P- Reviewer: Kietzmann T, Tasci I, Verrotti A S- Editor: Tian YL L- Editor: A E- Editor: Liu SQ
Published online Mar 15, 2015. doi: 10.4239/wjd.v6.i2.296
Peer-review started: August 30, 2014
First decision: September 30, 2014
Revised: October 10, 2014
Accepted: December 29, 2014
Article in press: December 31, 2014
Published online: March 15, 2015
Prediabetes is an intermediate state of hyperglycemia with glycemic parameters above normal but below the diabetes threshold. While, the diagnostic criteria of prediabetes are not uniform across various international professional organizations, it remains a state of high risk for developing diabetes with yearly conversion rate of 5%-10%. Observational evidence suggests as association between prediabetes and complications of diabetes such early nephropathy, small fiber neuropathy, early retinopathy and risk of macrovascular disease. Several studies have shown efficacy of lifestyle interventions with regards to diabetes prevention with a relative risk reduction of 40%-70% in adults with prediabetes. While there is increasing evidence to prove the efficacy of pharmacotherapy in prevention of diabetes in adults with prediabetes, pharmaceutical treatment options other than metformin are associated with adverse effects that limit their use for prediabetes. There are no reports of systematic evaluation of health outcomes related to prediabetes in children. The effects of pharmacotherapy of prediabetes on growth and pubertal development in children remains unknown. Secondary intervention with pharmacotherapy with metformin is advocated for high-risk individuals but criteria for such consideration benefit of early intervention, long term cost effectiveness of such interventions and the end point of therapy remain unclear. Pharmacotherapy must be used with caution in children with prediabetes. Prediabetes is a condition defined as having blood glucose levels above normal but below the defined threshold of diabetes. It is considered to be an at risk state, with high chances of developing diabetes. While, prediabetes is commonly an asymptomatic condition, there is always presence of prediabetes before the onset of diabetes. The elevation of blood sugar is a continuum and hence prediabetes can not be considered an entirely benign condition. This aim of this review is to describe the challenges associated with diagnosis of prediabetes, the possible adverse medical outcomes associated with prediabetes and the treatment options and rationale for their use in context of prediabetes.
Core tip: Prediabetes is a state of intermediate hyperglycemia. While there are several controversies about the diagnosis of prediabetes, it remains an at-risk state for development of diabetes. Several adverse health outcomes have been associated with prediabetes. This review provides a detailed description of the current literature regarding diagnosis, health consequences and treatment of prediabetes and also provides an insight for clinical management.
- Citation: Bansal N. Prediabetes diagnosis and treatment: A review. World J Diabetes 2015; 6(2): 296-303
- URL: https://www.wjgnet.com/1948-9358/full/v6/i2/296.htm
- DOI: https://dx.doi.org/10.4239/wjd.v6.i2.296
Various organizations have defined prediabetes with criteria that are not uniform. The World Health Organization (WHO) has defined prediabetes as a state of intermediate hyperglycemia using two specific parameters, impaired fasting glucose (IFG) defined as fasting plasma glucose (FPG) of 6.1-6.9 mmol/L (110 to 125 mg/dL) and impaired glucose tolerance (IGT) defined as 2 h plasma glucose of 7.8-11.0 mmol/L (140-200 mg/dL) after ingestion of 75 g of oral glucose load or a combination of the two based on a 2 h oral glucose tolerance test (OGTT). The American Diabetes Association (ADA), on the other hand has the same cut-off value for IGT (140-200 mg/dL) but has a lower cut-off value for IFG (100-125 mg/dL) and has additional hemoglobin A1c (HbA1c) based criteria of a level of 5.7% to 6.4% for the definition of prediabetes. Several studies have shown poor correlation between HbA1c and IFG and IGT[3-5]. The usefulness of diagnosis of diabetes or prediabetes on basis of IFG and IGT have been challenged due to inability of these blood glucose cut points to capture pathology related to diabetes and probability of developing diabetes in future. These cut-offs further loose their credibility due to poor reproducibility of these tests in adults and children[7,8]. Although, HbA1c is believed to represent an average blood sugar level and should ideally represent hyperglycemia more accurately, this may not be entirely true. HbA1c is substantially determined by genetic factors independent of blood glucose levels and may be an imprecise tool to measure average blood sugar[9,10]. While there are valid concerns about diagnostic criteria of prediabetes, prediabetes remains to have a lower reproducibility (approximately 50%) than diabetes (approximately 70%). Based on the available evidence, it appears that prediabetes defined by various alternative criterions consists of an overlapping group of individuals with one or more abnormalities in their glucose excursions. It is possible that presence of IFG and IGT identifies subjects with different pathological abnormalities in their glucose metabolism and presence of both of these signifies more advanced impairment in overall glucose homeostasis.
