Pharmacotherapy Review article| Volume 33, ISSUE 6, P665-678, June 2011

Early and Intensive Therapy for Management of Hyperglycemia and Cardiovascular Risk Factors in Patients With Type 2 Diabetes



      Type 2 diabetes mellitus (T2DM) results in significant morbidity and mortality. Results of recent randomized controlled trials demonstrated the ability of early and intensive therapy to reduce the risk of microvascular complications. However, controversy surrounds the ability of such therapy to reduce the risk for macrovascular complications.


      This article reviews results from recent clinical trials in patients with T2DM as well as extended follow-up of earlier trials to determine if early, intensive, and individualized therapy aimed at the underlying pathogenesis of the disease could decrease the risk for long-term complications, including cardiovascular disease (CVD).


      Information was obtained by a search of the PUBMED and EMBASE databases using the search terms type 2 diabetes mellitus, glycosylated hemoglobin, pathophysiology of type 2 diabetes, glycemic control, early intervention, multifactorial intervention, cardiovascular disease, β-cell function, and antidiabetes therapy for the period between 1995 and 2010. Articles dealing with outcomes trials, impact of therapy on microvascular and macrovascular complications, effects of therapeutic agents on the pathophysiology of T2DM, and the impact of agents on CV risk factors were then preferentially selected for in-depth review.


      Large-scale clinical trials in patients with T2DM, although largely negative at 5 years for macrovascular end points, suggested benefit for patients with a shorter duration of T2DM (ie, <10 years) and still supported a treatment strategy of early, intensive, and individualized therapy to prevent long-term complications of the disease. In Steno-2, after 13 years of follow-up, early, intensive, multifactorial therapy was associated with a 56% lower risk of all-cause death (P = 0.02) and a 57% lower risk of death from CVD (P = 0.04). In the 10-year follow-up to the United Kingdom Prospective Diabetes Study, intensive therapy was associated with a significant 15% reduction in the risk of myocardial infarction (P = 0.01) and a significant 13% reduction in the risk of death from any cause (P = 0.007). Therapy should be aimed at correcting underlying pathophysiologic defects, including β-cell failure and insulin resistance, and should also correct underlying risk factors for CVD whenever possible.


