A case for prevention of type 2 diabetes mellitus Joseph Cook, DO Diabetes is a disease that has reached epidemic proportions in the United States and around the world. This is troubling because, as bad as the disease itself is, it comes with a tremendous number of complications and these complications are usually what kills most people with diabetes. February 2010 DOs Against DIABETES AOA Health Watch 3
Therefore, public health efforts are most efficient if they are focused on preventing the disease and thus heading off its attendant complications. One of the keys in doing so is to better recognize prediabetes, which is characterized by impaired glucose tolerance and/or impaired fasting glucose. Approximately 54 million people in the United States who are over the age of 20 suffer from prediabetes. Although prediabetes is considered a silent disease, its effects are very real, and 30% of people who have the condition will have already developed a complication by the time they are diagnosed with diabetes mellitus. Therefore, many people are at risk and may not be aware. Physicians should strive to identify these people and work to prevent the development of diabetes and its related complications. Background Diabetes is the leading cause of adult legal blindness, end-stage kidney disease, non-traumatic lower extremity amputations and cardiovascular disease. Type 2 diabetes accounts for 90% to 95% of all cases of diabetes in adults. For details on the prevalence of diagnosed and undiagnosed diabetes in people ages 20 years or older, by age group, see Table 1. Diabetes is characterized by hyperglycemia and is generally diagnosed according to the criteria of the American Diabetes Association, which are detailed in Table 2. 1 The International Expert Committee recently noted that diabetes mellitus may be diagnosed when the patient s hemoglobin A1c level is 6.5%. 2 Diagnosis based on HgA1c should be confirmed with a repeated test. However, confirmation is not required in symptomatic subjects with plasma glucose levels 200 mg/dl ( 11.1 mmol/l). 2 Patients with high blood sugar levels but not high enough to meet the criteria for the diagnosis of diabetes have prediabetes. The criteria for the diagnosis of prediabetes are outlined in Table 3. The International Expert Committee also recently noted that patients with HgA1c levels below the threshold for Table 1 Estimated prevalence of diagnosed and undiagnosed diabetes in people ages 20 years or older, by age group, United States, 2007. Source: 2003-2006 National Health and Nutrition Examination Survey, Centers for Disease Control. Percent 25 20 15 10 5 0 2.6 10.8 23.1 20-39 40-59 60+ Age Group Table 2 Criteria for the diagnosis of diabetes mellitus 1 1. Symptoms of diabetes plus casual plasma glucose concentration 200 mg/dl (11.1 mmol/l). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss. Or FPG 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least eight hours. Or 2. Two-hour post-load glucose 200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. In the absence of unequivocal hyperglycemia, these criteria should be confirmed by repeat testing on a different day. The third measure (OGTT) is not recommended for routine clinical use. Source: Standards of Medical Care in Diabetes, 2010, American Diabetes Association. 4 AOA Health Watch DOs Against DIABETES February 2010
diabetes (below 6.5%) but 5.7% have prediabetes and should receive effective preventive interventions. 1,3 With some 54 million individuals in the United States aged 21 and older having prediabetes, 2 a very large population of people who are considered to be at high risk for the development of diabetes and macrovascular disease exists. 4,5 It is now recognized that 30% of people will have a microvascular or macrovascular complication by the time that they are diagnosed with diabetes, further emphasizing the need for vigilance and early intervention. Illustrative case Jason is a 43-year-old male who presents for his annual physical exam. He denies any physical complaints. Additional history reveals that Jason has gained about eight pounds over the past year, does not exercise regularly, and smokes about one pack of cigarettes per day. PMHx: Asthma PSHx: Cholecystectomy Meds: Advair Diskus, Albuterol Allergies: NKDA SocHx: As described above FamHx: Mother with DM, HTN ROS: Weight gain over past year, otherwise negative Objective findings include: Body mass index (BMI): 37 kg per m2 Blood pressure: 138/78 mm Hg Brown, velvety appearance to skin around neck Remainder of physical exam is unremarkable Blood glucose level (two hours after lunch): 189 mg per dl Spot urine microalbumin/creatinine: 42 mg/g Fasting blood work shows blood glucose level of 118 mg/dl Fasting lipids: Total cholesterol 220, Triglycerides 174, HDL 38, LDL 124 CBC and CMP were unremarkable Question 1: What are his diagnoses? Prediabetes, impaired fasting glucose, impaired glucose tolerance, metabolic Table 3 Criteria for the diagnosis of prediabetes 2 1. Fasting plasma