There have been reports of increased mean FPG and prevalence of diabetes in developed as well as developing countries. The Centers of Disease Control and Prevention National Diabetes Statistics Report suggested that 37% of United States adults older than 20 years and 51% of those older than 65 had prediabetes in 2009-2012 defined by fasting glucose or HbA1c levels. When applied to the entire United States population in 2012, these estimates suggest that, there are nearly 86 million adults with prediabetes in United States alone. The world wide prevalence of IGT in 2010 was estimated to be 343 million (7.8%) ranging from 5.8% in South East Asia to 11.4% in North American and Caribbean Countries of the nation’s population. International Diabetes Federation projects an increase in prevalence of prediabetes to 471 million globally by 2035.
The conversion rate of individuals from prediabetes to diabetes changes with population characteristics and the criteria used to define prediabetes[14,15]. In a meta-analysis evaluating the progression of prediabetes to diabetes published in 2007, the annual incidence rate of diabetes was found to be 4%-6% for isolated IGT, for isolated IFG 6%-9% and for both IGT and IFG was 15%-19%. This meta-analysis only consisted of studies published prior to 2004. In subsequently reported major studies, the annual incidence rates of conversation from prediabetes to diabetes were similar. In the Diabetes Prevention Program (DPP) Outcomes Study, the incidence of diabetes was noted to be 11% in the control group. In the United States Multi-Ethnic Study of Atherosclerosis the annual incidence of diabetes in IFG group slightly above 4%. In the The Toranomon Hospital Health Management Center Study the incidence of diabetes was reported as 7% in the group with an HbA1c 5.7%-6.4% and 9% in the IFG group. In the China Da Qing Diabetes Prevention Study (CDQDPS), the cumulative incidence of diabetes over a 20 years period, was noted to be higher than 90% among subjects with IGT defined by repeated OGTT in the control group. The use of ADA vs WHO criteria to define prediabetes has also been shown to affect the incidence rate of diabetes with lower incidence in individuals defined by ADA criteria compared to WHO criteria.
According to an expert panel, continuous rather than dichotomous risk scores are more useful for predicting the risk of developing diabetes. A diabetes risk score based more easily accessible variable such as age, sex, ethnicity, fasting glucose, systolic blood pressure, HDL cholesterol, BMI and history of diabetes in parents or siblings has been shown to have better predictive value than either IFG or IGT.
Several studies have shown an association of increased risk of chronic kidney disease and early nephropathy with prediabetes[24-28]. The causal nature of this relationship remains unclear as this association may be due increased incidence of diabetes in this group or the presence of other factors associated with both hyperglycemia and nephropathy rather than the effect of prediabetes itself[29,30].
Prediabetes is found to be associated with dysfunction of cardiac autonomic activity, reflected by reduced heart rate variability[31-35], decreased parasympathetic modulation of the heart and increased prevalence of male erectile dysfunction in individuals with prediabetes. Non-invasive evaluation of neural impairment in subjects with IGT has shown significantly greater abnormalities detected by four of five cardiovascular reflex tests, increase prevalence of both hyperesthesia and hypoesthesia, and increased heat detection thresholds. There is also increasing evidence to demonstrate a higher frequency of idiopathic polyneuropathy, painful sensory neuropathy[38-43] and small fiber neuropathy[38,40,41] among prediabetic individuals with IGT. These findings suggest an involvement of the small unmyelinated nerve fibers that carry pain, temperature, and regulate autonomic function during prediabetes, prior to development of diabetes.
Nearly 8 percent of participants with prediabetes in the DPP study were found to have evidence of diabetic retinopathy. While prediabetes has been associated with an increased risk of diabetic retinopathy in some studies, these findings vary depending on the method used for detection[24,45-49].
Prediabetes has been associated with increased risk of developing macrovascular disease but whether this elevated risk is due to prediabetes itself or due to development of diabetes remains unclear[50,51]. While cross sectional studies have shown an increased prevalence of coronary heart disease in individuals with prediabetes[52,53] but this relationship may be confounded by the common risk factors present between cardiovascular diseases and prediabetes.
The encompassing theme of lifestyle intervention programs is to change the modifiable risk factors of prediabetes and diabetes by targeting obesity with increase in physical activity and dietary changes. The two largest diabetes prevention studies, the United States DPP and the Finnish Diabetes Prevention Study (DPS) have both shown beneficial effects of lifestyle interventions[54,55]. In the DPP study, after a 3 year follow-up, intensive lifestyle interventions (ILS) lead to a 58% risk reduction. The ILS involved changes in diet and physical activity aimed at producing weight. The biggest determinant of risk reduction was note to be weight loss. This study showed that for every 1 kg decrease in weight, the risk of developing diabetes in future was reduced by 16%. In the DPS, the benefits were found to be dependent on achievement of the number of pre-defined goals of the intervention by the participant. These goals consisted of weight reduction greater than 5 percent, total fat intake less than 30 percent of energy intake, saturated-fat intake less than 10 percent of energy intake, fiber intake greater than or equal to 15 g per 1000 kcal , and exercise greater than 4 h/wk. While both of these studies were largely among Caucasians, studies in Asian population have also shown similar benefits[57,58].
