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Type 2 Diabetes: Assessing the Relative Risks and Benefits of Glucose-lowering Medications

      Abstract

      The selection of appropriate pharmacologic therapy for any disease requires a careful assessment of benefit and risk. In the case of type 2 diabetes, this decision typically balances the benefits accrued from improved glycemic control with the risks inherent in glucose-lowering medications. This review is intended to assist therapeutic decision-making by carefully assessing the potential benefit from improved metabolic control relative to the potential risks of a wide array of currently prescribed glucose-lowering agents. Wherever possible, risks and benefits have been expressed in terms of absolute rates (events per 1000 patient-years) to facilitate cross-study comparisons. The review incorporates data from new studies (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation, Action to Control Cardiovascular Risk in Diabetes, and the Veterans Affairs Diabetes Trial), as well as safety issues associated with newer glucose-lowering medications.

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      References

        • Meinert C.L.
        • Knatterud G.L.
        • Prout T.E.
        • Klimt C.R.
        A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes.
        Diabetes. 1970; 19: 789-830
        • Nissen S.E.
        • Wolski K.
        Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.
        N Engl J Med. 2007; 356: 2457-2471
        • Shah B.R.
        • Juurlink D.N.
        • Austin P.C.
        • Mamdani M.M.
        New use of rosiglitazone decreased following publication of a meta-analysis suggesting harm.
        Diabet Med. 2008; 25: 871-874
        • Starner C.I.
        • Schafer J.A.
        • Heaton A.H.
        • Gleason P.P.
        Rosiglitazone and pioglitazone utilization from January 2007 through May 2008 associated with five risk-warning events.
        J Manag Care Pharm. 2008; 14: 523-531
        • Barter P.J.
        • Caulfield M.
        • Eriksson M.
        • et al.
        Effects of torcetrapib in patients at high risk for coronary events.
        N Engl J Med. 2007; 357: 2109-2122
        • Hammad T.A.
        • Laughren T.
        • Racoosin J.
        Suicidality in pediatric patients treated with antidepressant drugs.
        Arch Gen Psychiatry. 2006; 63: 332-339
        • Mukherjee D.
        • Nissen S.E.
        • Topol E.J.
        Risk of cardiovascular events associated with selective COX-2 inhibitors.
        JAMA. 2001; 286: 954-959
        • Rossouw J.E.
        • Anderson G.L.
        • Prentice R.L.
        • et al.
        Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial.
        JAMA. 2002; 288: 321-333
        • Cramer J.A.
        A systematic review of adherence with medications for diabetes.
        Diabetes Care. 2004; 27: 1218-1224
        • Donnan P.T.
        • MacDonald T.M.
        • Morris A.D.
        Adherence to prescribed oral hypoglycaemic medication in a population of patients with Type 2 diabetes: a retrospective cohort study.
        Diabet Med. 2002; 19: 279-284
        • Morris A.D.
        • Boyle D.I.
        • McMahon A.D.
        • et al.
        Adherence to insulin treatment, glycaemic control, and ketoacidosis in insulin-dependent diabetes mellitus.
        Lancet. 1997; 350: 1505-1510
        • 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
        • Skyler J.S.
        • Bergenstal R.
        • Bonow R.O.
        • et al.
        Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association.
        Diabetes Care. 2009; 32: 187-192
        • Centers for Disease Control and Prevention
        National Diabetes Fact Sheet, 2007.
        (Accessed November 19, 2008)
        • American Diabetes Association
        Total prevalence of diabetes & prediabetes.
        (Accessed November 20, 2008)
        • American Diabetes Association
        Complications of diabetes in the United States.
        (Accessed November 20, 2008)
        • American Diabetes Association
        Economic costs of diabetes in the U.S. in 2007.
        Diabetes Care. 2008; 31: 596-615
        • Narayan K.M.
        • Boyle J.P.
        • Thompson T.J.
        • et al.
        Lifetime risk for diabetes mellitus in the United States.
        JAMA. 2003; 290: 1884-1890
        • Haffner S.M.
        • Lehto S.
        • Ronnemaa T.
        • et al.
        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
      1. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.
        Lancet. 1998; 352: 837-853
      2. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.
        Lancet. 1998; 352: 854-865
      3. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group.
