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Home , Prediabetes

CLINICAL PRACTICE

Guidelines on the Management and Prevention of

The Indonesian Association

Diabetes and Nutrition Center, Comprehensive Diagnostic Center Building, Surabaya, Indonesia.

Correspondence address: Agung Pranoto, PhD., Prof., Dyah Purnamasari, MD. The Indonesian Diabetes Association. Diabetes and Nutrition Centre, Integrated Diagnostic Centre Building, 7th floor. Jl. Mayjen Prof. Dr. Moestopo 6-8, Surabaya, Indonesia. email: [email protected].

ABSTRAK Pandemi obesitas dan diabetes mellitus (DM), khususnya DM tipe 2 (DMT2) kini menjadi ancaman yang serius bagi umat manusia di dunia. International Diabetes Federation (IDF) menyebutkan bahwa prevalensi DM dunia adalah 1,9% dan telah menjadikan DM sebagai penyebab kematian urutan ke-7 dunia. Proyeksi prevalensi diabetes tahun 1994 sampai 2010 diperkirakan 215,6 juta jiwa, namun dari evaluasi tahun 2007 jumlah penderita diabetes sudah mencapai 246 juta jiwa bahkan tahun 2025 dikhawatirkan jumlah tersebut akan meningkat sampai lebih dari 300 juta jiwa. Pasien DM berpotensi menderita berbagai komplikasi, meliputi penyakit makrovaskular (penyakit jantung, stroke, dan penyakit pembuluh darah tepi) dan penyakit mikrovaskular (retionopati, neuropati, dan nefropati). Komplikasi DM sudah dimulai sejak dini sebelum diagnosis DM ditegakkan. Sekitar 50% pasien ketika didiagnosis telah menyandang satu komplikasi kronik. Karena itu, perlu adanya panduan yang dapat menatalaksana prediabetes terkait dengan pencegahan risiko komplikasi kronik diabetes dan risiko kardiovaskular. Panduan ini diharapkan dapat menambah keahlian tenaga medis untuk mengenali prediabetes, mengidentifikasi orang-orang dengan risiko tinggi diabetes, dan memberikan penatalaksanaan yang tepat agar kejadian DM dan komplikasinya dapat dikurangi.

Kata kunci: diagnosis, risiko, prediabetes, diabetes mellitus, penatalaksanaan.

ABSTRACT Pandemic and diabetes mellitus (DM), particularly type-2 DM (T2DM) now has become a serious threat for people worldwide. The International Diabetes Federation (IDF) suggests that the prevalence of DM in the world is 1.9% and it has made DM as the 7th leading cause of worldwide. It has been estimated that the prevalence of diabetes between 1994 and 2010 was projected as much as 215.6 milion people; however an evaluation in 2007 revealed that the number of diabetic patients has reached 246 million people and it has been concerned that the number would increase in 2025 reaching more than 300 million people. Patients with DM may have various complilcations, including macrovascular (heart , stroke and peripheral vascular disease) and microvascular diseases (, neuropathy and nephropathy). Complications of DM have started early before the diagnosis of DM has been made. About 50% of patients have alreadly had one chronic complication at the time of diagnosis. Therefore, it is necessary to have a guideline on management of prediabetes condition associated with prevention of chonic complication and cardiovascular risk of diabetes. The guideline is expected to improve the skills of health care professionals in recognizing prediabetes condition, identifying people at high risk for diabetes and providing an appropriate management so that the incidence and complication of DM can be reduced.

Key words: diagnosis, risk, prediabetes, diabetes mellitus, management.

348 Acta Medica Indonesiana - The Indonesian Journal of Internal Medicine Vol 46 • Number 4 • October 2014 Guidelines on the management and prevention of prediabetes