glucose of 100 to 125 mg/dl (5.6 to 6.9 mmol/l) = IFG (impaired fasting glucose) Or 2. Two-hour post-load glucose 140 to 199 mg/dl (7.8 to 11.1 mmol/l) = IGT (impaired glucose tolerance) Source: The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Follow-up report on the Diagnosis of Diabetes Mellitus. American Diabetes Association. Diabetes Care 26:3160-3167, 2009. Figure 1 Cumulative Incidence of Diabetes (%) 40 35 30 25 20 15 10 5 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Year syndrome, microalbuminuria and medically complicated obesity. Insulin resistance syndromes have substantial overlap but they are not Placebo Metformin Lifestyle The diagnosis of diabetes was based on the criteria of the American Diabetes Association. The incidence of diabetes differed significantly among the three groups (P 0.001 for each comparison). Source: Diabetes Prevention Program Research Group. The DPP: Reduction in the incidence of type 2 diabetes with lifestyle modifications or metformin. NEJM 2002. 346 (6):393-403. Copyright 2010, Massachusetts Medical Society. All rights reserved. synonymous. These include metabolic syndrome, prediabetes (both impaired fasting glucose and impaired glucose tolerance), fatty liver disease and February 2010 DOs Against DIABETES AOA Health Watch 5
Table 4 Lifestyle interventional studies to reduce T2DM diagnosis Lifestyle Trials Diabetes Prevention Program Intervention Supervised weight loss and physical activity Population with IGT or IFG Results DM diagnoses decreased 58% Da Qing IGT study Diet, physical activity or both Chinese men and women 45 y/o with IGT Each arm decreased DM 31%-46% Finnish DM Prevention Trial Dietary counseling and physical activity Women and men 55 y/o with IGT 58% reduction in DM diagnosis polycystic ovarian syndrome. All of these conditions have distinct diagnostic criteria but they overlap significantly. Perhaps most importantly, each of them shares an increased risk for the development of future diabetes and cardiovascular disease. Question 2: Is progression from prediabetes to diabetes inevitable? The resounding answer is no. The Diabetes Prevention Program (DPP) compared lifestyle and the diabetes medication metformin in patients with prediabetes to determine what method better prevents diabetes development in individuals with prediabetes. The lifestyle intervention in the intensive lifestyle group included the goals of 7% loss of body weight, 150 minutes per week of moderate intensity physical activity, and a diet of less than 25% of calories from fat. The winner in the DPP was intensive lifestyle changes, which reduced diabetes development by 58% compared to placebo, followed by metformin, which reduced diabetes development by 31% relative to placebo. 7,8 For details, see Figure 1. 8 The diagnosis of diabetes was based on the criteria of the American Diabetes Association. The incidence of diabetes differed significantly among the three groups (P 0.001 for each comparison). The Finnish Diabetes Prevention Study also showed the benefit of lifestyle changes in helping to prevent the progression from prediabetes to diabetes. 9 For a summary of lifestyle studies that demonstrate reduction of new diagnosis of diabetes, see Table 4. Because these goals may seem daunting to some patients, I believe it is important to initially set smaller goals. For example, striving for a weight loss of one pound per week may seem more realistic than to simply tell a patient that he or she needs to lose 15 pounds. I also will sometimes ask patients to try five minutes of physical activity per day initially, with the goal of eventually getting to 30 minutes per day. As patients want to progress, they can try to add one minute of exercise per day each week. Setting realistic goals may result in better adherence. Medications have also shown ability to delay or prevent the diagnosis of type 2 diabetes mellitus (T2DM). As mentioned previously, metformin 6 AOA Health Watch DOs Against DIABETES February 2010
Table 5 Pharmacologic studies to prevent diabetes Medication Trials Diabetes Prevention Program Intervention metformin, troglitazone briefly Population with IGT or IFG Results Metformin reduced DM 31% TRiPOD troglitazone Hispanic women with gestational DM Troglitazone reduced DM 55% STOP-NIDDM acarbose with IGT Acarbose reduced DM 24% XENIDOS orlistat with IGT and/or obesity Orlistat reduced DM 37% reduced new diagnosis of T2DM by 31% in those participants in the Diabetes Prevention Program. 8 Further, there was an initial arm in this study using troglitazone. This arm was prematurely stopped due to some participants developing liver failure. However, in those who took troglitazone, there was a reduction in new T2DM. This was confirmed in the TRiPOD study, in which a 55% reduction was observed. Troglitazone is now not available due to safety reasons, but it has been shown that pioglitazone and rosiglitazone also have protective effects. 