Several groups of antidiabetic drugs such as Biguanides, Thiazolidinediones, α-Glucosidase Inhibitors, GLP-1 analogies and non-antidiabetic drugs and therapies such as anti-obesity drugs, and bariatric surgery have been studied in context of prediabetes.
Metformin has been used for several decades for treatment of diabetes and has been noted to have additional favorable outcomes such as body mass index (BMI) reduction and improved cholesterol profile. The collective evidence of trials among subjects with IGT, suggests a 45% risk reduction for development of type 2 diabetes. Metformin was noted to be less effective than lifestyle in the United States DPP trial but in the indian DPP (IDPP) trial it was noted to be as effective as lifestyle intervention[54,57]. Metformin has been found to be more beneficial to individuals with higher BMI and higher FPG. Metformin has also been studied in obese children by several investigators. The collective evidence shows a slight benefit in BMI reduction over lifestyle interventions, while the benefit was statistically significant it was noted to be only short term with the greatest benefit at 6 mo and no difference at 12 mo duration.
The glitazones are synthetic ligands for peroxisome proliferator-activated receptors-γ. They increase glucose uptake and utilization in the peripheral organs and decrease gluconeogenesis in the liver, thereby reducing insulin resistance. In the double blind placebo controlled Diabetes Reduction Assessment with Ramipril and rosiglitazone Medication study, rosiglitazone was found to be effective in decreasing incidence risk of diabetes by 60% over a 3 year period but was associated with significant side effects such as an additional average weight of 2.2 kg in intervention group compared to controls and a higher incidence of heart failure (0.5% vs 0.1%) and total cardiovascular events (2.9% vs 2.1%)[62,63]. Pioglitazone was found to decrease the risk of diabetes by > 70% in obese subjects with IGT in the ACT NOW study. Some of the added benefits were, decrease in diastolic blood pressure, reduction in rate of carotid intima-media thickness and a greater increase in HDL cholesterol but it was associated with increased weight gain (approximately 3 kg more than placebo) and edema (13% vs 6% in controls). In the double blinded placebo controlled 3 years prospective IDPP-2 study, there was no difference in incidence of diabetes between subjects receiving lifestyle intervention and placebo and subjects receiving lifestyle intervention and pioglitazone. In the more recent Canadian Normoglycemia Outcomes Evaluation trial, low does combination of rosiglitazone and metformin was tested against placebo to investigate whether low dose combination therapy would decrease the incidence of type 2 diabetes with a lower risk of adverse events. Incident diabetes occurred in significantly fewer individuals in the active treatment group (14%) than in the placebo group (39%). The relative risk reduction was 66% and the absolute risk reduction was 26%, and 80% subjects in the treatment group reverted to normoglycemia compared to 53% in the control group, but the subjects in active treatment group had increased reports of diarrhea (16% vs 6% in controls). Overall, there are safety concerns for thiazolidinedione such as weight gain, liver toxicity, increased cardiovascular risk and possible link with bladder cancer which have limited the use of these mediations for treatment of prediabetes.
α-glucosidase inhibitors such as acarbose and voglibose, prolong the overall carbohydrate digestion time, and reduce the rate of glucose absorption, thus decrease the postprandial rise in blood glucose. In the STOP-NIDDM trial, acarbose was found to decrease the relative risk for diabetes by 25% among subjects with IGT during a 3.3 years of follow-up[68,69]. The medication was associated with several gastrointestinal side effects such as flatulence and diarrhea and 31% of the participants in the acarbose arm dropped out before completion of the study. A Japanese trail found a 40% risk reduction in incidence of diabetes in high-risk individuals with IGT with voglibose over a 48 wk period. Voglibose was noted to have a similar side effect profile as acarbose but only 7% subjects discontinued the use of drug due to adverse effects.
GLP-1 analogs exploit the physiological effects of GLP-1, they have been shown to augment post prandial insulin secretion, suppress glucagon and hepatic glucose production, slow gastric emptying, and reduce appetite. Exenatide and liraglutide have been demonstrated to have long term efficacy for sustained weight loss in obese subjects and reduce prevalence of prediabetes over a follow-up period of 1-2 years. The most common side effects with these drugs are nausea and vomiting and they remain injectable preparations[72-74].
Anti-obesity drugs Orlistat has also been studied in context of prediabetes. Orlistat is a gastrointestinal lipase inhibitor used for treatment of obesity that acts by inhibiting the absorption of dietary fats by approximately 30%. Research has shown that over a 1.5 year follow-up period, use of Orlistat in conjunction with low energy diet is associated with greater weight loss as compared to placebo (6.7 kg vs 3.8 kg) and a decrease in conversion rate from IGT to overt diabetes (7.6% vs 3.0%) in obese adults. Similar finding have also been reported by the XENDOS trail regarding the efficacy of Orlistat with a 37% relative risk reduction in development of diabetes after 4 years of treatment.