INTRODUCTION blood level is above normal but still Results of basic health care research/riset below the blood glucose level for diabetes. The kesehatan dasar (RISKESDAS) reported by diagnosis of prediabetes is established when the Department of Health Care in 2008 revealed blood glucose level is 100-125 mg/dl that the prevalence of DM in Indonesia at that ( = IFG) or when the time was 5.7%. According to WHO, the number 2-hour postprandial blood glucose level is 140- of diabetic patients in Indonesia will increase 199 mg/dl (impaired glucose tolerance = IGT), from 8.4 million people in 2000 and it will or both (impaired glucose = IGH).6,7 become 21.3 million people in 2030. The high Based on observations, individuals with morbidity rate has made Indonesia on the 4th prediabetes may develop into 3 possibilities: rank worldwide after China, India and United approximately 1/3 of cases will develop into States. Without prevention measures and an T2DM, the other 1/3 of cases will stay unchanged effective controlling program, the prevalence as prediabetes and the other remaining 1/3 cases will be continuously increasing.1 may be back to normoglycemia condition. Patients with DM may have various Prediabetes condition raises absolut risk by 2- complilcations, including macrovascular diseases to 10-fold; moreover, the risk of cardiovascular (heart disease, stroke and peripheral vascular disease in prediabetes is comparable with DM. disease) and microvascular diseases (retinopathy, Those conditions provide more convincing neuropathy and nephropathy).2 Complications of facts that early prevention measures and DM have started early before the diagnosis of programs of DM is very essential, inter alia DM has been made. About 50% of patients have through management of prediabetes condition, already had one chronic complication at the time identification and early management of patients of diagnosis, 21% among them have retinopathy, with prediabetes condition that may reduce the 18% have an abnormal electrocardiogram incidence and complications of DM, which will (ECG) findings, and 14% have impaired blood be very useful not only for patients, but also their flow to the limb causing undetected limb pulse families and the government.8 or leg ischemia. Those various complications Different epidemiological data between of diabetes has caused modified lifestyle and IGT and IFG shows that there are different reduced life expectancy in individuals with mechanisms of pathophysiology of both DM. The life expectancy rate has become conditions. Although the determination of IGT 15 years lower and 75% of them died due to and IFG is made based on resistance, macrovascular complications.3,4 In keeping with but both show differences on the site of insulin the development of normal glucose tolerance resistance occurs. in IFG into obvious DM, the morbidity and mortality is mainly occurs in ; while the insulin associated with diabetes and its complication sensitivity in muscle tissues is still normal. In has also been increasing.5 IGT, insulin sensitivity in the liver stays normal Blood glucose level is a continuous spectrum. or slightly reduced; while in the muscle tissues, The limit of blood glucose levels considered as the insulin resistance has occurred. The patterns normal, prediabetes and diabetes is determined of insulin resistance in both conditions are also arbitrarily based on a consensus. Currently, the different. In IFG, phase-one reduced insulin diagnosis of diabetes is established when the secretion occurs (in the first 10 minutes) after fasting blood glucose level is >126 mg/dl or intravenous glucose is given and initial-phase of when the 2-hour postprandial blood glucose reduced response of insulin secretion (in the first level >200 mg/dl. In oral glucose tolerance 30 minutes) after oral glucose administration; test (OGTT), it is determined based on blood while the delay-phase of insulin secretion (60- glucose level associated with the development 120 minutes) during the OGTT stays normal. In of complications, which have IGT, there is also impaired initial-phase insulin specific characteristics for diabetes, particularly secretion after oral glucose administration, retinopathy. Prediabetes is diagnosed when the which is accompanied by significant decrease on

349 The Indonesian Diabetes Association Acta Med Indones-Indones J Intern Med end-phase of insulin secretion.9 Type-2 diabetes - Subsequently, the subject is given 75 emerges due to progressive impairment of insulin gram glucose solution in 300 cc water to secretion with a background of insulin resistance. drink Both impairment of insulin secretion and insulin - 2 hours after the glucose loading, blood resistance have been affected by genetic and is drawn for measurement of 2-hour environment risk factors, which also includes postprandial or post challenge glucose the embryonic environment. Obesity, particularly level.11 central obesity, is one of the most important risk factors for type-2 diabetes. Table 1. Diagnosis criteria for prediabetes Obesity may cause insulin resistance Impaired Fasting Glucose (IFG), whenever: through two mechanisms, i.e.: secretion of -- Fasting blood glucose level is 100-125 mg/dl (5.6- various adipokines (Tumor Necrosis Factor)5,6,8 6.9 mmol/L) Until now, there is no recommendation on -- 2-hour postprandial blood glucose level is <140 mg/ dL management of prediabetes in Indonesia. Impaired Glucose Tolerance (IGT), whenever: This guideline discusses the aims and goals -- Normal fasting blood glucose level is <100 mg/dL of prediabetes management associated with -- After 75 gram glucose challenge, the 2-hour prevention of diabetes chronic complication postprandial blood glucose level is 140-199 mg/dL, risks and cardiovascular risks. By having (7,8-11 mmol/L) this guideline, health care professionals are Prediabetes, if there is IFG and/or IGT expected to have improved skills in recognizing prediabetes condition, identifying people Not all of various epidemiological studies at high risk for diabetes and providing an have incorporated the use of 2-hour postprandial appropriate management so that the incidence blood glucose level to establish the diagnosis of and complication of DM can be reduced. prediabetes and only use the fasting blood glucose level. It may result in false negative since the IGT DIAGNOSIS AND RISK FACTORS OF would be undetected. Individuals with normal PREDIABETES fasting blood glucose would be categorized as IGT when OGTT is performed. Detecting the Diagnosis presence of IGT should be performed considering Prediabetes (IFG and/or IGT) is diagnosed that it may develop into T2DM and higher risk according to WHO recommendation. Diagnosis of cardiovascular complication in subjects with of IFG is made when the blood glucose level after IGT than individuals with IFG.2,10 8-to 10-hour fasting is 100–125 mg/dl. Diagnosis Several cardiovascular risk factors are of IGT is established when the blood glucose found concomitantly along with risk factors of level after 2-hour postprandial challenge with 75 diabetes in an individual. Those risk factors are: gram glucose is between 140 and 199 mg/dl.6,7,10 obesity, , a low cholesterol level Preparation and procedures of OGTT of high density lipoprotein (HDL), increased according to WHO (appendix): level, and glucose metabolism - Preparation. In the days before the test, the disorder, which is known as the metabolic patient is instructed to consume carbohydrate syndrome. is considered intake in adequate amount. On the test day, to a prediabetes equivalent. Approximately 50% patient should not do excessive physical patients with IGT meet the National Cholesterol activities or having caffeine intake or other Education Program – Adult Treatment Panel III drugs that may affect blood glucose level. (NCEP-ATP III) criteria for the diagnosis of - Procedures metabolic syndrome.5,11,12 - Patient is instructed to fast for at least 8 hours. Risk Factors for Prediabetes - Blood is withdrawn first for measurement Risk factors for prediabetes are similar with of fasting blood glucose the risk factors for the development of T2DM.

