This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and

Transcription

1 This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier s archiving and manuscript policies are encouraged to visit:

2 International Journal of Diabetes Mellitus 1 (2009) Contents lists available at ScienceDirect International Journal of Diabetes Mellitus journal homepage: ees.elsevier.com/locate/ijdm Review Approach to dysglycemia: Do we need to treat impaired glucose tolerance and impaired fasting glucose? Mousa A. Abujbara, Kamel M. Ajlouni * National Center for Diabetes, Endocrinology and Genetics, P.O. Box Amman 11942, Jordan article info abstract Article history: Received 7 October 2008 Accepted 7 November 2008 Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are not only a surrogate for the state of insulin resistance but are also associated with the microvascular and macrovascular complications traditionally linked to diabetes. They predict an increased risk for death and morbidity due to cardiovascular disease. There is growing evidence that early detection of this state of pre-diabetes enables us to limit these recognized complications and perhaps to halt the progression to diabetes. For all pre-diabetes patients life style modifications, emphasizing modest weight loss & moderate physical activity are strongly recommended. Pharmacological intervention may also be necessary. Many studies have shown several drugs, both antidiabetic and nonhypoglycemic agents to be useful. If pharmacological treatment is required, Metformin is considered the first choice because of its safety, tolerability, efficacy and low cost. Ó 2009 International Journal of Diabetes Mellitus. Published by Elsevier Ltd. All rights reserved. 1. Introduction Diabetes and its complications are a growing concern worldwide. It has become an epidemic menace in most developed and many developing countries. Globally, the number of people with diabetes is expected to almost double in the next two decades, increasing from 194 million in 2003 to 380 million in 2025 [1]. The associated morbidity, mortality and high costs of health care, made type 2 diabetes an important global public health challenge and target for prevention. In Jordan, it was estimated that the total treatment costs (direct and indirect) incurred in regards to diabetes was 1,308 Billion JD per year [2], an enormous public health burden, and made the prevention of diabetes a critical health goal. Progression to overt diabetes from a pre-diabetic state occurs gradually, over a period of many years; however, current estimates indicate that most individuals (perhaps up to 70%) with pre-diabetic state eventually develop diabetes [3 5]. Studies have shown that patients during the pre-diabetic state are at increased risk of microvascular (retinopathy, nephropathy and neuropathy) and macrovascular (cardiovascular disease and stroke) complications and thus have higher morbidity and mortality than individuals with normal glucose homeostasis [6]. * Corresponding author. Tel.: ; fax: address: ajlouni@ju.edu.jo (K.M. Ajlouni). Between 1997 and 2006, eight major clinical trials examined whether lifestyle or pharmacologic interventions would prevent or delay the development of diabetes in populations with IFG and/or IGT [4,5,7,12]. All of these trials demonstrated a reduction in the development of diabetes of 25 60% over the period of follow-up depending on the type of intervention applied [8 11]. 2. Definition of pre-diabetes and its natural history The ADA defines normal glucose tolerance as a FPG < 100 mg/dl and 2 h PG in response to a 75 g OGTT of <140 mg/dl [13]. Diabetes is defined as a FPG P 126 mg/dl or a 2 h PG P 200 mg/dl during an OGTT. IFG and IGT represent intermediate states of abnormal glucose regulation that exist between normal glucose homeostasis and diabetes. It is a state of heightened risk of developing type 2 diabetes and other associated complications. Two different categories of pre-diabetes exist: IFG which is defined by an elevated fasting plasma glucose (FPG) concentration (P100 and <126 mg/dl) [14] and IGT which is defined by an elevated 2-h plasma glucose concentration (P140 and <200 mg/dl) after a 75-g glucose load on the oral glucose tolerance test (OGTT) in the presence of an FPG concentration <126 mg/dl [14]. Studies have shown that an oral glucose tolerance test (OGTT) is a more sensitive measure of early abnormalities in glucose regulation than fasting plasma glucose or HbA 1c [6]. This is possibly due to the fact that IGT is a consequence of two processes that are /$ - see front matter Ó 2009 International Journal of Diabetes Mellitus. Published by Elsevier Ltd. All rights reserved. doi: /j.ijdm