Bariatric surgery includes a variety of procedures aimed at either creating a mal-absorptive state, a restrictive state or a combination of the two to limit caloric intake. The procedures commonly used include Roux-en-Y gastric bypass, Laparoscopic adjustable gastric banding, Sleeve gastrectomy, and Duodenal switch with biliopancreatic diversion. In the Swedish Obese Subject, bariatric surgery was found to result in sustained weight loss (23.4% at 2 years and 16.1% at 10 years) and a 75% relative risk reduction of diabetes compared to controls. Bariatric surgery was also associated with a lower 2 year and 10 year rate of development of type 2 diabetes, cardiovascular disease and reduced number of cardiovascular deaths in obese adults[77,78]. A previous study had demonstrated that after gastric bypass surgery, 78% subjects with previous diabetes and 98% subjects with IGT reverted to normoglycemia.
The rationale behind treatment of prediabetes includes, prevention of development of diabetes, prevention of consequences of diabetes and prevention of the consequences of prediabetes itself. Several research studies have shown success of interventions designed for treatment of prediabetes with sustained reduction in incidence of diabetes[20,54,80-82]. The CDQDPS study, with lifestyle intervention and 20 year follow-up showed nearly 50% relative risk reduction in incidence of severe retinopathy, but there was no difference between the intervention and control groups in the risk of developing other microvascular complications, such as neuropathy and nephropathy. The evidence regarding effects of interventions on macrovascular complications is inconsistent. The Malmo Preventive Project with a 12 year follow-up, showed reduce mortality in subjects with IGT after a long-term lifestyle intervention program, with emphasis on dietary counseling and physical activity, but this was not a randomized trial. The Collective evidence of all randomized control trails among prediabetic subjects with lifestyle and drug based interventions in a recent meta-analysis showed that these interventions resulted in reduction in stroke risk but did not result in any risk reduction for all-cause mortality, cardiovascular death or myocardial infarction over a mean follow-up period of 3.8 years. While, the current evidence suggests efficacy of several treatment modalities regarding prevention of progression to diabetes, the long term benefits on microvascular or macrovascular complications remains debatable. There is no evidence to suggest that early intervention is better than late intervention and long term studies looking at cost vs benefit and long terms of outcomes related to the point at which glycemic intervention should begin are lacking. Majority of published literature and guidelines support that lifestyle interventions focusing on dietary modification and increased physical activity should be the foundation of therapy for diabetes prevention in patients with prediabetes. Although, lifestyle interventions are safe and have proven efficacy in prevention of diabetes, these programs are not reimbursed by most health care insurance plans. There is increasing evidence to prove the efficacy of pharmacotherapy and support its use in adults with prediabetes. Due to the favorable long term safety profile and observed positive outcomes with metformin, organizations such as ADA have recommended the use of metformin in certain high risk individuals but the end point of pharmacotherapy is yet to be defined. The concept of prediabetes or its treatment has not been systematically studied in children with prediabetes. Long term effect of common medications used for prediabetes on growth and pubertal development in children have not been studied. Moreover in children, due to puberty related insulin resistance, incidence of diabetes may be over all inflated. There is lack of evidence with regards to long term efficacy as well as safety for use of pharmacotherapy in children with prediabetes.
In conclusion, there remains a need of systematic evaluation of the health outcomes of prediabetes and benefits if any with its early treatment. It is very important to choose the right outcomes for such a study. Moreover, the criteria used to define prediabetes needs to be refined in accordance to the long term medical outcomes. While, these studies seem essential, the length of duration needed to study the adverse outcomes of prediabetes and low frequency of some of these outcomes may be a limiting factor for such studies. At present there is no concrete evidence to formulate clinical guidelines for treatment of prediabetes. Lifestyle interventions remain an essential part of management of prediabetes. The use of pharmacotherapy should be on an individual case based approach. When pharmacotherapy is used to treat prediabetes, such treatment plan should be initiated with predefined goals and end points by the physician. A cautious approach is warranted for used of pharmacotherapy in children and youth.
The author would like to thank Dr. Siripoom McKay for her valuable advice on the preparation of this manuscript.