350 Vol 46 • Number 4 • October 2014 Guidelines on the management and prevention of prediabetes

Those risk factors can be categorized into ratio of polyunsaturated fatty acid (PUFA) modifiable and non-modifiable risk factors. The to saturated fats are risk factors for the most important factors are obesity (particularly development of DM. ) and lack of physical activity. d. Other risk factors. Although genetic factor Non-modifiable risk factors: and lifestyle have been the greates risk a. Genetic factors. Until now, genes associated factors for the development of DM, some risk with the risk for DM have not been confirmed. factors are modifiable including low birth However, there is an obvious difference of weight, exposure to intrauterine diabetic DM event among different ethnic groups environment and some of inflammatory although they live in the same environment, components.8 which indicates that genetic factor may have Blood Glucose Spectrum and Cardiovascular considerable contribution in the development Risks of DM (Alberti et al, 2007).8 Blood glucose spectrum. Actually, blood b. Age. The prevalence of DM is increasing glucose level is a continuous spectrum between with age. In the last decades, the age of DM the glucose level considered normal (fasting onset has decreased, particularly in countries glucose level of <100 mg/dl; postprandial with an imbalance between energy intake and glucose level of <140 mg/dl) and the level of output. blood glucose, which is considered as diagnostic c. . In gestational diabetes, for diabetes (fasting glucose level of >126 mg/ glucose tolerance returns to normal after dl; postprandial glucose level after 75 gram birth; however, the woman is at risk of glucose challenge of >200 mg/dl). The limits of developing DM in the future.8 those blood glucose levels are associated with the Modifiable risk factors: onset of complications specific for diabetes (end- a. Obesity. Obesity is the most important risk organ complication), particularly the retinopathy. factor. Some longitudinal studies show Various population studies indicate that values that obesity is a strong predictor for the of fasting blood glucose level and the 2-hour development of T2DM. Furthermore, an postprandial glucose levels associated with intervention aimed to reduce obesity may the development of complication are actually actually also reduce the incidence of T2DM. lower than the threshold limit of blood glucose Various longitudinal studies have also level used currently for diagnosing diabetes. demonstrated that waist circumference or It is assumed that despite the blood glucose waist-to-hip ratio which represents visceral level still below the “normal” threshold limit, (abdominal) fat condition, is actually a better the individual may already have increased risk indicator than as the risk for microvascular and macrovascular diabetes factor for prediabetes. Those data confirm complications.11 that fat distribution is more important than The natural history of illness shows that the total amount of fat. 6-10% patients with IGT will have progression b. Physical activities. In last decades recently, to diabetes in 1 year period of time; while for reduced intensity of physical activities patients with both IGT and IFG, the cumulative in various populations has been a great incidence of diabetes by 6 years is as much as contributor to increased obesity worldwide. 60%. In addition, for individuals with normal Various cross-sectional and longitudinal glucose tolerance level, the incidence of diabetes studies have shown that reduced physical is only about 5%. activity is an independent predictor for the Prediabetes and risks for cardiovascular development of T2DM either in men or disease (CVD). Various studies demonstrated women. a linear correlation between glycemia status c. Nutrition. High total caloric intake, low and the risks for CVD. Subjects in prediabetes fiber diet, high-glycemic load and low group had an equal risk for the development

