg R, Johnson C, Egan D, Kostis J B, Sheps D S, Brinton for the Investigators E AADMIT.
Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease. The ADMIT Study: A randomized trial.
JAMA.
2000;
284
1263-1270
-
20
Evans M, Khan N, Rees A.
Diabetic dyslipidaemia and coronary heart-disease: new perspectives.
Curr Opin Lipidol.
1999;
10
387-391
-
21
Executive Summary of the Third Report of the National Cholesterol Education Program expert panel on detection ( NCEP), evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel I II).
.
JAMA.
2001;
285
2486-2497
-
22 Farnier M, Picard S. . Diabetes; Statins, fibrates, or both? Curr Atheroscl Reports 2001 3: 19-28
-
23
Frost R JA, Otto C, Geiss H C, Schwandt P, Parhofer K G.
Effects of atorvastatin versus fenofibrate on lipoprotein profiles, low-density lipoprotein subfraction distribution, and hemorheologic parameters in type 2 diabetes mellitus with mixed hyperlipoproteinemia.
Am J Cardiol.
2001;
87
44-48
-
24
Fruchart J C, Brewer Jr H B, Leitersdorf E.
Consensus for the use of fibrates in the treatment of dyslipoproteinemia and coronary heart disease. Fibrate Consensus Group.
Am J Cardiol.
1998;
81
912-917
-
25
Geiss H C, Dietlein M, Parhofer K G.
Influence of etofibrate on LDL-subtype distribution in patients with diabetic dyslipoproteinemia.
Exp Clin Endocrinol Diabetes.
2003;
(in press)
-
26
Gokcel A, Karakose H, Ertorer E M, Tanaci N, Tutuncu N B, Guvener N.
Effects of sibutramine in obese female subjects with type 2 diabetes and poor blood glucose control.
Diabetes Care.
2001;
24
1957-1960
-
27
Goldberg R B, Mellies M J, Sacks F M, Moye L A, Howard W J, Davis B R, Cole T G, Pfeffer M A, Braunwald E.
Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol and recurrent events (CARE) trail. The Care Investigators.
Circulation.
1998;
98
2513-2519
-
28
Haffner S M, Alexander C M, Cook T J, Boccuzzi S J, Musliner T A, Pedersen T R, Kjekshus J, Pyörälä K.
Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study.
Arch Intern Med.
1999;
159
2661-2667
-
29
Haffner S M, Lehto S, Ronnemaa T, Pyörälä K, Laakso M.
Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.
N Engl J Med.
1998;
339
229-234
-
30
Haire-Joshu D, Glasgow R E, Tibbs T L.
Smoking and diabetes.
Diabetes Care.
1999;
22
1887-1889
-
31
Hanefeld M, Fischer S, Julius U, Schulze J, Schwanebeck U, Schmechel H, Ziegelasch H J, Lindner J, The Group D IS.
Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up.
Diabetologia.
1996;
39
1577-1583
-
32
Heart Protection Study Collaborative Group .
MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomized placebo controlled trail.
Lancet.
2002;
360
7-22
-
33
Herrera E, Lasuncion M A, Castro M, Gomez-Coronado D, Martin A, Quack G.
Studies with etofibrate in the rat. Part 1: Effects on glycerol, free fatty acid and triacylglycerol metabolism.
Biochim Biophys Acta.
1988;
963
42-52
-
34
Hollander P A, Elbein S C, Hirsch I B, Kelley D, McGill J, Taylor T, Weiss S R, Crockett S E, Kaplan R A, Comstock J, Lucas C P, Lodewick P A, Canovatchel W, Chung J, Hauptmann J.
Role of orlistat in the treatment of obese patients with type 2 diabetes.
Diabetes Care.
1998;
21
1288-1294
-
35
Howard B V, Robbins D C, Sievers M L, Lee E T, Rhoades D, Devereux R B, Cowan L D, Gray R S, Welty T H, Go O T, Howard W J.