|1.||World Health Organization, World Health Organization. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation. Geneva: World Health Organization 2006; 1-50.|
|2.||American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014;37 Suppl 1:S81-S90. [PubMed] [DOI]|
|3.||Gosmanov AR, Wan J. Low positive predictive value of hemoglobin A1c for diagnosis of prediabetes in clinical practice. Am J Med Sci. 2014;348:191-194. [PubMed] [DOI]|
|4.||Guo F, Moellering DR, Garvey WT. Use of HbA1c for diagnoses of diabetes and prediabetes: comparison with diagnoses based on fasting and 2-hr glucose values and effects of gender, race, and age. Metab Syndr Relat Disord. 2014;12:258-268. [PubMed] [DOI]|
|5.||van ‘t Riet E, Alssema M, Rijkelijkhuizen JM, Kostense PJ, Nijpels G, Dekker JM. Relationship between A1C and glucose levels in the general Dutch population: the new Hoorn study. Diabetes Care. 2010;33:61-66. [PubMed] [DOI]|
|6.||Genuth S, Kahn R. A step backward--or is it forward? Diabetes Care. 2008;31:1093-1096. [PubMed] [DOI]|
|7.||Balion CM, Raina PS, Gerstein HC, Santaguida PL, Morrison KM, Booker L, Hunt DL. Reproducibility of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) classification: a systematic review. Clin Chem Lab Med. 2007;45:1180-1185. [PubMed] [DOI]|
|8.||Libman IM, Barinas-Mitchell E, Bartucci A, Robertson R, Arslanian S. Reproducibility of the oral glucose tolerance test in overweight children. J Clin Endocrinol Metab. 2008;93:4231-4237. [PubMed] [DOI]|
|9.||Bloomgarden ZT, Inzucchi SE, Karnieli E, Le Roith D. The proposed terminology ‘A(1c)-derived average glucose’ is inherently imprecise and should not be adopted. Diabetologia. 2008;51:1111-1114. [PubMed] [DOI]|
|10.||Cohen RM, Snieder H, Lindsell CJ, Beyan H, Hawa MI, Blinko S, Edwards R, Spector TD, Leslie RD. Evidence for independent heritability of the glycation gap (glycosylation gap) fraction of HbA1c in nondiabetic twins. Diabetes Care. 2006;29:1739-1743. [PubMed] [DOI]|
|11.||Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ, Lin JK, Farzadfar F, Khang YH, Stevens GA, Rao M, Ali MK, Riley LM, Robinson CA, Ezzati M; Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Blood Glucose). National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2-7 million participants. The Lancet. 2011;378:31-40. [PubMed] [DOI]|
|12.||Centers for Disease Control and Prevention. National Diabetes Statitiscs Report: Estimates of Diabtes and Its Burden in the United States, 2014. Atlanta, GA: US Department of Health and Human Services 2014; .|
|13.||International Diabetes Federation. IDF Diabetes Atlas, 6th ed. Brussels, Belgium: International Diabetes Federation 2013; .|
|14.||Forouhi NG, Luan J, Hennings S, Wareham NJ. Incidence of Type 2 diabetes in England and its association with baseline impaired fasting glucose: the Ely study 1990-2000. Diabet Med. 2007;24:200-207. [PubMed] [DOI]|
|15.||Nathan DM, Davidson MB, DeFronzo RA, Heine RJ, Henry RR, Pratley R, Zinman B; American Diabetes Association. Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes Care. 2007;30:753-759. [PubMed] [DOI]|
|16.||Gerstein HC, Santaguida P, Raina P, Morrison KM, Balion C, Hunt D, Yazdi H, Booker L. Annual incidence and relative risk of diabetes in people with various categories of dysglycemia: a systematic overview and meta-analysis of prospective studies. Diabetes Res Clin Pract. 2007;78:305-312. [PubMed] [DOI]|
|17.||Diabetes Prevention Program Research Group, Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, Brenneman AT, Brown-Friday JO, Goldberg R, Venditti E, Nathan DM. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374:1677-1686. [PubMed] [DOI]|
|18.||Yeboah J, Bertoni AG, Herrington DM, Post WS, Burke GL. Impaired fasting glucose and the risk of incident diabetes mellitus and cardiovascular events in an adult population: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2011;58:140-146. [PubMed] [DOI]|
|19.||Heianza Y, Hara S, Arase Y, Saito K, Fujiwara K, Tsuji H, Kodama S, Hsieh SD, Mori Y, Shimano H. HbA1c 5·7-6·4% and impaired fasting plasma glucose for diagnosis of prediabetes and risk of progression to diabetes in Japan (TOPICS 3): a longitudinal cohort study. Lancet. 2011;378:147-155. [PubMed] [DOI]|
|20.||Li G, Zhang P, Wang J, Gregg EW, Yang W, Gong Q, Li H, Li H, Jiang Y, An Y. The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study. Lancet. 2008;371:1783-1789. [PubMed] [DOI]|