351 The Indonesian Diabetes Association Acta Med Indones-Indones J Intern Med of complication as subjects in diabetes group. measures include: Regarding diabetes and CVD risks in the Lifestye intervention prediabetes group, IGT is more associated with Lifestyle modification should be the core of 4 both risks compared to those with IFG. treatment and it should be provided to all patients The results of epidemiologic studies even should be reinforced in every patient’s on CVD incidence rate, such as AusDiab visit. Lifestyle is a fundamental management (Australian diabetes, obesity, and lifestyle study), approach that can effectively prevent or delay Framingham Study and intervention studies such the progression from prediabetes to diabetes, as Study to Prevent Non-Insulin-Dependent as well to reduce both microvascular and Diabetes Mellitus (STOP-NIDDM) and Diabetes risks. More importantly, reduction Assessment with Ramipril and lifestyle interventions improve all risk factors Rosiglitazone Medication (DREAM) study, for diabetes and components of the metabolic suggest that cardiovascular risk in individuals syndrome, obesity, hypertension, with IFG and IGT doubles compared to those and . In accordance with the 3 without IFG or IGT. The results of The Nurse Diabetes Prevention Program (DPP) findings, Health Study showed that women destined patients with prediabetes should reduce weight to convert to T2DM have 3 times the risk of by 5% to 10% and should maintain this level CVD risks compared to those remained as non- for a long-term. A moderate degree of weight T2DM individuals. A meta-analysis conducted loss results in reduced fat mass, decreased by Levitan et al confirmed that prediabetes is , glucose, low density lipoprotein associated with increased fatal and non-fatal risk (LDL) cholesterol and triglycerides levels. of CVD. The increased risks were comparable These benefits can also appear in long-term between individuals in IFG and IGT groups. outcome, especially if and lifestyle Cardiovascular risks increased with linear intervention are maintained. A long-term follow- pattern when associated with blood glucose level up in a Finish Diabetes Prevention Program after meal; while when it was associated with showed that lifestyle intervention in patients at fasting blood glucose, the assumed threshold of high risk for T2DM has resulted in reduction in 13 increased risk was 99 mg/dl. diabetes incidence, which persisted even after A cohort study of The Diabetes Epidemiology the individual lifestyle counseling was stopped.6,8 Collaborative Analysis of Diagnosis Criteria A program of regular moderate-intensity in Europe (DECODE) and a similar study in physical activity for 30 to 60 minutes daily, at Asia (DECODA) have also found that the least 4 days weekly or minimal 150 minutes/ 2-hour postprandial glucose level after glucose week, is recommended.8 challenge is a better predictor for cardiovascular The recommended diet includes calorie mortality than fasting glucose level. Moreover, restriction, increased fiber intake and limitations other various studies have also demonstrated in carbohydrate intake. Specifically for patients a association of postprandial hyperglycemia with hypertension, dietary recommendations with increased risk of retinopathy, thickening include lower sodium intake and limitation in of carotid intima-media layers, endothelial alcohol consumption.6,8 dysfunction, oxidative stress, inflammation, Although adjustment on individual basis reduced blood flow volume to cardiac myocytes, may be necessary, lifestyle modification can cognitive impairment in elderly and increased be recommended for all ages but it may be 4 risk for cancer. difficult to maintain. Physicians should focus and emphasize on the importance of maintaining A REVIEW OF STUDIES ON DM PREVENTION weight loss as the long-term goal. Some efforts Some immediate measures of prevention are expected to increase the likelihood success are: necessary to reduce the number of patients with patient self-monitoring, realistic and stepwise prediabetes, T2DM and goal setting, social support, reinforcement on the associated with diabetes. Those prevention importance of healthy lifestyle.8 The following

352 Vol 46 • Number 4 • October 2014 Guidelines on the management and prevention of prediabetes studies demonstrate the benefit of lifestyle which included 3234 individuals with prediabetes intervention as an effective prevention measure: in Amerika involving women (68%) and Malmo Study. This study was a preliminary minorities (45%). The study compared lifestyle study about the role of lifestyle intervention on intervention and drug intervention () T2DM prevention in Sweden; the study was with a control group over 2.8 years. The study conducted in men aged 47-49 years old. Some reported that both lifestyle modification and patients with prediabetes and normal glucose metformin had positive effects on DM prevention tolerance (NGT) received usual care/treatment; and restoring the prediabetes into a normal while patients with prediabetes and the other condition. Furthermore, it is known that lifestyle T2DM underwent a lifestyle intervention. intervention was more effective than metformin. Those who received lifestyle intervention had There was a lower mortality rate in the group demonstrated a lower incidence of T2DM with lifestyle intervention compared to those compared to the group receving usual treatment receiving metformin. The cost-effectiveness of and had reversal of IGT to normal value. At the generic metformin is comparable with lifestyle 12-year follow-up, patients in prediabetes group intervention without using any medication. who received lifestyle intervention showed no Results of DPP study published afterward difference in mortality rate when compared to suggested that an increase of physical activity those in the NGT group. Moreover, the mortality in individuals without weight loss helps them to rate was less than half of men who did not maintain body weight and independently reduces received lifestyle intervention.8 diabetes risks. In addition, there was also positive Da Qing Study. The Da Qing study examined effect on fasting glucose and post-prandial the effect of 6-year diet and exercise intervention glucose tolerance. Lifestyle intervention has in Chinese subjects with a mean age of 45 years also improved lipid parameters of the metabolic and prediabetes. The diet intervention alone syndrome and reduced the risks of hypertension.8 reduced the risk of developing type-2 DM of Indian Diabetes Prevention Program 31%; while the invertention of physical activity (IDPP). IDPP was a prospective community- alone reduced the risk about 46%. A combination based study that examined whether lifestyle of diet and physical activity reduced the risk as interventions and medication could influence the much as 42%.8 progression to DM in Asian-Indians population The Finnish Diabetes Prevention Study. It with IGT who were leaner and more insulint was the first randomized trial which specifically resistant than other population (multiethnic evaluate the effect of lifestyle intervention on American, Finnish and Chinese population). The T2DM prevention. This lifestyle intervention results showed that progression of IGT to DM in was followed for 3.2 years and it was joined by the population was high. 522 /obese subjects with IGT and a Both lifestyle modification and metformin control group without lifestyle intervention. may significantly reduce the development of IGT Lifestyle intervention was provided by to T2DM; however, there was no added benefit individualized counseling focused on achieving from combining them compared to separate and maintaining ideal body weight, reducing fat treatment alone. With lifestyle modification, intake and increasing fiber intake and increasing metformin and combination of both treatment, physical activity. After 2 years of follow-up, the the risk of DM was reduced by 28.5%, 26.4%, incidence of DM reduced as much as 50% in the and 28.2%, respectively.8 intervention group compared to those in control group. The study also reported that the effect of Pharmacologic Intervention lifestyle modification in reducing DM incidence In reality, lifestyle modification is very may last for at least 4 years after the intensive difficult to be applied without help and monitoring intervention study completed.8 from a professional health care practitioner. The Diabetes Prevention Program (DPP). DPP potential parameter to determine successful is one of the largest randomized clinical trials, lifestyle intervention is reduced body weight of

