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Type 2 diabetes care: the role of insulin-sensitizing agents and practical implications for cardiovascular disease prevention

  • Robert R. Henry
    Correspondence
    Requests for reprints should be addressed to Robert R. Henry, MD, Veterans Administration Hospital, 3350 La Jolla Village Drive, La Jolla, California 92161
    Affiliations
    Department of Medicine, School of Medicine, University of California, San Diego, San Diego, California, USA
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      Abstract

      Millions of Americans are at risk for cardiovascular morbidity and mortality related to disorders of glucose intolerance—particularly type 2 diabetes and prediabetic conditions, including the insulin resistance, or “cardiovascular dysmetabolic,” syndrome. The latter is apparently more intricately associated with macrovascular disease—myocardial infarction, stroke, and peripheral vascular disease. In some situations the risk of cardiovascular disease might be reduced by the prevention of diabetes and also by prevention or treatment of the cardiovascular dysmetabolic syndrome. Studies have shown that intensive glycemic control can delay the development of microvascular complications in type 1, and possibly type 2, diabetes. Several longitudinal observational studies have demonstrated a relationship between glycemic control and the development of cardiovascular disease. Prospective clinical intervention trials to address this issue are underway. Insulin may have a role in atherogenesis, both directly and by promoting development of such risk factors as hypertension and dyslipidemia. Genetic factors and mechanisms promoting or discouraging development of glucose intolerance are also under investigation. Lifestyle changes—dietary and exercise modification, weight loss, and smoking cessation—have been shown to have a positive effect on cardiovascular disease risk. Clinical trials suggest that oral antidiabetic agents—particularly the new noninsulin secretagogues (including troglitazone and metformin, which act on the liver and on skeletal muscle)—may be useful in delaying or preventing development of type 2 diabetes and the cardiovascular dysmetabolic syndrome, as well as in their treatment, when present. Both agents, acting primarily by different mechanisms of action, have also demonstrated potential beneficial effects on serum lipid profiles and other cardiovascular risk factors and may be useful in patients with cardiovascular dysmetabolic syndrome who do not yet meet the criteria for diabetes.
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      References

      1. Kenny SJ, Aubert RE, Geiss LS. Prevalence and incidence of non-insulin-dependent diabetes. In: Harris MI, ed. Diabetes in America. 2nd ed. Washington, DC: National Institutes of Health; 1995:47–67. National Institute of Diabetes and Digestive and Kidney Diseases NIH publication 95–1468.

        • Harris M.I.
        Impaired glucose tolerance in the U.S. population.
        Diabetes Care. 1989; 12: 464-474
        • Godsland I.F.
        • Stevenson J.C.
        Insulin resistance.
        Lancet. 1995; 346: 100-103
        • Haffner S.M.
        The insulin resistance syndrome revisited.
        Diabetes Care. 1996; 19: 275-277
        • The Diabetes Control and Complications Trial Research Group
        The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.
        N Engl J Med. 1993; 329: 977-986
        • Reichard P.
        • Nilsson B.Y.
        • Rosenqvist U.
        The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus.
        N Engl J Med. 1993; 329: 304-309
        • Ohkubo Y.
        • Kishikawa H.
        • Araki E.
        • et al.
        Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus.
        Diab Res Clin Pract. 1995; 28: 103-117
        • Kuusisto J.
        • Mykkänen L.
        • Pyörälä K.
        • Laakso M.
        NIDDM and its metabolic control predict coronary heart disease in elderly subjects.
        Diabetes. 1994; 43: 960-967
        • Uusitupa M.I.J.
        • Niskanen L.K.
        • Siitonen O.
        • et al.
        Ten-year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in type 2 (non-insulin-dependent) diabetic and non-diabetic subjects.
        Diabetologia. 1993; 36: 1175-1184
        • Klein R.
        Hyperglycemia and microvascular and macrovascular disease in diabetes.
        Diabetes Care. 1995; 18: 258-268
        • Knatterud G.L.
        • Klimt C.R.
        • Goldner M.G.
        • et al.
        Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes: VIII. Evaluation of insulin therapy: final report.
        Diabetes. 1982; 31: 1-81
        • U.K. Prospective Diabetes Study Group
        Overview of 6 years’ therapy of type II diabetes.
        Diabetes. 1995; 44: 1249-1258
        • Eastman R.C.
        • Cowie C.C.
        • Harris M.I.
        Undiagnosed diabetes or impaired glucose tolerance and cardiovascular risk.
        Diabetes Care. 1997; 20 (Editorial): 127-128
        • Kruszynska Y.T.
        • Olefsky J.M.
        Cellular and molecular mechanisms of non-insulin dependent diabetes mellitus.
        J Investig Med. 1996; 44: 413-428
        • Stewart M.W.
        • Trajano L.R.
        • Humphriss D.B.
        • et al.
        Features of syndrome X in first-degree relatives of NIDDM patients.
        Diabetes Care. 1995; 18: 1020-1022
        • Reaven G.M.
        • Bernstein R.
        • Davis B.
        • Olefsky J.M.
        Nonketotic diabetes mellitus.
        Am J Med. 1976; 60: 80-88
      2. Wingard DL, Barrett-Connor E. Heart disease and diabetes. In: Harris MI, ed. Diabetes in America. 2nd ed. Washington, DC: National Institutes of Health; 1995: 429–448. National Institute of Diabetes and Digestive and Kidney Diseases NIH publication 95–1468.