      Early and intensive antidiabetes treatment was recommended in patients with T2DM, particularly those with a shorter duration of disease and without a history of CVD. The goal was to safely lower glycosylated hemoglobin to <7%, therefore providing beneficial effects on the risk for complications. Hypoglycemia should be avoided. In addition, less aggressive treatment might be suitable for older patients with longstanding diabetes and a history of CVD events. Clinical trial results also provided support for a second important aspect of individualized treatment for patients with T2DM—multifactorial intervention aimed at controlling CVD risk factors.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Centers for Disease Control and Prevention
        National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011.
        US Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, Ga2011
        • National Diabetes Information Clearinghouse
        National diabetes statistics.
        2007 (Updated June 2008) (Accessed March 29, 2010)
        • Bate K.L.
        • Jerums G.
        Preventing complications of diabetes.
        Med J Aust. 2003; 179: 498-503
        • Lloyd-Jones D.
        • Adams R.
        • Carnethon M.
        • et al.
        • American Heart Association Statistics Committee and Stroke Statistics Subcommittee
        Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.
        Circulation. 2009; 119: 480-486
        • Erhardt L.R.
        Rationale for multiple risk intervention: the need to move from theory to practice.
        Vasc Health Risk Manag. 2007; 3: 985-997
        • American Diabetes Association
        Standards of medical care in diabetes—2010.
        Diabetes Care. 2010; 33: S11-S61
        • Nathan D.M.
        • Buse J.B.
        • Davidson M.B.
        • et al.
        Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes.
        Diabetes Care. 2009; 32: 193-203
        • Rustenbeck I.
        • Krautheim A.
        • Jörns A.
        • Steinfelder H.J.
        Beta-cell toxicity of ATP-sensitive K+ channel-blocking insulin secretagogues.
        Biochem Pharmacol. 2004; 67: 1733-1741
        • DeFronzo R.A.
        Banting lecture: from the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus.
        Diabetes. 2009; 58: 773-795
        • Wajchenberg B.L.
        Beta-cell failure in diabetes and preservation by clinical treatment.
        Endocr Rev. 2007; 28: 187-218
        • Klonoff D.C.
        • Buse J.B.
        • Nielsen L.L.
        • et al.
        Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years.
        Curr Med Res Opin. 2008; 24: 275-286
        • Rodbard H.W.
        • Jellinger P.S.
        • Davidson J.A.
        • et al.
        Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control.
        Endocr Pract. 2009; 15: 540-559
        • Saydah S.H.
        • Fradkin J.
        • Cowie C.C.
        Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes.
        JAMA. 2004; 291: 335-342
        • Ong K.L.
        • Cheung B.M.
        • Wong L.Y.
        • et al.
        Prevalence, treatment, and control of diagnosed diabetes in the U.S. National Health and Nutrition Examination Survey 1999–2004.
        Ann Epidemiol. 2008; 18: 222-229
        • Cheung B.M.Y.
        • Ong K.L.
        • Cherny S.S.
        • et al.
        Diabetes prevalence and therapeutic target achievement in the United States, 1999 to 2006.
        Am J Med. 2009; 122: 443-453
        • Iqbal N.
        The burden of type 2 diabetes: strategies to prevent or delay onset.
        Vasc Health Risk Manag. 2007; 3: 511-520
        • Del Prato S.
        • Wishner W.J.
        • Gromada J.
        • Schluchter B.J.
        Beta-cell mass plasticity in type 2 diabetes.
        Diabetes Obes Metab. 2004; 6: 319-331
        • Standl E.
        The importance of beta-cell management in type 2 diabetes.
        Int J Clin Pract Suppl. 2007; 153: 10-19
        • Skyler J.S.
        • Bergenstal R.
        • Bonow R.
        • et al.
        Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials.
        Diabetes Care. 2009; 32: 187-192
        • Gerstein H.C.
        • Miller M.E.
        • Byington R.P.
        • et al.
        • Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group
        Effects of intensive glucose lowering in type 2 diabetes.
        N Engl J Med. 2008; 358: 2545-2559
        • Patel A.
        • MacMahon S.
        • Chalmers J.
        • et al.
        • Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release and Controlled Evaluation (ADVANCE) Collaborative Group
        Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
        N Engl J Med. 2008; 358: 2560-2572
        • Duckworth W.C.
        • Abraira C.
        • Moritz T.
        • et al.
        • VADT Investigators
        Glucose control and vascular complications in veterans with type 2 diabetes.
        N Engl J Med. 2009; 360: 129-139
        • Currie C.J.
        • Peters J.R.
        • Tynan A.
        • et al.
        Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study.
        Lancet. 2010; 375: 481-489
        • Gæde P.
        • Lund-Andersen H.
        • Parving H.H.
        • Pedersen O.
        Effect of a multifactorial intervention on mortality in type 2 diabetes.
        N Engl J Med. 2008; 358: 580-591
        • Stratton I.M.
        • Adler A.I.
        • Neil H.A.
        • et al.
        Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.
        BMJ. 2000; 321: 405-412
        • Holman R.R.
        • Paul S.K.
        • Bethel M.A.
        • et al.
        10-year follow-up of intensive glucose control in type 2 diabetes.
        N Engl J Med. 2008; 359: 1577-1589
      1. Hypoglycemia associated with increased risk of MI among US veterans with diabetes.
        ([news release]) Heartwire, Vienna, AustriaOctober 5, 2009 (Updated) (Accessed March 29, 2010)
        • Reaven P.D.
        • Moritz T.E.
        • Schwenke D.C.
        • et al.
        Intensive glucose-lowering therapy reduces cardiovascular disease events in veterans affairs diabetes trial participants with lower calcified coronary atherosclerosis.
        Diabetes. 2009; 58: 2642-2648
        • Tabak A.G.
        • Jokela M.
        • Akbaraly T.
        • et al.
        Trajectories of glycemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study.
        Lancet. 2009; 373: 2215-2221
        • Matthews D.R.
        • Cull C.A.
        • Stratton I.M.
        • et al.
        UKPDS 26: Sulfonylurea failure in non-insulin-dependent diabetic patients over six years.
        Diabetic Med. 1998; 15: 297-303
        • Turner R.C.
        • Cull C.A.
        • Frighi V.
        • et al.
        • UKPDS 49 Study Group
        Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies.
        JAMA. 1999; 281: 2005-2012
        • Xiang A.H.
        • Peters R.K.
        • Kjos S.L.
        • et al.
        Effect of pioglitazone on pancreatic β-cell function and diabetes risk in Hispanic women with prior gestational diabetes.
        Diabetes. 2006; 55: 517-522
        • Kahn S.E.
        • Haffner S.M.
        • Heise M.A.
        • et al.
        Glycemic durability of rosiglitazone, glyburide, or metformin monotherapy.
        N Engl J Med. 2006; 355: 2427-2443
      2. ACTos NOW for the Prevention of Diabetes (ACTNOW)Study. Pioglitazone prevents conversion to diabetes among insulin-resistant patients. Presented at the 68th Scientific Sessions of the American Diabetes Association, San Francisco, CA, June 11, 2008. Updated June 11, 2008. Accessed March 29, 2010.

        • Kendall D.M.
        Thiazolidinediones: the case for early use.
        Diabetes Care. 2006; 29: 154-156
        • Buse J.B.
        • Henry R.R.
        • Han J.
        • et al.
        Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes.
        Diabetes Care. 2004; 27: 2628-2635
        • DeFronzo R.A.
        • Ratner R.E.
        • Han J.
        • et al.
        Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes.
        Diabetes Care. 2005; 28: 1092-1100
        • Kendall D.M.
        • Riddle M.C.
        • Rosenstock J.
        • et al.
        Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea.
        Diabetes Care. 2005; 28: 1083-1091
        • Bunck M.C.
        • Diamant M.
        • Cornér A.
        • et al.
        One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial.
        Diabetes Care. 2009; 32: 762-768
        • Madsbad S.
        Liraglutide Effect and Action in Diabetes (LEAD) trial.
        Expert Rev Endocrinol Metab. 2009; 4: 119-129
        • Nauck M.A.
        • Ratner R.E.
        • Kapitza C.
        • et al.
        Treatment with the human once-weekly glucagon-like peptide-1 analog taspoglutide in combination with metformin improves glycemic control and lowers body weight in patients with type 2 diabetes inadequately controlled with metformin alone: a double-blind placebo-controlled study.
        Diabetes Care. 2009; 32: 1237-1243
        • Rosenstock J.
        • Reusch J.
        • Bush M.
        • et al.
        • Albiglutide Study Group
        Potential of albiglutide, a long-acting GLP-1 receptor agonist, in type 2 diabetes: a randomized controlled trial exploring weekly, biweekly, and monthly dosing.
        Diabetes Care. 2009; 32: 1880-1886
        • Tourrel C.
        • Bailbe D.
        • Lacorne M.
        • et al.
        Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the beta-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4.
        Diabetes. 2002; 51: 1443-1452