353 The Indonesian Diabetes Association Acta Med Indones-Indones J Intern Med

2 kg in 1 month or 5% body weight reduction these facts limited its use for DM prevention. in 6 months. It is similar to reduced glucose STOP-NIDDM study results recommend the plasma level as the expected response of lifestyle use of in those who can tolerate the intervention. However, not all of individuals at gastrointestinal side-effects for DM prevention high risk can accept lifestyle modification and and cardiovascular risk reduction.15 to achieve this goal, another intervention is In China, Japan and other Asian countries, necessary, i.e. with medication. acarbose is often used as the first line drug for Pharmacologic intervention for DM patients with newly diagnosed type 2 DM. It is prevention is usually recommended as secondary also applied for countries with high consumption intervention to follow or to be use in conjunction of complex carbohydrates. with lifestyle modification intervention. If with In some patients, acarbose may reduce body lifestyle intervention, the weight loss has not weight. Results of long-term studies in patients occurred, then the use of medication should be with IGT and T2DM showed that acarbose started.8,14 significantly reduced body weight of 0.7 – 0.9 kg. Metformin. The rationale for the use of In STOP-NIDDM study, the incidence of newly metformin is largely based on its 40-year-long- diagnosed hypertension has also reduced by term safety record. The data on safety was 34%. Acarbose may also reduce the lipid levels, obtained through results of the DPP and IDPP particularly the fasting lipid and triglycerides studies. Results of DPP showed that metformin levels of 15%. Acarbose may also reduce in the dose of 850 mg twice daily with meals atherogenicity of LDL in patients with IGT.8,15 reduced the development of DM by 31% and Glitazones. In the DPP, troglitazone the development of metabolic syndrome by 17% treatment was withdrawn after about one year in 2.8 years compared to placebo. The relative due to hepatotoxicity. In the Troglitazone risk reduction was found more obviously in the in prevention of diabetes (TRIPOD) study, group with body mass index (BMI) >30 kg/ troglitazone treatment for more than 3 years m2. The reduction of relative risk in this group has caused cummulative reduction in incidence reached 16-35%; while those with BMI of 22- of diabetes to zero point. Results of a cohort 30 kg/m2, the relative risk reduction was only study (DREAM study) using rosiglitazone and as much as 3%. ramipril with a large number and multiethnic Different results were found in IDPP, which population showed that subjects in IFG and/or showed a benefit with metformin in those with IGT group who had received rosiglitazone for 3 BMI <30 kg/m2 considering that obesity in years showed a 60% decrease in progression to Asians presents at a lower BMI, i.e. >25 kg/m2. diabetes compared to 25% in placebo group and However, metformin is not recommended for 70% among them returned to normal glucose everyone with IGT. It may cause lactic acidosis tolerance. The group receiving rosiglitazone (ischemic disorder in kidney and liver). DPP showed a higher likelihood of significant body results also demonstrated that metformin was less weight increase and increased incidence of effective in DM prevention in individuals aged congestive heart failure.8,16 >65 tahun. Metformin limitation may also be Orlistat. Orlistat is a drug acts by a caused by gastrointestinal side effects, which can mechanism of inhibiting enzyme that breaks be overcome by increasing the dose gradually.8 down triglycerides in the intestine. Results of Acarbose. Acarbose acts by inhibiting one study showed that orlistat may cause weight enzymes that digest carbohydrate. In the study loss of 3-5 kg over 6 months, which could be of STOP-NIDDM with 3.3 years of follow-up, maintained over 4 years. Treatment of obese acarbose reduced the risk for DM as much as subjects with IGT by orlistat as an adjuvant 25% and the risk for cardiovascular disease as treatment to diet and lifestyle modification can much as 49%. The presence of gastrointestinal reduce the risk of developing T2DM. In Xenical side-effects have caused a 31% drop-out rate in the Prevention of Diabetes in Obese Subjects (vs. 19% in the placebo group); therefore, (XENDOS) study, all of 3304 non-diabetic obese