        N Engl J Med. 1993; 329: 977-986
        • Nathan D.M.
        • Cleary P.A.
        • Backlund J.Y.
        • et al.
        Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.
        N Engl J Med. 2005; 353: 2643-2653
        • 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
        • Patel A.
        • MacMahon S.
        • Chalmers J.
        • et al.
        Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
        N Engl J Med. 2008; 358: 2560-2572
        • Gerstein H.C.
        • Miller M.E.
        • Byington R.P.
        • et al.
        Effects of intensive glucose lowering in type 2 diabetes.
        N Engl J Med. 2008; 358: 2545-2559
        • Duckworth W.
        • Abraira C.
        • Moritz T.
        • et al.
        Glucose control and vascular complications in veterans with type 2 diabetes.
        N Engl J Med. 2009; 360: 129-139
        • Ray K.K.
        • Seshasai S.R.
        • Wijesuriya S.
        • et al.
        Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials.
        Lancet. 2009; 373: 1765-1772
        • Mannucci E.
        • Monami M.
        • Lamanna C.
        • et al.
        Prevention of cardiovascular disease through glycemic control in type 2 diabetes: a meta-analysis of randomized clinical trials.
        Nutr Metab Cardiovasc Dis. 2009 May 7; ([Epub ahead of print])
        • Diamond G.A.
        • Bax L.
        • Kaul S.
        Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death.
        Ann Intern Med. 2007; 147: 578-581
        • Hernandez A.V.
        • Walker E.
        • Ioannidis J.P.
        • Kattan M.W.
        Challenges in meta-analysis of randomized clinical trials for rare harmful cardiovascular events: the case of rosiglitazone.
        Am Heart J. 2008; 156: 23-30
        • Rucker G.
        • Schumacher M.
        Simpson's paradox visualized: the example of the rosiglitazone meta-analysis.
        BMC Med Res Methodol. 2008; 8: 34
        • Shuster J.J.
        • Jones L.S.
        • Salmon D.A.
        Fixed vs random effects meta-analysis in rare event studies: the rosiglitazone link with myocardial infarction and cardiac death.
        Stat Med. 2007; 26: 4375-4385
        • Singh S.
        • Loke Y.K.
        • Furberg C.D.
        Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis.
        JAMA. 2007; 298: 1189-1195
        • Dahabreh I.J.
        Meta-analysis of rare events: an update and sensitivity analysis of cardiovascular events in randomized trials of rosiglitazone.
        Clin Trials. 2008; 5: 116-120
        • Monami M.
        • Marchionni N.
        • Mannucci E.
        Winners and losers at the rosiglitazone gamble A meta-analytical approach at the definition of the cardiovascular risk profile of rosiglitazone.
        Diabetes Res Clin Pract. 2008; 82: 48-57
        • Gerrits C.M.
        • Bhattacharya M.
        • Manthena S.
        • et al.
        Comparison of pioglitazone and rosiglitazone for hospitalization for acute myocardial infarction in type 2 diabetes.
        Pharmacoepidemiol Drug Saf. 2007; 16: 1065-1071
        • Mannucci E.
        • Monami M.
        • Lamanna C.
        • et al.
        Pioglitazone and cardiovascular risk.
        Diabetes Obes Metab. 2008; 10: 1221-1238
        • Wilcox R.
        • Kupfer S.
        • Erdmann E.
        Effects of pioglitazone on major adverse cardiovascular events in high-risk patients with type 2 diabetes: results from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive 10).
        Am Heart J. 2008; 155: 712-717
        • Berlie H.D.
        • Kalus J.S.
        • Jaber L.A.
        Thiazolidinediones and the risk of edema: a meta-analysis.
        Diabetes Res Clin Pract. 2007; 76: 279-289
        • Lago R.M.
        • Singh P.P.
        • Nesto R.W.
        Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials.
        Lancet. 2007; 370: 1129-1136
        • Bailey C.J.
        • Campbell I.W.
        • Chan J.C.N.
        Metformin: The Gold Standard.
        John Wiley & Sons, Chichester, UK; Hoboken, NJ2007
        • Alvarez G.F.
        • Tofe P.S.
        • Krishnarajah G.
        • et al.
