Diabetes Treatments

Corridor Consult
By Alan D Jacknow, MD
54

clinical contributions

Clinical Overview:

How Do I Treat the Adults Ive Been Seeing with New Type 2 Diabetes?
feet Blood glucose level, determined by fingerstick in Diabetes mellitus has rapidly become an epidemic in the examination room, is 338 mg/dL 188 mmol/L the Western world, especially in the United States The number of patients who present with diabetes, along Discussion with the closely associated obesity and metabolic syn- Diagnosis of Type 2 Diabetes Although probable, Type 2 diabetes cannot be dedrome syndrome X, has exploded–in part because of the contemporary American lifestyle Approximately finitively diagnosed on the basis of this patients pre79 of all Americans have diabetes up from 49 just sentation alone The diagnosis of diabetes depends on a decade ago1 Although diabetes is more prevalent any one of three criteria: 1 symptoms of diabetes and among Americans aged 60 years or more, increase in a casual blood glucose level of 200 mg/dL 111 mmol/L; incidence is most rapid in those under 30 years, espe- 2 fasting no caloric intake for at least eight hours cially in the Latino/Hispanic, African American, and blood glucose
125 mg/dL 69 mmol/L; or 3 2-hour blood glucose 200 mg/dL 111 mmol/L during an Native American populations2 Diabetes is the sixth largest killer in the United States,3 oral glucose tolerance test OGTT The OGTT should and the overall risk of death among people with dia- be performed as described by the World Health Orgabetes is about twice that among people without diabe- nization, ie, using a glucose load containing the equivates However, the increased risk associated with diabe- lent of 75 grams of anhydrous glucose dissolved in tes is greater for younger people that is, 36 times higher water5 A positive test result must be confirmed by any for people age 25 to 44 years versus 15 times higher for of these same three methods, but on another day, to those age 65 to 74 years and for women that is, 27 authoritatively diagnose diabetes mellitus Glycosylated hemoglobin HbA1c levels are not currently times higher for women aged 45 to 64 Treatment used in diagnosis, although dramatically elyears versus 20 times higher for men in begins evated levels provide presumptive evidence that age group2 One million people are with selfdiagnosed with diabetes yearly, yet the The patient should be
scheduled for a confirmanagement matory test as soon as possible estimate is that one of every three patients with diabetes remains undiagnosed1 Treatment of Type 2 Diabetes Case Example Aside from gender, this patient typifies new-onset A resident working in the walk-in clinic calls you at diabetic patients He is obese and has not been in close home about a patient who is being seen for the first contact with the health care system time A 58-year-old Latino/Hispanic male who has been Treatment begins with self-management He does not feeling weak and tired for the last few months, the smoke, but smoking cessation would be a priority if he patient has difficulty sleeping because he has to wake did Smoking in cases of diabetes increases the risk of up so often to urinate He also complains of weight cardiovascular disease by 356 The basis of clinical loss, thirst, and blurred vision, even though he got new management of Type 2 diabetes is emphasis on and glasses two weeks ago He hasnt seen his physician frequent return to the basics of self-management: diet, for several years and takes no medication Physical increased physical activity, and home glucose moniexamination reveals an
obese Latino/Hispanic male toring The patient should be referred to the basic diawith blood pressure of 164/88 mm Hg, dry mouth, betes classes offered at his care institution If classes and skin with decreased turgor The rest of the exami- are successfully completed, diabetes self-care can imnation shows normal fundi, heart sounds, prostate, and prove glucose control and can decrease complications7

Introduction

Alan D Jacknow, MD, is a clinical endocrinologist at the Panorama City Medical Center, CA He also chairs the Panorama City Diabetes Task Force E-mail: alandjacknow@kporg
The Permanente Journal/ Summer 2003/ Volume 7 No 3

clinical contributions
Clinical Overview: How Do I Treat the Adults Ive Been Seeing with New Type 2 Diabetes?