|21.||Forouhi NG, Balkau B, Borch-Johnsen K, Dekker J, Glumer C, Qiao Q, Spijkerman A, Stolk R, Tabac A, Wareham NJ. The threshold for diagnosing impaired fasting glucose: a position statement by the European Diabetes Epidemiology Group. Diabetologia. 2006;49:822-827. [PubMed] [DOI]|
|22.||Bloomgarden ZT. American College Of Endocrinology Pre-Diabetes Consensus Conference: part one. Diabetes Care. 2008;31:2062-2069. [PubMed] [DOI]|
|23.||Stern MP, Williams K, Haffner SM. Identification of persons at high risk for type 2 diabetes mellitus: do we need the oral glucose tolerance test? Ann Intern Med. 2002;136:575-581. [PubMed]|
|24.||Gabir MM, Hanson RL, Dabelea D, Imperatore G, Roumain J, Bennett PH, Knowler WC. 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;23:1113-1118. [PubMed]|
|25.||Hoehner CM, Greenlund KJ, Rith-Najarian S, Casper ML, McClellan WM. Association of the insulin resistance syndrome and microalbuminuria among nondiabetic native Americans. The Inter-Tribal Heart Project. J Am Soc Nephrol. 2002;13:1626-1634. [PubMed]|
|26.||Metcalf PA, Baker JR, Scragg RK, Dryson E, Scott AJ, Wild CJ. Microalbuminuria in a middle-aged workforce. Effect of hyperglycemia and ethnicity. Diabetes Care. 1993;16:1485-1493. [PubMed]|
|27.||Plantinga LC, Crews DC, Coresh J, Miller ER, Saran R, Yee J, Hedgeman E, Pavkov M, Eberhardt MS, Williams DE, Powe NR; CDC CKD Surveillance Team. Prevalence of chronic kidney disease in US adults with undiagnosed diabetes or prediabetes. Clin J Am Soc Nephrol. 2010;5:673-682. [PubMed] [DOI]|
|28.||Xu M, Li XY, Wang JG, Wang XJ, Huang Y, Cheng Q, Huang HE, Li R, Xiang J, Tan JR. Retinol-binding protein 4 is associated with impaired glucose regulation and microalbuminuria in a Chinese population. Diabetologia. 2009;52:1511-1519. [PubMed] [DOI]|
|29.||Fox CS, Larson MG, Leip EP, Meigs JB, Wilson PW, Levy D. Glycemic status and development of kidney disease: the Framingham Heart Study. Diabetes Care. 2005;28:2436-2440. [PubMed]|
|30.||Thomas G, Sehgal AR, Kashyap SR, Srinivas TR, Kirwan JP, Navaneethan SD. Metabolic syndrome and kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2011;6:2364-2373. [PubMed] [DOI]|
|31.||Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, Lauria G, Malik RA, Spallone V, Vinik A. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33:2285-2293. [PubMed] [DOI]|
|32.||Gerritsen J, Dekker JM, TenVoorde BJ, Bertelsmann FW, Kostense PJ, Stehouwer CD, Heine RJ, Nijpels G, Heethaar RM, Bouter LM. Glucose tolerance and other determinants of cardiovascular autonomic function: the Hoorn Study. Diabetologia. 2000;43:561-570. [PubMed] [DOI]|
|33.||Schroeder EB, Chambless LE, Liao D, Prineas RJ, Evans GW, Rosamond WD, Heiss G; Atherosclerosis Risk in Communities (ARIC) study. Diabetes, glucose, insulin, and heart rate variability: the Atherosclerosis Risk in Communities (ARIC) study. Diabetes Care. 2005;28:668-674. [PubMed]|
|34.||Singh JP, Larson MG, O’Donnell CJ, Wilson PF, Tsuji H, Lloyd-Jones DM, Levy D. Association of hyperglycemia with reduced heart rate variability (The Framingham Heart Study). Am J Cardiol. 2000;86:309-312. [PubMed]|
|35.||Wu JS, Yang YC, Lin TS, Huang YH, Chen JJ, Lu FH, Wu CH, Chang CJ. Epidemiological evidence of altered cardiac autonomic function in subjects with impaired glucose tolerance but not isolated impaired fasting glucose. J Clin Endocrinol Metab. 2007;92:3885-3889. [PubMed] [DOI]|
|36.||Grover SA, Lowensteyn I, Kaouache M, Marchand S, Coupal L, DeCarolis E, Zoccoli J, Defoy I. The prevalence of erectile dysfunction in the primary care setting: importance of risk factors for diabetes and vascular disease. Arch Intern Med. 2006;166:213-219. [PubMed] [DOI]|
|37.||Putz Z, Tabák AG, Tóth N, Istenes I, Németh N, Gandhi RA, Hermányi Z, Keresztes K, Jermendy G, Tesfaye S. Noninvasive evaluation of neural impairment in subjects with impaired glucose tolerance. Diabetes Care. 2009;32:181-183. [PubMed] [DOI]|
|38.||Hoffman-Snyder C, Smith BE, Ross MA, Hernandez J, Bosch EP. Value of the oral glucose tolerance test in the evaluation of chronic idiopathic axonal polyneuropathy. Arch Neurol. 2006;63:1075-1079. [PubMed] [DOI]|
|39.||Nebuchennykh M, Løseth S, Jorde R, Mellgren SI. Idiopathic polyneuropathy and impaired glucose metabolism in a Norwegian patient series. Eur J Neurol. 2008;15:810-816. [PubMed] [DOI]|
|40.||Singleton JR, Smith AG, Bromberg MB. Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care. 2001;24:1448-1453. [PubMed]|
|41.||Smith AG, Ramachandran P, Tripp S, Singleton JR. Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy. Neurology. 2001;57:1701-1704. [PubMed]|