        Hypoglycaemic symptoms, treatment satisfaction, adherence and their associations with glycaemic goal in patients with type 2 diabetes mellitus: findings from the Real-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) Study.
        Diabetes Obes Metab. 2008; 10: 25-32
        • Cryer P.E.
        Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes.
        Diabetologia. 2002; 45: 937-948
        • Ridderstrale M.
        • Gudbjornsdottir S.
        • Eliasson B.
        • et al.
        Obesity and cardiovascular risk factors in type 2 diabetes: results from the Swedish National Diabetes Register.
        J Intern Med. 2006; 259: 314-322
        • Pischon T.
        • Boeing H.
        • Hoffmann K.
        • et al.
        General and abdominal adiposity and risk of death in Europe.
        N Engl J Med. 2008; 359: 2105-2120
        • Bessesen D.H.
        Update on obesity.
        J Clin Endocrinol Metab. 2008; 93: 2027-2034
        • Williamson D.F.
        • Thompson T.J.
        • Thun M.
        • et al.
        Intentional weight loss and mortality among overweight individuals with diabetes.
        Diabetes Care. 2000; 23: 1499-1504
        • Hermansen K.
        • Mortensen L.S.
        Bodyweight changes associated with antihyperglycaemic agents in type 2 diabetes mellitus.
        Drug Saf. 2007; 30: 1127-1142
        • Purnell J.Q.
        • Weyer C.
        Weight effect of current and experimental drugs for diabetes mellitus: from promotion to alleviation of obesity.
        Treat Endocrinol. 2003; 2: 33-47
        • Dluhy R.G.
        • McMahon G.T.
        Intensive glycemic control in the ACCORD and ADVANCE trials.
        N Engl J Med. 2008; 358: 2630-2633
        • Krentz A.J.
        • Ferner R.E.
        • Bailey C.J.
        Comparative tolerability profiles of oral antidiabetic agents.
        Drug Saf. 1994; 11: 223-241
        • Bailey C.J.
        • Nattrass M.
        Treatment—metformin.
        Baillieres Clin Endocrinol Metab. 1988; 2: 455-476
      4. Glucophage [package insert].
        Bristol-Myers Squibb Company, Princeton, NJ2006
        • Bailey C.J.
        • Turner R.C.
        Metformin.
        N Engl J Med. 1996; 334: 574-579
        • Salpeter S.
        • Greyber E.
        • Pasternak G.
        • Salpeter E.
        Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.
        Cochrane Database Syst Rev. 2002; (CD002967)
        • Bolen S.
        • Feldman L.
        • Vassy J.
        • et al.
        Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus.
        Ann Intern Med. 2007; 147: 386-399
        • Masharani U.
        • Karam J.H.
        • German M.S.
        Pancreatic hormones & diabetes mellitus.
        in: Greenspan F.S. Gardner D.G. Basic & Clinical Endocrinology. McGraw-Hill, New York2004: 658-746
        • Grey A.
        Thiazolidinedione-induced skeletal fragility—mechanisms and implications.
        Diabetes Obes Metab. 2009; 11: 275-284
        • Hampton T.
        Diabetes drugs tied to fractures in women.
        JAMA. 2007; 297: 1645
        • Meier C.
        • Kraenzlin M.E.
        • Bodmer M.
        • et al.
        Use of thiazolidinediones and fracture risk.
        Arch Intern Med. 2008; 168: 820-825
        • Loke Y.K.
        • Singh S.
        • Furberg C.D.
        Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis.
        CMAJ. 2009; 180: 32-39
        • Sandler R.S.
        • Everhart J.E.
        • Donowitz M.
        • et al.
        The burden of selected digestive diseases in the United States.
        Gastroenterology. 2002; 122: 1500-1511
        • Fagenholz P.J.
        • Castillo C.F.
        • Harris N.S.
        • et al.
        Increasing United States hospital admissions for acute pancreatitis, 1988-2003.
        Ann Epidemiol. 2007; 17: 491-497
        • Frey C.F.
        • Zhou H.
        • Harvey D.J.
        • White R.H.
        The incidence and case-fatality rates of acute biliary, alcoholic, and idiopathic pancreatitis in California, 1994-2001.
        Pancreas. 2006; 33: 336-344
        • Trivedi C.D.
        • Pitchumoni C.S.
        Drug-induced pancreatitis: an update.