Because retinopathy can be present at diagnosis in a patient with Type 2 diabetes, the patient should be referred for retinal screening dilated eye examination too8 The question of whether to treat this patient with diabetic medication at this time is difficult to answer No long-term studies appear to evaluate this question Although he presents with some acute hyperglycemic symptoms such as blurred vision and nocturia, a threemonth trial of
lifestyle modification is recommended If HbA1c level is not reduced below 70 of total hemoglobin, pharmaceutical treatment is indicated Again, when a desirable medication is sought, few studies compare treatment regimens directly But the results of the United Kingdom Prospective Diabetes Study UKPDS9 strongly suggest that in obese patients, metformin Glucophage is the preferred drug for initiation of therapy In a report from the UK Prospective Diabetes Study Group,9 treatment with metformin resulted in a 39 lower risk of myocardial infarction when compared with conventional treatment primarily diet but not when compared with intensive treatment with sulfonylureas–even when the same level of glucose control was achieved Metformin rarely causes hypoglycemia, an important advantage over other standard agents, and metformin causes less weight gain9 Gastrointestinal side effects nausea and bloating are lessened by beginning with 500 mg daily I like patients to start this regimen at bedtime, because the side effects seem better tolerated and because of the theoretical advantage to treating fasting blood glucose I recommend gradually increasing dosage to a daily maximum of 255 g 850 mg
three times daily This regimen is contraindicated for patients with mild renal failure creatinine clearance of 70 mL/min per 173 m2, active congestive heart failure, pregnancy, and hepatic dysfunction because of risk of developing of lactic acidosis For the same reason, metformin is routinely withheld for 48 hours before certain radiologic and surgical procedures No studies appear to have compared cardiovascular complications from thiazolidinedione versus metformin If metformin is contraindicated, thiazolidinedione glitazone may be a useful alternative Glitazone therapy may be used in patients with renal insufficiency and mild hepatic dysfunction In fact, early studies10-12 suggest that thiazolidinedione may be a treatment for fatty liver disease, a common cause of liver dysfunction in insulin-resistant patients The major side effect of thiazolidinedione is fluid retention, but recent studies13-15 suggest its safety for treating controlled congestive heart failure class A or B The

first thiazolidinedione, Rezulin Parke-Davis/WarnerLambert, caused hepatic failure that resulted in several patient deaths16,17 and was withdrawn from the market in 2000 For this reason, close monitoring
of liver function is recommended, although few longterm liver problems have been reported18 Most often used in the past as first-line therapy, sulfonylurea and insulin are today used more often in combined therapy for patients who do not have adequate glucose control from metformin or for whom metformin is contraindicated Although sulfonylurea and insulin may still be used as first-line agents, they do not have the same positive cardiovascular effects as metformin In addition, because insulin can control blood glucose more quickly, insulin is sometimes used at diagnosis to establish quick control and is then discontinued High blood glucose levels have a stunting effect on pancreatic beta cells, so rapid control with insulin may maximize the effectiveness of lifestyle changes, metformin therapy, or both The UK Prospective Diabetes Study in obese showed that excellent control of blood glupatients, cose HbA1c level 70 of total hemoglometformin bin; fasting blood glucose level 80-120 mg/ Glucophage is dL [44-67 mmol/L]; postprandial blood gluthe preferred cose level 180 mg/dL [100 mmol/L] redrug for duces cardiovascular events in diabetic painitiation of tients 9 We therefore
recommend that therapy treatment of diabetes include more use of combined medication therapy until these laboratory value goals are achieved Additional Forms of Therapy for Type 2 Diabetes Two thirds of all diabetic patients die from cardiovascular disease, including cardiovascular accidents Recent studies illustrate ways to decrease these risks The Heart Protection Study19 evaluated ability of statins to prevent heart attacks and showed that statins lower risk of myocardial infarction in diabetic patients by nearly 20, regardless of initial cholesterol level The Heart Outcomes Prevention Evaluation HOPE study20 analyzed use of angiotensin-converting-enzyme ACE inhibitors in diabetic patients who had at least one other cardiac risk factor The study showed a 25 decrease in combined risk of myocardial infarction, stroke, or death from cardiovascular disease when ACE inhibitors were used, regardless of their effect on blood pressure and even when used for normotensive or wellcontrolled hypertensive diabetes20 This decrease in risk was achieved without increased adverse effects, and the

The Permanente Journal/ Summer 2003/ Volume 7 No 3

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clinical contributions
Clinical Overview:
How Do I Treat the Adults Ive Been Seeing with New Type 2 Diabetes?

blood pressure in diabetic patients should be aggressively treated to reach 130/80 mm Hg or lower