LDL cholesterol as a strong predictor of coronary heart disease in diabetic individuals with insulin resistance and low LDL.
Arterioscler Thromb Vasc Biol.
2000;
20
830-835
-
36
Jastrzebska M, Zorbus-Lisiecka B, Pieczul-Mroz J, Chelstowski K, Kopciewicz M.
Etofibrate decreases factor VII and fibrinogen levels in patients with polymetabolic syndrome.
Int J Clin Pharmacol Res.
1999;
19
19-25
-
37
Julius U.
Influence of free fatty acids on lipoprotein synthesis and diabetic dyslipidemia.
Exp Clin Endocrinol Diabetes.
2003;
(in press)
-
38
Kado S, Murakami T, Aoki A, Nagase T, Katsura Y, Noritake M, Matsuoka T, Nagata N.
Effect of acarbose on postprandial lipid metabolism in type 2 diabetes mellitus.
Diab Res Clin Pract.
1998;
41
49-55
-
39
Kawamura T, Egusa G, Fujikawa R, Watanabe T, Oda K, Kataoka S, Takayama S, Kubo K, Yamamoto S, Noma K, Orita R, Yamakido M.
Effect of acarbose on glycemic control and lipid metabolism in patients with non-insulin-dependent diabetes mellitus.
Curr Ther Res.
1998;
59
97-105
-
40
Kennedy L, Walshe K, Hadden D R, Weaver J A, Buchanan K D.
The effect of intensive dietary therapy on serum high density lipoprotein cholesterol in patients with type 2 (non-insulin-dependent) diabetes mellitus: a prospective study.
Diabetologia.
1982;
23
24-27
-
41
Khan M A, St. Peter J V, Xue J L.
A prospective, randomized comparison of the metabolic effects of pioglitazone or rosiglitazone in patients with type 2 diabetes who were previously treated with troglitazone.
Diabetes Care.
2002;
25
708-711
-
42
Koskinen P, Manttari M, Manninen V, Huttunen J K, Heinonen O P, Frick M H.
Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study.
Diabetes Care.
1992;
15
820-825
-
43
Kreisberg R A.
Diabetic dyslipidemia.
Am J Cardiol.
1998;
82
67U-73U
-
44
Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais G R, Lupien P J, Depres J P.
Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study.
Circulation.
1997;
95
69-75
-
45
Lean M E, Powrie J K, Anderson A S, Gathwaite P H.
Obesity, weight loss and prognosis in type 2 diabetes.
Diab Med.
1990;
7
228-233
-
46
Leitersdorf E, Muratti E N, Eliav O, Meiner V, Eisenberg S, Dann E J, Sehayek E, Peters T K, Stein Y.
Efficacy and safety of a combination fluvastatin-bezafibrate treatment for familial hypercholesterolemia: comparative analysis with a fluvastatin-cholestyramine combination.
Am J Med.
1994;
96
401-407
-
47
Mikhailidis D P, Papadakis J A, Ganotakis E S.
Smoking, diabetes and hyperlipidemia.
J R Soc Health.
1998;
118
91-93
-
48
Pereira M A, Jacobs D R, van Horn L, Slattery M L, Kartashov A I, Ludwig D S.
Dairy consumption, obesity, and the insulin resistance syndrome in young adults.
JAMA.
2002;
287
2081-2089
-
49
Pyörälä K, Pedersen T R, Kjekshus J, Faergeman O, Olsson A G, Thogeirsson G.
Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4 S).
Diabetes Care.
1997;
20
614-620
-
50
Rabkin S W, Boyko E, Streja D A.
Changes in high density lipoprotein cholesterol after initiation of insulin therapy in noninsulin dependent diabetes mellitus: relationship to changes in body weight.
Am J Med Sci.
1983;
285
14-20
-
51
Reitsma J B, Castro-Cabezas M, de Bruin T WA, Erkelens D W.