354 Vol 46 • Number 4 • October 2014 Guidelines on the management and prevention of prediabetes subjects received intensive lifestyle modification - Step 1: identification of those groups who and were randomized into either orlistat or may be at high risk placebo group. After 4 years, the orlistat group - Step 2: measurement of risk had 6.9 kg weight loss; while the placebo group - Step 3: Intervention had 4.1 kg weight loss. The weight loss was Step 1. Identification of high-risk group associated with reduced risk for developing The first step is the identification of DM as much as 37%. The high number of drop individuals who have higher risk than average out (52%) in the orlistat group was associated population. The IDF recommend the use of with gastrointestinal side-effects and therefore, opportunistic screening by health-care personnel 8 limiting its use. (genereal physicians, nurses and pharmacists). Poly-e-pill. Considering the high probability Strategies to predict future risk of diabetes on classification of various risk factors for T2DM usually use demographic and clinical data from and CVD (obesity-metabolic syndrome) in one prospective cohort studies, statistical models and individual, the concept of “” - one drug risk scores. In the first step, the strategy usually that can manage all of those various risk factors has not relied on measurements of blood glucose - has been attractive for the experts since a long but has utilized various personal measures or while ago. However, until now, the expectation family history of high blood glucose level. to find the abovementioned drug has not been In longitudinal approach, age and history of satisfied. Actually, the concept of polypill high blood glucose level appear to be the most is integrated in physical activity (exercise). important data. Physical activity has been proven to be relatively In general, these strategies can not be applied safe (almost without any side effects). It can be for different population due to differences in applied for all ages with dose-dependent results population characteristics. For different ethnic and inexpensive. It also contributes a good effect group, different strategies are recommended. on targets at molecular level of all components Questionnaire is a simple, practical, non- for obesity and metabolic syndrome. invasive and inexpensive method to identify A systematic review and meta-analysis individuals at high risk for prediabetes and comparing lifestyle intervention and drug diabetes. It is also used to reduce the application treatment showed that both interventions may of OGTT. The IDF recommend the use of brief lower the progression of prediabetes to diabetes questionnaires to help health-care professonals 17 with equal effectiveness. to quickly identify population at high risk that need further investigation. The questionnaire can STRATEGY FOR DIABETES MELLITUS also be used for self-assessment.8 PREVENTION Some criteria that should be included in the Results of studies showed that early detection questionnaire: and intervention to improve glucose control - Central obesity is most easily calculated by and to prevent the progression of prediabetes measuring abdominal circumference with to T2DM in individuals at high risk will cut-off points that are gender and ethnic results in reduced incidence, comorbidity and group specific Table( 2). complication of diabetes. According to the - The presence of family member diagnosed IDF, T2DM prevention strategy is based on with diabetes controlling modifiable risk factors (modifiable - Age >35 tahun risks). The prevention strategy can be categorized - Cardiovascular history into 2 target groups.8 - History of hypertension and/or heart disease - Gestational history A High-Risk Population - Previous occurrence of gestational diabetes The high-risk approach: - History of treatment. Use of drugs that The IDF proposes a three-step plan for predispose type-2 DM, including: nicotinic T2DM prevention for those in in high-risk group: acid, glucocorticoids, thyroid hormones.

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If there are some items present in an Step 3. Intervention individual at high risk, further investigation Various substantial evidences showed that should be undertaken to evaluate the level of lifestyle modification can prevent the progression risk.8 of prediabetes to T2DM. Therefore, lifestyle modification must be the initial intervention for Step 2. Measuring level of risk If a person is at high risk for type-2 diabetes, all patients. For patients who can not change we will proceed to step 2. At this stage, other risk their lifestyle sufficiently and those with a factors are assessed and determined. high level of risk (for developing diabetes), The measurement for level of risk is pharmacotherapy should be encouraged along performed by health-care professionals. The key with lifestyle modification. Lifestyle changes investigation in the step 2 is the measurement of should be maintained since it will continue to blood glucose level. deliver long-term health benefits. - Plasma glucose. Measurement of blood - Lifestyle modification (lifestyle changes). In glucose level with glucose challenge will order to prevent or delay the development not only able to detect IFG or IGT cases, but of diabetes, lifestyle modification should also cases of undiagnosed diabetes. Positive be the first choice measure for all patients. findings of IFG and/or IGT may increase the The lifestyle modification must be risk for progression to T2DM. Interventions emphasized in each visit. In addition to its aimed for individual target provide an effectiveness in preventing the development opportunity to delay or prevent the onset of of T2DM, lifestyle modification can also T2DM. improve risk factors for diabetes and other - Other risk factors include: increased abdominal components of metabolic syndrome such circumference, hypertension, family history as obesity, hypertension, dyslipidemia, and of diabetes, increased triglycerides/TG hyperglycemia. level or previous cardiovascular disease - Weight. Obesity, particularly abdominal (Table 2). Furhter investigation on other obesity is “central” to the development cardiovascular risk factors should also be of T2DM and other associated disorders. performed such as HDL cholesterol, LDL Therefore, abdominal obesity has become cholesterol, and . The presence of a focus of attention in reducing the risk of the abovementioned factors can increase T2DM. In short term period, weight loss the risk of developing diabetes and those improves insulin resistance, hyperglycemia individuals should receive appropriate and dyslipidemia as well as reduces treatment.8 hypertension. Patients should be encouraged to achieve and maintain a healthy body composition. A structured approach of Table 2. Other risk factors for diabetes long-term weight loss program as has been Risk factors taken in DPP study can reduce 5-7% of Triglycerides >150 mg/dl (>1.7 mmol/L) initial baseline body weight. The target HDL cholesterol Male <40 mg/dl (<1.03 is gradual weight loss (0.5-1.0 kg/week) mmol/L) Female <50 mg/dl (<1.29 through calorie restriction and increased mmol/L) physical activity. A self-monitoring of or dyslipidemia on treatment weight and waist circumference must be Waist circumference Male >90 cm performed daily/weekly. Standard weight- Female >80 cm loss diet recommend reducing daily intake Blood pressure >130/80 mmHg or hypertension on calorie by 500 – 1000 calorie (depending treatment on gender and age), which is aimed to Family history of DM Father / mother / siblings maintain body weight. Although very-low Preexisting heart disease CHD, cerebrovascular calorie diet and meal-replacement plans disease, peripheral arterial disease can produce impressive results in short-