same beneficial effect was seen in diabetic patients with decreased renal function in a subgroup analysis, risk of cardiovascular disease increased with decreased baseline renal function creatinine level 14 mg/dL [1238 mmol/L]20 Blood pressure control is among the most important interventions currently available for preventing diabetic complications According to the American Diabetes Association, blood pressure in diabetic patients should be aggressively treated to reach 130/80 mm Hg or lower,21 a goal that frequently necessitates use of multiple antihypertensive drugs The Hypertension Optimal Treatment HOT Trial22 examined effects of 75 mg daily aspirin versus placebo in 18,790 hypertensive patients, including 1501 diabetic subjects Aspirin significantly reduced cardiovascular events by 15 and myocardial infarction by 3622 Fatal bleeding episodes, including intracerebral bleeding, were equal in the aspirin and placebo groups; nonfatal, minor bleeding episodes were more common in the aspirin group22 As a result of
these clinical trials,19,20,22 we now recommend that men age 50 years and older and women age 60 years and older receive a statin, an ACE inhibitor, and aspirin without regard to baseline cholesterol and blood pressure levels Because our hypothetical patient falls within these parameters, all three therapies should be started unless contraindicated
References 1 Mokdad AH, Ford ES, Bowman BA, et al Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001 JAMA 2003 Jan 1;2891:76-9 2 American Diabetes Association National diabetes fact sheet: general information and national estimates on diabetes in the United States [Web site] Available from: wwwdiabetesorg/main/info/facts/facts_natljsp accessed June 18, 2003 3 National Institute of Diabetes Digestive Kidney Diseases National diabetes statistics: general information and national estimates on diabetes in the United States, 2000 [Web site] Available from: wwwniddknihgov/health/ diabetes/pubs/dmstats/dmstatshtm accessed June 18, 2003 4 The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Report of the expert committee on the diagnosis and classification of diabetes mellitus Diabetes Care
2003 Jan;26 Suppl 1:S5-20 5 WHO Study Group on Diabetes Mellitus Diabetes mellitus: report of a WHO Study Group Geneva: World Health Organization; 1985 6 Stevens RJ, Kothari V, Adler AI, Stratten IM; United Kingdom Prospective Diabetes Study UKPDS Group The UKPDS risk engine: a model for the risk of coronary heart disease in Type II diabetes UKPDS 56 [published erratum appears in Clin Sci Lond 2002 Jun;1026:679] Clin Sci Lond 2001 Dec;1016:671-9

7 Norris SL, Engelgau MM, Narayan KM Effectiveness of selfmanagement training in type 2 diabetes: a systematic review of randomized controlled trials Diabetes Care 2001 Mar;243:561-87 8 Vijan S, Hofer TP, Hayward RA Cost-utility analysis of screening intervals for diabetic retinopathy in patients with type 2 diabetes mellitus JAMA 2000 Feb 16;2837:889-96 9 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 [published erratum appears in Lancet 1998 Nov 7;3529139:1557] Lancet 1998 Sep 12;3529131:854-65 10 Battle EH, Hespenheide EE, Caldwell SH Pilot study of troglitazone Rezulin for nonalcoholic steatohepatitis [abstract]
Hepatology 1998 Oct;284 Pt 2:304A 11 Caldwell SH, Hespenheide EE, Redick JA, Iezzoni JC, Battle EH, Sheppard BL A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis Am J Gastroenterol 2001 Feb;962:519-25 12 Katoh S, Hata S, Matsushima M, et al Troglitazone prevents the rise in visceral adiposity and improves fatty liver associated with sulfonylurea therapy–a randomized controlled trial Metabolism 2001 Apr;504:414-7 13 Wang F, Aleksunes LM, Reagan LA, Vergara CM Management of rosiglitazone-induced edema: two case reports and a review of the literature Diabetes Technol Ther 2002;44:505-14 14 Viberti GC Rosiglitazone: potential beneficial impact on cardiovascular disease Int J Clin Pract 2003 Mar;572:128-34 15 Tang WH, Francis GS, Hoogwerf BJ, Young JB Fluid retention after initiation of thiazolidinedione therapy in diabetic patients with established chronic heart failure J Am Coll Cardiol 2003 Apr 16;418:1394-8 16 Gale EA Lessons from the glitazones: a story of drug development Lancet 2001 Jun 9;3579271:1870-5 17 Chaudhry MU, Simmons DL Case of the month Hepatic and renal failure in a patient taking troglitazone and metformin J Ark Med Soc 2001
Jul;981:16-9 18 Lebovitz HE, Kreider M, Freed MI Evaluation of liver function in type 2 diabetic patients during clinical trials: evidence that rosiglitazone does not cause hepatic dysfunction Diabetes Care 2002 May;255:815-21 19 Heart Protection Study Collaborative Group MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial Lancet 2002 Jul 6;3609326:7-22 20 Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy Heart Outcomes Prevention Evaluation Study Investigators Lancet 2000 Jan 22;3559200;253-9 21 American Diabetes Association Treatment of hypertension in adults with diabetes Diabetes Care 2002 Jan;251:199-201 22 Hansson L, Zanchetti A, Carruthers SG, et al Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment HOT randomised trial HOT Study Group Lancet 1998 Jun 13;3519118:175562

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Source:ama-assn.org