        • Reaven G.M.
        Role of insulin resistance in human disease.
        Diabetes. 1988; 37: 1595-1607
        • Reaven G.M.
        Syndrome X.
        J Intern Med. 1994; 236: 13-22
        • Stout R.W.
        Insulin and atheroma.
        Diabetes Care. 1990; 13: 631-654
        • McKeigue P.
        • Davey G.
        Associations between insulin levels and cardiovascular disease are confounded by comorbidity.
        Diabetes Care. 1995; 18: 1294-1298
        • Mykkänen L.
        • Haffner S.M.
        • Ronnemaa T.
        • et al.
        Low insulin sensitivity is associated with clustering of cardiovascular disease risk factors.
        Am J Epidemiol. 1997; 146: 315-321
        • Henry R.R.
        • Gumbiner B.
        • Ditzler T.
        • et al.
        Intensive conventional insulin therapy of Type II diabetes.
        Diabetes Care. 1993; 16: 21-31
        • Inzucchi S.E.
        • Maggs D.G.
        • Spollett G.R.
        • et al.
        Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus.
        N Engl J Med. 1998; 338: 867-872
        • Bailey C.J.
        • Turner R.C.
        Metformin.
        N Engl J Med. 1996; 334: 574-579
        • Henry R.R.
        Thiazolidinediones.
        Endocrinol Met Clin North Am. 1997; 26: 553-573
        • Lenhard J.M.
        • Kliewer S.A.
        • Paulik M.A.
        • et al.
        Effects of troglitazone and metformin on glucose and lipid metabolism.
        Biochem Pharmacol. 1997; 54: 801-808
        • Suter S.L.
        • Nolan J.J.
        • Wallace P.
        • et al.
        Metabolic effects of new oral hypoglycemic agent CS-045 in NIDDM subjects.
        Diabetes Care. 1992; 15: 193-203
        • Tack C.J.J.
        • Demacker P.N.M.
        • Smits P.
        • Stalenhoef A.F.H.
        Troglitazone decreases the proportion of small, dense LDL and increases the resistance of LDL to oxidation in obese subjects.
        Diabetes Care. 1998; 21: 796-799
        • Gardner C.D.
        • Fortmann S.P.
        • Krauss R.M.
        Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women.
        JAMA. 1996; 276: 875-881
        • Tribble D.L.
        Lipoprotein oxidation in dyslipidemia.
        Curr Opin Lipidol. 1995; 6: 196-208
        • Cominacini L.
        • Garbin U.
        • Pastorino A.M.
        • et al.
        Effects of troglitazone on in vitro oxidation of LDL and HDL induced by copper ions and endothelial cells.
        Diabetologia. 1997; 40: 165-172
        • Inoue I.
        • Katayama S.
        • Takahashi K.
        • et al.
        Troglitazone has a scavenging effect on reactive oxygen species.
        Biochem Biophys Res Comm. 1997; 235: 113-116
        • Noguchi N.
        • Sakai H.
        • Kato Y.
        • et al.
        Inhibition of oxidation of low density lipoprotein by troglitazone.
        Atherosclerosis. 1996; 123: 227-234
        • Ogihara T.
        • Rakugi H.
        • Ikegami H.
        • et al.
        Enhancement of insulin sensitivity by troglitazone lowers blood pressure in diabetic hypertensives.
        Am J Hypertens. 1995; 8: 316-320
        • Ghazzi M.N.
        • Perez J.E.
        • Antonucci T.K.
        • et al.
        Cardiac and glycemic benefits of troglitazone treatment in NIDDM.
        Diabetes. 1997; 46: 433-439
        • Fonseca V.A.
        • Reynolds T.
        • Hemphill D.
        • et al.
        Effect of troglitazone on fibrinolysis and activated coagulation in patients with non-insulin-dependent diabetes mellitus.
        J Diab Compl. 1998; 12: 181-186
        • DeFronzo R.A.
        • Barzilai N.
        • Simonson D.C.
        Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects.
        J Clin Endocrinol Metab. 1991; 73: 1294-1301
        • DeFronzo R.A.
        • Goodman A.M.
        Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus.
        N Engl J Med. 1995; 333: 541-549
        • Reaven G.M.
        • Johnston P.
        • Hollenbeck C.B.
        • et al.
        Combined metformin-sulfonylurea treatment of patients with noninsulin-dependent diabetes in fair to poor glycemic control.
        J Clin Endocrinol Metab. 1992; 74: 1020-1026
        • Nagi D.K.
        • Yudkin J.S.
        Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects.
        Diabetes Care. 1993; 16: 621-629
        • Nolan J.J.
        • Ludvik B.
        • Beerdsen P.
        • et al.
        Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone.
        N Engl J Med. 1994; 331: 1188-1193
        • Antonucci T.
        • McLain R.
        • Whitcomb R.
        • Lockwood D.
        Impaired glucose tolerance is normalized by treatment with the thiazolidinedione troglitazone.
        Diabetes Care. 1997; 20: 188-193
        • Widen E.I.
        • Eriksson J.G.
        • Groop L.C.
        Metformin normalized nonoxidative glucose metabolism in insulin-resistant normoglycemic first-degree relatives of patients with NIDDM.
        Diabetes. 1992; 41: 354-358
        • Carlsen S.M.
        • Rossvoll O.
        • Bjerve K.S.
        • et al.
        Metformin improves blood lipid pattern in nondiabetic patients with coronary heart disease.
        J Intern Med. 1996; 239: 227-233
        • Landin K.
        • Tengborn L.
        • Smith U.
        Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors.
        J Intern Med. 1991; 229: 181-187
        • Snorgaard O.
        • Kober L.
        • Carlsen J.
        The effect of metformin on blood pressure and metabolism in nondiabetic hypertensive patients.
        J Intern Med. 1997; 242: 407-412