|42.||Smith AG, Singleton JR. The diagnostic yield of a standardized approach to idiopathic sensory-predominant neuropathy. Arch Intern Med. 2004;164:1021-1025. [PubMed] [DOI]|
|43.||Sumner CJ, Sheth S, Griffin JW, Cornblath DR, Polydefkis M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology. 2003;60:108-111. [PubMed]|
|44.||Diabetes Prevention Program Research Group. The prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program. Diabet Med. 2007;24:137-144. [PubMed] [DOI]|
|45.||Algvere P, Efendić S, Luft R, Wajngot A. Retinal microangiopathy and pigment epithelial lesions in subjects with normal, borderline, and decreased oral glucose tolerance. Br J Ophthalmol. 1985;69:416-419. [PubMed]|
|46.||Nguyen TT, Wang JJ, Islam FM, Mitchell P, Tapp RJ, Zimmet PZ, Simpson R, Shaw J, Wong TY. Retinal arteriolar narrowing predicts incidence of diabetes: the Australian Diabetes, Obesity and Lifestyle (AusDiab) Study. Diabetes. 2008;57:536-539. [PubMed] [DOI]|
|47.||Nguyen TT, Wang JJ, Wong TY. Retinal vascular changes in pre-diabetes and prehypertension: new findings and their research and clinical implications. Diabetes Care. 2007;30:2708-2715. [PubMed] [DOI]|
|48.||Tapp RJ, Tikellis G, Wong TY, Harper CA, Zimmet PZ, Shaw JE. Longitudinal association of glucose metabolism with retinopathy: results from the Australian Diabetes Obesity and Lifestyle (AusDiab) study. Diabetes Care. 2008;31:1349-1354. [PubMed] [DOI]|
|49.||Wong TY, Klein R, Sharrett AR, Schmidt MI, Pankow JS, Couper DJ, Klein BE, Hubbard LD, Duncan BB; ARIC Investigators. Retinal arteriolar narrowing and risk of diabetes mellitus in middle-aged persons. JAMA. 2002;287:2528-2533. [PubMed]|
|50.||Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, Ingelsson E, Lawlor DA, Selvin E, Stampfer M. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215-2222. [PubMed] [DOI]|
|51.||Seshasai SR, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar N, Whincup PH, Mukamal KJ, Gillum RF, Holme I. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011;364:829-841. [PubMed] [DOI]|
|52.||Barr EL, Zimmet PZ, Welborn TA, Jolley D, Magliano DJ, Dunstan DW, Cameron AJ, Dwyer T, Taylor HR, Tonkin AM. Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Circulation. 2007;116:151-157. [PubMed] [DOI]|
|53.||Brunner EJ, Shipley MJ, Witte DR, Fuller JH, Marmot MG. Relation between blood glucose and coronary mortality over 33 years in the Whitehall Study. Diabetes Care. 2006;29:26-31. [PubMed]|
|54.||Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. [PubMed] [DOI]|
|55.||Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M; 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;344:1343-1350. [PubMed] [DOI]|
|56.||Hamman RF, Wing RR, Edelstein SL, Lachin JM, Bray GA, Delahanty L, Hoskin M, Kriska AM, Mayer-Davis EJ, Pi-Sunyer X. Effect of weight loss with lifestyle intervention on risk of diabetes. Diabetes Care. 2006;29:2102-2107. [PubMed] [DOI]|
|57.||Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V; 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;49:289-297. [PubMed] [DOI]|
|58.||Saito T, Watanabe M, Nishida J, Izumi T, Omura M, Takagi T, Fukunaga R, Bandai Y, Tajima N, Nakamura Y, Ito M; Zensharen Study for Prevention of Lifestyle Diseases Group. Lifestyle modification and prevention of type 2 diabetes in overweight Japanese with impaired fasting glucose levels: a randomized controlled trial. Arch Intern Med. 2011;171:1352-1360. [PubMed] [DOI]|
|59.||Lily M, Godwin M. Treating prediabetes with metformin: systematic review and meta-analysis. Can Fam Physician. 2009;55:363-369. [PubMed]|
|60.||McDonagh MS, Selph S, Ozpinar A, Foley C. Systematic review of the benefits and risks of metformin in treating obesity in children aged 18 years and younger. JAMA Pediatr. 2014;168:178-184. [PubMed] [DOI]|
|61.||Smith U. Pioglitazone: mechanism of action. Int J Clin Pract Suppl. 2001;13-18. [PubMed]|
|62.||DREAM Trial Investigators, Dagenais GR, Gerstein HC, Holman R, Budaj A, Escalante A, Hedner T, Keltai M, Lonn E, McFarlane S. 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. [PubMed] [DOI]|
|63.||DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators, Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006;368:1096-1105. [PubMed] [DOI]|
|64.||DeFronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, Henry RR, Hodis HN, Kitabchi AE. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med. 2011;364:1104-1115. [PubMed] [DOI]|