356 Vol 46 • Number 4 • October 2014 Guidelines on the management and prevention of prediabetes

term period, but the long-term benefits are activated receptor-g agonist (PPARg) had limited. A complete change of dietary habits shown promising results, but its side-effects and restricting calorie and fat consumption on and congestive heart failure are the most important actions to achieve has become a great concern and its routine sustained weight loss. Moreover, control of use is not recommended.A further option for carbohydrate intake also has important role. the obese patients is orlistat. Newer agents Simple carbohydrates with a high glycemic such as rimonabant has also been very index will cause additional metabolic load promising, but long-term safety and efficacy to patients. data on diabetes prevention are lacking and - Physical activity. Increased physical activity it is not recommended for prevention in 8,17 is also important in maintaining weight individuals at high risk. loss. Regular physical activity improves (All) Population Approach insulin resistance, reduces insulin level in In planning the national prevention patients with , improves measures, both population groups should be dyslipidemia and lowers blood pressure. targeted simultaneously. Moreover, all important Physical activity increases metabolic activity activities should be adjusted to the characteristic of muscle tissue and improves cardiovascular local situation. The aim of population approach health in general. Increased physical acitivity is to bring important changes in the health of also reduces the risk of T2DM. Moderate a large percentage of population. It is based physical activity (brisk exercise) of at least on promoting healthy lifestyle which is quite 30-60 minutes (brisk walking, swimming, effective in preventing T2DM, including cycling, dancing) for at least 4 days of the cardiovascular disease, hypertension, and week, may reduce the risk of diabetes by many other non-communicable and chronic 35-40%. The determination of physical diseases. The most dominant effect of obesity is activity should consider the condition of to induce glucose intolerance along with all of patient comprehesnsively and identification its consequences. The occurrence of epidemic of any contraindication is a very essential diabetes can only be prevented by substantial issue. For patients who have had usual lifestyle modification and it must be performed sedentary lifestyle, exercise program should immediately. The prevention of T2DM is based be initiated slowly and increased gradually. on an increase in daily activity and healthier - Pharmacological intervention. The IDF eating habits, thus resulting in a better balance recommend that when lifestyle intervention between energy intake and energy utilization.8 alone has not achieved adequate desired Population approach to prevent diabetes weight loss, and/or improved glucose according to the IDF recommendation based on tolerance, then metformin at the dose of 2 x results of lifestyle prevention studies: 250-850 mg/day (depending on tolerance) - Everyone is encouraged to perform moderate should be considered as a diabetes prevention physical activity (e.g. brisk walking) at least strategy. Pharmacological therapy with 4 times of the week. metformin is aimed for patients aged <60 - Everyone is encouraged to maintain a healthy years with BMI >30 kg/m2 (in Indonesia, weight. BMI >25 kg/m2) and FPG >110 mg/ - Adults with BMI >23/kg/m2 should be dl (6.1 mmol/l) who do not have any encouraged to achieve and maintain a healthy contraindication. For those who consume weight and/or 5-10% weight reduction large amount of carbohydrates in their diet, - Children should be encouraged to achieve acarbose is worthy of consideration to be the and maintain the normal range weight for first line drug. Acarbose can be administered height. at the dose of 3 x 50 mg/day taken during - The approach taken needs to be culturaly the meal and the dose can be increased up sensitive. Cultural beliefs (e.g. about obesity) to 3 x 100 mg/day. Peroxisome proliferator have to be understood and addressed.8

357 The Indonesian Diabetes Association Acta Med Indones-Indones J Intern Med

The National Diabetes Prevention Plans is similar to those with diabetes (triglycerides should include: <130 mg/dl, HDL >45 mg/dl, LDL <100 mg/ 1. Advocacy for community groups by dl) supporting national associations and non- 3. Target blood pressure in subjects with government organizations. prediabetes is similar to those with diabetes 2. Community support on : (sistolik <130 mmHg, diastolic <80 mmHg) - Providing education at school about Diet nutrition and physical activity Recommended diet is low fat, low saturated - Promoting opportunities for physical fat and trans-fatty acid and low sodium intake. acitivity through urban design (e.g. Avoid alcohol intake and get an adequate fiber improving the facilities for walking, intake. cycling and play grounds) - Supporting sports facilities for the general Physical activities population 1. Individuals with prediabetes need to have 3. Fiscal and legislative / regulation policy, by: 5-10% weight loss of their initial weight and - ‘Organizing’ food pricing, labeling and maintain their weight for long-term period advertising 2. Regular and moderate physical activities are - Enforcing environmental and recommended for 30-60 minutes daily and it infrastructure regulation (e.g. urban should be performed at least 4 days in a week. planning and transportation policy to Pharmacological treatment enchance physical activity) 1. In individual with prediabetes at high risk, 4. Engagement of private sector pharmacological treatment is considered as - Promoting health in the workplace adjuvant treatment of lifestyle modification/ - Ensuring healthy food policies in food changes. industry 2. No drug has been approved today by the Food 5. Utilization of communication media (press, Drug Administration (FDA) for prediabetes; TV, radio) to improve the level of knowledge therefore, the decision for treatment is based and motivation of the community.8 on risk-benefit analysis 3. Metformin and acarbose are safe and RECOMMENDATION effective to help preventing diabetes 4. Although reduces the risk General Recommendation of prediabetes progression to diabetes, but 1. Prediabetes may be associated or increase there is a risk of developing congestive heart the risk of cardiovascular disease and failure and fracture that should be concerned. microvascular complication and will progress 5. Statins are recommended to achieve treatment to type-2 diabetes; therefore, it should be target of LDL cholesterol (<100 mg/dl), managed appropriately. nonHDL (<130 mg/dl), and apolipoprotein 2. All patients with prediabetes must receive B (<90 mg/dl) adequate treatment including intensive 6. In some patients, fibrate, bile acid lifestyle changes, which is safe and effective sequestrants, ezetimibe and other drugs may in order to improve the glycemic condition be beneficial as adjuvant treatments. and to reduce cardiovascular risk. 7. improves lipid profile but it has a Target potency to cause glycemic effect 1. Target blood glucose level in subjects with 8. When there is a hypertension, angiotensin- prediabetes is similar to those with diabetes converting enzyme inhibitors or angiotensin (A1c < 6.5%, FBG < 100 mg/dl, 2-hour receptor blockers are recommended as the postprandial blood glucose (PPBG) < 140 first line treatment and calcium channel mg/dl blockers are recommended as the second 2. Target lipid level in subjects with prediabetes line.