3 M.A. Abujbara, K.M. Ajlouni / International Journal of Diabetes Mellitus 1 (2009) intimately associated with obesity and drive pre-diabetic hyperglycemia: insulin resistance and dyslipidemia [15]. In obesity, as skeletal muscles lose sensitivity to insulin, more glucose is taken up by adipocytes, stimulating the production and release of more free fatty acids (FFAs) and triglycerides (TG). Elevated circulating FFAs in turn promote hyperglycemia by stimulating hepatic gluconeogenesis while inhibiting insulin-mediated glucose uptake and storage as glycogen. The prevalence of IFG and IGT varies considerably among different ethnic groups. Data also indicate that the prevalence of IFG and IGT is 26% and 15% respectively [16]. Also in Jordan Ajlouni et al reported the prevalence of pre-diabetes (IFG and IGT) to be 10% in 1997 [17]and the prevalence of IFG to be 7.8% in 2004 [18]. The prevalence of IFG and IGT also differs by age and sex, being more common in women than in men and increasing with advancing age [19]. complications are also present in the pre-diabetic state and that their risk increases with the distribution of blood glucose concentration well below the overt diabetes. The Aus Diab studies, for example, which is a population-based survey of 11,247 adults aged over 25 years found that 21.7% of individuals with pre-diabetes (IGT and/or IFG) had at least one microvascular complication [22]. In a cross-sectional study, neuropathy was found in 26% of 279 patients with diabetes, 11.2% of 89 patients with IGT, and only 3.9% of 577 age-matched normal control subjects [23]. IGT associated neuropathy is a symmetric, distal sensory polyneuropathy with prominent neuropathic pain which is phenotypically similar to diabetic neuropathy [24,25]. This reflects similar fiber loss and altered nerve morphology in both IGT and diabetes. Autonomic dysfunction manifested mainly as vagal dysautonomia (abnormal heart rate recovery following exercise, blunted R R interval variability to deep breathing, and reduced expiration to inspiration ratio) is also prevalent in pre-diabetes [26]. Microalbuminuria also has an increased prevalence in IGT. A very large population based study in China [27] demonstrated that the rate of albumin excretion was significantly higher among IGT subjects compared with the non-diabetic control group (7.2 ± 5.7 vs. 4.5 ± 2.8). Independent studies have noted an approximate fourfold increase in the prevalence of retinopathy among Pima Indians with IGT compared with age-matched control subjects [28]. Data suggest that the first stage of retinal injury occurs during IGT [28]. 5. Macrovascular complications of prediabetes The course of pre-diabetes (both IGT and IFG) is variable and difficult to predict. The different rates of progression reflect different genetic and environmental factors. Furthermore, patients with both IGT and IFG develop diabetes twice the rate as do individuals who manifest a single abnormality [20]. Patients with a higher FPG (i.e mmol/l [ mg/dl]) are also at much higher risk of progression to diabetes than those with lower (but abnormal) FPG levels ( mmol/l [ mg/dl]) [4]. 3. Pathogenesis of IFG and IGT The basic patho-physiological mechanisms underlying pre-diabetes are insulin resistance and defective insulin secretion. However, IFG and IGT differ in the nature of both of these defects [21]. In isolated IFG, there is a predominant hepatic insulin resistance with relatively preserved skeletal muscle sensitivity to insulin. On the other hand, in isolated IGT the hepatic insulin sensitivity is normal to slightly reduced and the resistance of skeletal muscles to insulin is moderate to severe. IFG and IGT also differ in their pattern of impairment of insulin secretion. In isolated IFG there is a decrease in the first-phase (0 10 min) insulin secretory response to intravenous glucose and a reduced early-phase (first 30 min) insulin response to oral glucose but the late-phase ( min) plasma insulin response during the OGTT is normal. In isolated IGT there is a defect in both early and late-phase insulin secretion. 4. Microvascular complications of prediabetes Classically diabetes is associated with microvascular and macrovascular complications but growing evidence shows that these A diagnosis of pre-diabetes not only identifies subjects who are at increased risk of diabetes but also at risk of cardiovascular and other macrovascular complications of diabetes. Data have shown that IGT patients are at greater risk of death from all causes and have a two to fivefold increased incidence of new-onset cardiovascular ischemia, fatal and total myocardial infarction, and stroke in comparison with their age-matched normoglycemic control subjects [29,30]. The Paris prospective study [31] has shown during the ten year follow up period that subjects with impaired glucose tolerance have about 50% increased risk of cardiovascular mortality. Other studies have shown an increased incidence of heart failure and coronary artery disease in patients with IGT irrespective of progression to diabetes [32,33]. While some studies have shown that both IGT and IFG confer an increased risk of cardiovascular disease [34], others, like the Funagata diabetes study, suggest that IGT is more strongly associated with cardiovascular disease risk than with fasting hyperglycemia [29]. 