Relationship between improved postprandial lipemia and LDL metabolism during treatment with tetrahydrolipstatin, a pancreatic lipase inhibitor.
Metabolism.
1994;
43
293-298
-
52
Rubins H B, Robins S J, Collins D, Fye C L, Anderson J W, Elam M B, Faas F H, Linares E, Schaefer E J, Schectman G, Wilt T J, Wittes J.
Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol,.
N Engl J Med.
1999;
341
410-418
-
53
Sacks F M, Tonkin A M, Shepherd J, Braunwald E, Cobbe S, Hawkins M, Keech A, Packard C, Simes J, Byington R, Furberg C D. for the Prospective Pravastatin Pooling Project Investigators Group .
Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors. The Prospective Pravastatin Pooling Project.
Circulation.
2000;
102
1893-1900
-
54
Schrezenmeir J, Keppler I, Fenselau S, Weber P, Biesalski H K, Probst R, Laue Ch, Zuchhold H D, Prellwitz W, Beyer J.
The phenomenon of a high triglyceride response to an oral lipid load in healthy subjects and its link to the metabolic syndrome.
Ann NY Acad Sci.
1993;
683
302-314
-
55
Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart J C.
Mechanism of action of fibrates on lipid and lipoprotein metabolism.
Circulation.
1998;
98
2088-2093
-
56
Steiner G.
Treating lipid abnormalities in patients with type 2 diabetes mellitus.
Am J Cardiol.
2001;
88 (Suppl)
37N-40N
-
57
Steinmetz A, Fenselau S, Schrezenmeir J.
Treatment of dyslipoproteinemia in the metabolic syndrome.
Exp Clin Endocrinol Diabetes.
2001;
109
S548-S559
-
58
Stern M P, Haffner S M.
Dyslipidemia in type II diabetes. Implications for therapeutic intervention.
Diabetes Care.
1991;
14
1144-1159
-
59
Stratton I M, Adler A I, Neil H A, Matthews D R, Manley S E, Cull C A, Hadden D, Turner R C, Holman R R.
Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.
BMJ.
2000;
321
405-412
-
60
Tan C E, Chew L S, Tai E S, Chio L F, Lim H S, Loh L M, Shepherd J.
Benefits of micronised fenofibrate in type 2 diabetes mellitus subjects with good glycemic control.
Atherosclerosis.
2001;
154
469-474
-
61
Taskinen M R.
Triglyceride is the major atherogenic lipid in NIDDM.
Diabetes Metab Rev.
1997;
13
93-98
-
62
Turner R C, Millns H, Neil H AW, Stratton I M, Manley S E, Matthews D R, Holman R R. for the United Kingdom Prospective Diabetes Study Group .
Risk factors for coronary heart disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS 23).
BMJ.
1998;
316
823-828
-
63
United Kingdom Prospective Diabetes Study Group ( UKPDS).
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).
Lancet.
1998 a;
352
854-865
-
64
United Kingdom Prospetive Diabetes Study Group .
United Kingdom Prospective Diabetes Study 24: A 6-year, randomised, controlled trial comparing sulphonylurea, insulin, and metformin therapy in patients with newly diagnosed type 2 diabetes that could not be controlled with diet therapy.
Ann Intern Med.
1998 b;
128
165-175
-
65
Weber P, Schrezenmeir J, Fenselau S, Ausieker S, Probst R, Zuchhold H D, Prellwitz W, Beyer J.
Prolonged postprandial increment in triglycerides and decreased postprandial response of VLDL in type 2 diabetics following an oral lipid load.
Ann NY Acad Sci.
1993;
683
315-322
M. D. Armin Steinmetz
St. Nikolaus-Stiftshospital GmbH Andernach
Teaching Hospital, University of Bonn
Hindenburgwall 1
56626 Andernach
Germany
Telefon: + 4926324045497
Fax: + 49 2 63 24 04 56 40
eMail: armin.steinmetz@stiftshospital-andernach.de