        J Clin Gastroenterol. 2005; 39: 709-716
        • Ahmad S.R.
        • Swann J.
        Exenatide and rare adverse events.
        N Engl J Med. 2008; 358: 1970-1971
        • Cure P.
        • Pileggi A.
        • Alejandro R.
        Exenatide and rare adverse events.
        N Engl J Med. 2008; 358: 1969-1970
        • Denker P.S.
        • Dimarco P.E.
        Exenatide (exendin-4)-induced pancreatitis: a case report.
        Diabetes Care. 2006; 29: 471
        • Audia P.
        • Feinfeld D.A.
        • Dubrow A.
        • Winchester J.F.
        Metformin-induced lactic acidosis and acute pancreatitis precipitated by diuretic, celecoxib, and candesartan-associated acute kidney dysfunction.
        Clin Toxicol (Phila). 2008; 46: 164-166
        • Fimognari F.L.
        • Corsonello A.
        • Pastorell R.
        • Antonelli-Incalzi R.
        Metformin-induced pancreatitis: a possible adverse drug effect during acute renal failure.
        Diabetes Care. 2006; 29: 1183
        • Mallick S.
        Metformin induced acute pancreatitis precipitated by renal failure.
        Postgrad Med J. 2004; 80: 239-240
        • Ben M.H.
        • Thabet H.
        • Zaghdoudi I.
        • Amamou M.
        Metformin associated acute pancreatitis.
        Vet Hum Toxicol. 2002; 44: 47-48
        • Dore D.D.
        • Seeger J.D.
        • Arnold Chan K.
        Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide.
        Curr Med Res Opin. 2009; 25: 1019-1027
        • Noel R.A.
        • Braun D.K.
        • Patterson R.E.
        • Bloomgren G.
        Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective, cohort study.
        Diabetes Care. 2009; 32: 834-838
        • Blomgren K.B.
        • Sundstrom A.
        • Steineck G.
        • Wiholm B.E.
        Obesity and treatment of diabetes with glyburide may both be risk factors for acute pancreatitis.
        Diabetes Care. 2002; 25: 298-302
        • Martinez J.
        • Johnson C.D.
        • Sanchez-Paya J.
        • et al.
        Obesity is a definitive risk factor of severity and mortality in acute pancreatitis: an updated meta-analysis.
        Pancreatology. 2006; 6: 206-209
        • Suazo-Barahona J.
        • Carmona-Sanchez R.
        • Robles-Diaz G.
        • et al.
        Obesity: a risk factor for severe acute biliary and alcoholic pancreatitis.
        Am J Gastroenterol. 1998; 93: 1324-1328
      5. Januvia [package insert].
        Merck & Co, Inc, Whitehouse Station, NJ2007
        • Amori R.E.
        • Lau J.
        • Pittas A.G.
        Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis.
        JAMA. 2007; 298: 194-206
        • Green B.D.
        • Flatt P.R.
        • Bailey C.J.
        Dipeptidyl peptidase IV (DPP IV) inhibitors: a newly emerging drug class for the treatment of type 2 diabetes.
        Diab Vasc Dis Res. 2006; 3: 159-165
        • Ulmer A.J.
        • Mattern T.
        • Feller A.C.
        • et al.
        CD26 antigen is a surface dipeptidyl peptidase IV (DPPIV) as characterized by monoclonal antibodies clone TII-19-4-7 and 4EL1C7.
        Scand J Immunol. 1990; 31: 429-435
        • Fleischer B.
        CD26: a surface protease involved in T-cell activation.
        Immunol Today. 1994; 15: 180-184
        • Zhu L.
        • Tamvakopoulos C.
        • Xie D.
        • et al.
        The role of dipeptidyl peptidase IV in the cleavage of glucagon family peptides: in vivo metabolism of pituitary adenylate cyclase activating polypeptide-(1-38).
        J Biol Chem. 2003; 278: 22418-22423
        • Foley R.N.
        • Murray A.M.
        • Li S.
        • et al.
        Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999.
        J Am Soc Nephrol. 2005; 16: 489-495
        • Trautner C.
        • Icks A.
        • Haastert B.
        • et al.
        Incidence of blindness in relation to diabetes.
        Diabetes Care. 1997; 20: 1147-1153