6. Rationale for the prevention of diabetes and recommendations for clinical management The considerable increase in the incidence of diabetes and its serious long term complications strongly support efforts to prevent or delay its occurrence. This is the rationale behind the consensus statement for the management of patients with prediabetes released by the ADA in October, The panel concluded that intervention was warranted, based on the expectation that delay of diabetes would postpone the requirement for complicated treatment regimens and that microvascular complications (and potentially CVD) would be delayed or prevented [13]. Fortuitously, a wide variety of interventions have been shown to alter the natural course of IFG and IGT and their progression

4 24 M.A. Abujbara, K.M. Ajlouni / International Journal of Diabetes Mellitus 1 (2009) Table 1 Diabetes prevention program. to diabetes. Results of the Diabetes Prevention Program (DPP) and other similar large well-designed prospective studies make it clear that aggressive modification of diet and exercise can prevent or slow the progression from IGT to diabetes [4]. In the Diabetes Prevention Program (DPP), diet and exercise modification was significantly more effective in diabetes risk reduction than pharmacological glucose reduction with Metformin [4] (Table 1). Diet and exercise were also more effective than Metformin in returning IGT subjects to a normal glucose tolerance. Since intensive lifestyle intervention provides the greatest reduction in the occurrence of diabetes, along with a modest reduction in CVD risk factors, patients with IGT should be referred to a nutritionist for counseling on exercise and diet with the goal of losing 5 7% of body weight and increasing moderate aerobic exercise to 150 min weekly (the DPP goals) [4] which is the treatment of choice for patients with prediabetes. Because lifestyle modification is usually difficult to maintain, pharmacological interventions have been studied to prevent the progression to type 2 diabetes. Several oral antidiabetic agents have been shown to be effective at delaying onset of type 2 diabetes. Thiazolidinediones (TZDs) reduced incidence of diabetes by 60% (PIPOD and DREAM trials) [35,36], whilst Metformin (in DPP) [4], Acarbose (in STOP-NIDDM study) [36] and Orlistat (in XENDOS study) [12] are only about half as effective as the TZDs. But the benefits of treatment still need to be balanced against the safety and tolerability of the intervention. If pharmacological treatment is warranted, metformin should be considered first because of its favourable overall safety, tolerability, efficacy, and cost profile. Finally, drugs that do not primarily target hyperglycemia may also reduce the risk for type 2 diabetes. A large number of trials of ACE-inhibitors or ARBs for various CV indications suggest that these drugs could reduce risk for type 2 diabetes by as much as 25% [37]. References Cumulative incidence of diabetes (%) P-value Metformin ; 31% <0.001 Lifestyle ; 58% <0.001 [1] International Diabetes Federation, < [2] The Ministry of Health, Jordan, Center for Disease Control (CDC) Report, [3] Tuomilehto J, Lindstrom J, Eriksson JG, et al. The Finnish diabetes prevention study group: prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344: [4] Knowler WC, Barrett-Conner E, Fowler SE, et al. The diabetes prevention program research group: reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346: [5] Vendrame F, Gottlieb PA. Prediabetes: prediction and prevention trials. Endocrinol Metab Clin North Am 2004;33: [6] Singleton Robinson, Smith A Gordon, Russell James W, et al. Microvascular complications of impaired glucose tolerance. Diabetes 2003;52(12): [7] Chiasson JL, Josse RG, Gomis R, et al. The STOPNIDDM trial research group: acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomized trial. Lancet 2002;359: [8] Ramachandran A, Snehalatha C, Mary S, et al. Indian Diabetes Prevention Programme (IDPP): the Indian diabetes prevention programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia 2006;49: [9] Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic b-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in highrisk Hispanic women. Diabetes 2002;51: [10] Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and diabetes study. Diabetes Care 1997;20: [11] Gerstein HC, Yusuf S, Boxch J, et al. DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication) trial investigators: effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomized controlled trial. Lancet 2006;368: [12] Torgerson JS, Hauptman J, Boldrin MN, et al. Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004;27: [13] Nathan David M, Davidson Mayer B, DeFronzo Ralph A, et al. Impaired fasting glucose and impaired glucose tolerance: implications for care. A consensus statement from the American Diabetes Association. Diabetes Care 2007;30: [14] Genuth S, Alberti KG, Bennett P, et al. Expert committee on the diagnosis and classification of diabetes mellitus: follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003;26: [15] Lewis GF, Carpentier A, Adeli K, et al. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocrine Rev 2002;23: [16] Cowie CC, Rust KF, Byrd-Holt DD, et al. Prevalence of diabetes and impaired fasting glucose in adults in the US population: National health and nutrition examination survey Diabetes Care 2006;29: [17] Ajlouni K, Jaddou H, Batieha A. Diabetes and impaired glucose tolerance in Jordan: prevalence and associated risk factors. J. Intern. Med. 1998;244: [18] Ajlouni K, Khader YS, Batieha A, et al. An increase in prevalence of diabetes mellitus in Jordan during ten years. J Diabetes Complications 2008;22: [19] Nathan David M, Davidson Mayer B, DeFronzo Ralph A, et al. Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes Care 2007;30(3): [20] Larson H, Lindgarde F, Berglund G, et al. Prediction of diabetes using ADA or WHO criteria in post-menopausal women: a 10-year follow-up study. Diabetologia 2004;43: [21] Abdul-Ghani MA, Tripathy D, DeFronzo RA. Contributions of ß-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care 2006;29: [22] Dunstan David W, Zimmet Paul Z, Welborn Timothy A, et al. The rising prevalence of diabetes and impaired glucose tolerance: the Australian diabetes, obesity and lifestyle study. Diabetes Care 2002;25: [23] Franklin GM, Kahn LB, Bender J, et al. Sensory neuropathy in non-insulindependent diabetes mellitus. The San Luis valley diabetes study. Am J Epidemiol 1990;131: [24] Singleton JR, Smith AG, Bromberg MB. Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care 2001;24: [25] Sumner CJ, Sheth S, Griffin JW, et al. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 2003;60: [26] Panzer C, Lauer MS, Brieke A, et al. Association of fasting plasma glucose with heart rate recovery in healthy adults: a population-based study. Diabetes 2002;51: [27] Pan XR, Hu YH, Li GW, et al. Impaired glucose tolerance and its relationship to ECG-indicated coronary heart disease and risk factors among Chinese. Da Qing IGT and diabetes study. Diabetes Care 1993;16: [28] Gabir MM, Hanson RL, Dabelea D, et al. Plasma glucose and prediction of microvascular disease and mortality: evaluation of 1997 American Diabetes Association and 1999 World Health Organization criteria for diagnosis of diabetes. Diabetes Care 2000;23: [29] Tominaga M, Eguchi H, Igarashi K, et al. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose: the Funagata diabetes study. Diabetes Care 1999;22: [30] Kuller LH, Velentgas P, Barzilay J, et al. Diabetes mellitus: subclinical cardiovascular disease and risk of incident cardiovascular disease and all-cause mortality. Arterioscler Thromb Vasc Biol 2000;20: [31] Jouven Xavier, Desnos Michel, Guerot Claude, et al. Predicting sudden death in the population. Circulation 1999: [32] Nielson Christopher, Lange Theodore. Blood glucose and heart failure in nondiabetic patients. Diabetes Care 2005;28: [33] Nielson Christopher, Lange Theodore, Hadjokas Nicholas. Blood glucose and coronary artery disease in nondiabetic patients. Diabetes Care 2006;29: [34] Levitan Emily B, Song Yiqing, Ford Earl S, et al. Is nondiabetic hyperglycemia a risk factor for cardiovascular disease? A meta-analysis of prospective studies. Arch Intern Med 2004;164: [35] Xiang Anny H, Peters Ruth K, Kjos Siri L, et al. Effect of pioglitazone on pancreatic beta cell function and diabetes risk in Hispanic women with prior gestational diabetes. Diabete 2006;55:

5 M.A. Abujbara, K.M. Ajlouni / International Journal of Diabetes Mellitus 1 (2009) [36] Chiasson Jean-Louis, Josse Robert G, Gomis Ramon, et al. STOP NIDDM trial research group: acarbose for prevention of type 2 diabetes mellitus: the STOPNIDDM randomised trial. Lancet 2002;359: [37] Scheen AJ. Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 1. A meta-analysis of randomized clinical trials. Diabetes Metab 2004;30: Cover Image Retinal Arteriolar Cholesterol Emboli A funduscopic image of a 59 year old man who was referred due to visual obscuration. Two years prior, multiple retinal arteriolar cholesterol emboli and a saddle embolus superior to the optic nerve was seen (Panel A, arrow). Two months later, an increase in number of cholesterol emboli occurred (Panel B). Four weeks later, whitening in the inferior macular region was noted (Panel C), consistent with an occlusion at the second major bifurcation of the inferior temporal branch of the retinal artery. For further information, please search on: Michael C. Retinal Arteriorlar Cholesterol Emboli. N Engl J Med. Feb p. 826.