10,11 Further, unlike metformin, these effects may be durable even after stopping the medication. Acarbose has also been shown to prevent or delay the progression from prediabetes to diabetes in the STOP-NIDDM trial. 12 It is also important to mention that although these medications reduced the progression from prediabetes to diabetes, they are not FDA-approved for the treatment of prediabetes. A number of other medications also showed in posthoc or secondary analysis that they may delay the development of diabetes. These include angiotensin converting enzyme inhibitors, statins, fibrates, angiotensin-2 receptor blockers and some calcium channel blockers. These findings should be confirmed in primary outcome trials. In addition, studies have shown that using oral hypoglycemic agents may be able to prevent diabetes, and you can see highlights of those findings in Table 5. Case follow-up For our patient Jason, he chose to try lifestyle changes, including increasing his exercise routine to 30 minutes per day, five days per week. He also hoped to decrease his caloric consumption. He was referred to a registered dietician, but did not make the appointment. February 2010 DOs Against DIABETES AOA Health Watch 7
At his follow-up visit in three months, his weight remained the same and his repeat labs were similar to the prior labs. He also agreed to start metformin. He has since lost four pounds and his blood sugar levels remain in the prediabetes range. Over time he also had improvements in his cholesterol and blood pressure. His low-density lipoprotein cholesterol improved to 112 mg/dl and the blood pressure improved to 132/72 mm HG. Furthermore, his urine microalbumin normalized the following year. In the STENO-2 trial, aggressive multi-factorial treatment of people with micro-albuminuria significantly reduced cardiovascular events and death in people with type 2 diabetes. 13,14 What is even more important for this patient is that while he was focused on preventing diabetes, he also reduced his other cardiovascular risk factors and reduced his overall cardiovascular risk. Final notes As primary care physicians, we are well-aware of the potential microvascular and macrovascular complications of diabetes mellitus. But we should also be aware of the opportunity to prevent diabetes mellitus by stopping or delaying the progression from prediabetes to full-fledged diabetes. For the interested reader, the American Diabetes Association has published a Position Statement on the Prevention or Delay of Type 2 Diabetes Mellitus. 15 References 1. American Diabetes Association. Standards of medical care in diabetes-january 2010. Diabetes Care. January 2010 vol 33 no. Suppl 1. S4-S10. 2. International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes. Diabetes Care. 2009. 32;7:1327-1334. 3. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care. 2003;26:3160-3167. 4. U.S. Centers for Disease Control and Prevention. National Diabetes Fact Sheet 2005 page. Available at: www.cdc.gov/diabetes/ pubs/factsheet05.htm. 5. Knowler WC, Sartor G, Melander A, Scherten B. Glucose tolerance and mortality, including a substudy of tolbutamide treatment. Diabetologia. 1997;40:680-686. 6. Alberti KG. The clinical implications of impaired glucose tolerance. Diabet Med. 1996;13:927-937. 7. Ratner RE, Christophi CA, Metzger BE, et al for the Diabetes Prevention Program Research Group. Prevention of diabetes in women with a history of gestational diabetes: effects of metformin and lifestyle interventions. J Clin Endocrinol Metab. 2008;93:4774-4779. 8. Diabetes Prevention Program Research Group. The DPP:Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. 9. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-1350. 10. Xiang A, Peters RK, Kjos SL, et al. Effect of pioglitazone on pancreatic beta-cell function and diabetes risk in Hispanic women with prior gestational diabetes. Diabetes. 2006;55:517-522. 11. The DREAM TRIAL Investigators. Effects of ramipril and rosiglitazone on cardiovascular and renal outcomes in people with impaired glucose tolerance or impaired fasting glucose: results of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial. Diabetes Care. 2008;31: 1007-1014. 12. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359:2072-2077. 13. Gaede P et al. Multifactorial Intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348: 383-393. 14. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580-591. 15. American Diabetes Association. Position statement on Prevention or delay of type 2 diabetes mellitus. Diabetes Care. 2004;27:S47. HW Joseph Cook, DO, is an NCQA-recognized physician for diabetes management who works at Affinity Medical Center in Massillon, Ohio. Dr. Cook completed his internship and residency at St. Joseph Health Center in Warren, Ohio. He also completed a one-year fellowship in diabetes management at the Cornwell Diabetes Center in Athens, Ohio. He is currently a family physician and diabetologist at Affinity Medical Center. He can be reached at joesephcook@gmail.com. 8 AOA Health Watch DOs Against DIABETES February 2010