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9. Thiazides and/or b-blocker are utilized by 7. Aroda VR, Ratner R. Approach to the patient with taking the effect of glycemia into account prediabetes. J Clin Endocrinol Metab. 2008;93:3259- 10. All individuals with prediabetes who have no 65. 8. Alberti K, Zimmet P, Shaw J. International Diabetes risk of gastrointestinal, intracranial or other Federation: a consensus on prevention. bleeding should receive low-dose aspirin. Diab Med. 2007;24:451-263. Monitoring 9. Nathan D, Davidson M, Defronzo R, et al. Impaired fasting glucose and impaired glucose tolerance. Diab 1. Monitoring of patients with prediabetes Care. 2007;30:753-9. includes annual OGTT and microalbuminuria 10. Pankow JS, Kwan DK, Duncan BB, et al. examination. Investigations on FBG, HbA1c Cardiometabolic risk in impaired fasting glucose and and lipid levels are performed at least twice impaired glucose tolerance. The risk a year. in communities study. Diab Care. 2007;30:325-31. 2. For patients at a very high risk, monitoring 11. Garber A, Handelsman Y, Einhorn D, Bergman D, Bloomgarden Z. Diagnosis and management of must be performed more often. prediabetes in the continuum of hyperglycemia - when do the risk of diabetes begin? A consensus statement REFERENCES from the American college of endicronology and the 1. Departemen Kesehatan. Riset Kesehatan Dasar American association of clinical endocrinologist. (Riskesdas). Departemen Kesehatan Republik Endocrine Practice. 2008;14:933-48. Indonesia. Jakarta. 2008. 12. Nakagami T, Qiao Q, Tuomilehto J, Balkau B, Tajima 2. Reyden L, Standhl E, Bartnik M, Berghe GVd, N, Hu G. Screen-detected diabetes, hypertension and Betteridge J. Guidelines on diabetes, pre-diabetes, and hypercholesterolemia as predictors of cardiovascular cardiovascular disease: Full Text. Eur Heart J. 2007:1- mortality in five populations of Asian origin. Eur J 72. Cardiovasc Prev Rehabil. 2006;13:566-81. 3. Iqbal N. The burden of type 2 diabetes: strategies 13. Levitan E, Song Y, Ford E, Liu S. Is non diabetic to prevent or delay onset. Vasc Health Risk Manag. hyperglicemia a risk factor for cardiovascular disease? 2007;3(4):511-20. A meta-analysis of porspective study. Arch Intern Med. 4. Decode Study Group. Glucose intolerance and 2004;164:2147-55. cardiovascular mortality: comparison of fasting 14. Gilles C, KR KA, Lambert P, Cooper N. Pharmacological and 2-hour diagnostic criteria. Arch Intern Med. and lifestyles interventions to prevent or delay 2001;161:397-405. type 2 diabetes in people with impaired glucose 5. Nguyen QM, Srinivasan SR, Xu J-H, Chen W, tolerance : systematic review and meta analysis. BMJ. Berenson GS. Changes in risk variables of metabolic 2007;334:229-308. syndrome since childhood in prediabetic and type 2 15. Hanefeld M. Cardiovascular benefits and safety profile diabetic subjects. The Bogalusa Heart Study. Diab of acarbose therapy in prediabetes and established type Care. 2008;31:2044-9. 2 diabetes. Cardiovascular Diabetol. 2007;6(0):1-10. 6. American Diabetes Association. ADA position 16. Association AD. Standards of medical care in diabetes. statement, standards of medical care in diabetes 2009. Diab Care. 2014;37(1):S14-79. Diab Care. 2009;32(Suppl 1):S13-S61. 17. Levine J, Davis R. The poly-e-pill finally arrives. Diabetes. 2008;57:1784-5.

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