|65.||Ramachandran A, Snehalatha C, Mary S, Selvam S, Kumar CK, Seeli AC, Shetty AS. Pioglitazone does not enhance the effectiveness of lifestyle modification in preventing conversion of impaired glucose tolerance to diabetes in Asian Indians: results of the Indian Diabetes Prevention Programme-2 (IDPP-2). Diabetologia. 2009;52:1019-1026. [PubMed] [DOI]|
|66.||Zinman B, Harris SB, Neuman J, Gerstein HC, Retnakaran RR, Raboud J, Qi Y, Hanley AJ. Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study. Lancet. 2010;376:103-111. [PubMed] [DOI]|
|67.||Bischoff H. The mechanism of alpha-glucosidase inhibition in the management of diabetes. Clin Invest Med. 1995;18:303-311. [PubMed]|
|68.||Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trail Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359:2072-2077. [PubMed] [DOI]|
|69.||Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trial Research Group. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003;290:486-494. [PubMed] [DOI]|
|70.||Kawamori R, Tajima N, Iwamoto Y, Kashiwagi A, Shimamoto K, Kaku K; Voglibose Ph-3 Study Group. Voglibose for prevention of type 2 diabetes mellitus: a randomised, double-blind trial in Japanese individuals with impaired glucose tolerance. Lancet. 2009;373:1607-1614. [PubMed] [DOI]|
|71.||Tasyurek HM, Altunbas HA, Balci MK, Sanlioglu S. Incretins: their physiology and application in the treatment of diabetes mellitus. Diabetes Metab Res Rev. 2014;30:354-371. [PubMed] [DOI]|
|72.||Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean ME, Niskanen L, Rasmussen MF, Rissanen A, Rössner S. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond). 2012;36:843-854. [PubMed] [DOI]|
|73.||Astrup A, Rössner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, Madsen J, Rasmussen MF, Lean ME; NN8022-1807 Study Group. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009;374:1606-1616. [PubMed] [DOI]|
|74.||Rosenstock J, Klaff LJ, Schwartz S, Northrup J, Holcombe JH, Wilhelm K, Trautmann M. Effects of exenatide and lifestyle modification on body weight and glucose tolerance in obese subjects with and without pre-diabetes. Diabetes Care. 2010;33:1173-1175. [PubMed] [DOI]|
|75.||Heymsfield SB, Segal KR, Hauptman J, Lucas CP, Boldrin MN, Rissanen A, Wilding JP, Sjöström L. Effects of weight loss with orlistat on glucose tolerance and progression to type 2 diabetes in obese adults. Arch Intern Med. 2000;160:1321-1326. [PubMed]|
|76.||Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. 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;27:155-161. [PubMed]|
|77.||Sjöström L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, Dahlgren S, Larsson B, Narbro K, Sjöström CD, Sullivan M, Wedel H; Swedish Obese Subjects Study Scientific Group Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 2004;351:2683-2693. [PubMed] [DOI]|
|78.||Sjöström L, Peltonen M, Jacobson P, Sjöström CD, Karason K, Wedel H, Ahlin S, Anveden Å, Bengtsson C, Bergmark G. Bariatric surgery and long-term cardiovascular events. JAMA. 2012;307:56-65. [PubMed] [DOI]|
|79.||Pories WJ, MacDonald KG, Flickinger EG, Dohm GL, Sinha MK, Barakat HA, May HJ, Khazanie P, Swanson MS, Morgan E. Is type II diabetes mellitus (NIDDM) a surgical disease? Ann Surg. 1992;215:633-642; discussion 643. [PubMed]|
|80.||Hopper I, Billah B, Skiba M, Krum H. Prevention of diabetes and reduction in major cardiovascular events in studies of subjects with prediabetes: meta-analysis of randomised controlled clinical trials. Eur J Cardiovasc Prev Rehabil. 2011;18:813-823. [PubMed] [DOI]|
|81.||Lindström J, Ilanne-Parikka P, Peltonen M, Aunola S, Eriksson JG, Hemiö K, Hämäläinen H, Härkönen P, Keinänen-Kiukaanniemi S, Laakso M, Louheranta A, Mannelin M, Paturi M, Sundvall J, Valle TT, Uusitupa M, Tuomilehto J; Finnish Diabetes Prevention Study Group. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet. 2006;368:1673-1679. [PubMed] [DOI]|
|82.||Natangelo R, Luè D, Bianchi GB, Ronchi E, Conti D. [The hypoglycemic reactions in diabetic patients in the emergency room. Which patients are going to be hospitalized?]. Minerva Med. 1990;81:561-565. [PubMed]|
|83.||Gong Q, Gregg EW, Wang J, An Y, Zhang P, Yang W, Li H, Li H, Jiang Y, Shuai Y. Long-term effects of a randomised trial of a 6-year lifestyle intervention in impaired glucose tolerance on diabetes-related microvascular complications: the China Da Qing Diabetes Prevention Outcome Study. Diabetologia. 2011;54:300-307. [PubMed] [DOI]|
|84.||Eriksson KF, Lindgärde F. No excess 12-year mortality in men with impaired glucose tolerance who participated in the Malmö Preventive Trial with diet and exercise. Diabetologia. 1998;41:1010-1016. [PubMed] [DOI]|