clinical practice Consensus Statement on Management of ... · PDF fileConsensus Statement on Management of Post-Prandial Hyperglycemia in Clinical Practice in India ... Parag Shah15,

Journal of The Association of Physicians of India ■ Vol. 63 ■ August 2015 45

Consensus Statement on Management of Post-Prandial Hyperglycemia in Clinical Practice in IndiaSR Aravind1, Banshi Saboo2, Shaukat Sadikot3, Siddharth N Shah4, BM Makkar5, Sanjay Kalra6, Johnny Kannampilly7, Jothydev Kesavadev8, Samit Ghoshal9, AH Zargar10, Anant Nigam11, DK Hazra12, Kamlakar Tripathi13, Mala Dharmalingam14, Parag Shah15, Pramod Gandhi16, Rakesh Sahay17, Ranjit Unnikrishnan18, Sachin Gupta19, Sarita Bajaj20, Satinath Mukhopadhyay21, Shailaja Kale22

c l i n i c a l p r a c t i c e

Introduction

The primary aim of treating diabetes is to establish and

maintain near-normal blood glucose levels, and to prevent micro and

1Director & Chief Diabetologist, Diacon Hospital, Bangalore, Karnataka; 2Department of Diabetology, Dia Care – Diabetes Care & hormone Clinic, Ahmedabad, Gujarat; 3Jaslok Hospital and Research Center, Mumbai, Maharashtra; 4Hon Diabetologist, Sir. H.N. Hospital, Bhatia Hospital, S.L. Raheja Hospital, Saifee Hospital, Mumbai; Post Graduate Teacher, University of Mumbai, Maharashta; 5Sr. Consulting Physician, Diabetologist & Obesity Specialist, Sri Balaji Action Medical Institute, Paschim Vihar, New Delhi; 6Department of Endocrinology, Bharti Research Institute of Diabetes and Endocrinology, Bharti Hospital, Karnal, Haryana; 7Diabetologist, Lakhsore hospital, Kochi; 8Department of Diabetology, Jothydev’s Diabetes and Research Centre (JDC), Trivandrum, Kerala; 9Medical Director, Nghtingale Hospital, Kolkata, West Bengal; 10Diabetologist, Advance Centre for Diabetes and Endocrine Care, Srinagar, Jammu and Kashmir; 11Diabetologist, Nigam Diabetes Center, Jaipur; 12Department of Medicine, Government Medical College, Agra, Uttar Pradesh; 13Prof. Dept. of Medicine, Institute of Medical Aciences, Varanasi; 14Department of Endocrinology, Bangalore Endocrinology and Diabetes Research Center, Bangalore, Karnataka 15Endocrinologist, Gujarat Endocrine Centre, Ahmedabad; 16Diabetologist, Gandhi Research Institute, Ahmedabad, Gujarat; 17Department of Endocrinology, Osmania Medical College and Hospital, Hyderabad; 18Department of Diabetology, Dr. Mohan’s Diabetes Specialities Centre and Madras Diabetes Research Foundation, Chennai, Tamil Nadu; 19Diabetologist, Krishna Diabetes Clinic and Educational Research Centre, Bhopal; 20Department of Medicine, MLN Medical College, Allahabad, Gujarat; 21Department of Endocrinology and Metabolism, IPGMER & SSKM Hospital, Kolkata, West Bengal; 22Diabetologist, Centre of Excellence for Diabetes, Sahayadri Hospital, Pune, MaharashtaReceived: 08.05.2014; Revised: ;Accepted: 28.05.2014

AbstractPostprandial hyperglycemia (PPHG) is a detrimental factor in the evolution of diabetes related complications. Numerous studies have established the role of PPHG in development of atherosclerosis and associated cardiovascular conditions. It is seen that management of PPHG can be more troublesome than fasting plasma glucose (FPG). Currently, there are various strategies both monitoring as well as therapeutic to control PPHG but there is no uniformity in practicing these strategies. In the absence of any standard guidelines, widespread variations in the management of PPHG are observed among physicians and diabetologists. The objective of this document is to set forth uniform guidelines to manage PPHG. This will not only result in optimal management and prevention of long term complications of diabetes but also better co-ordination and collaboration among the care providers. Moreover, an Indian perspective that can take into consideration the issues relevant to Indian patient pool will be effective. An expert committee comprising of prominent physicians and researchers associated with diabetes care provided their inputs to provide a basic platform for the formulations of guidelines. Their inputs were supplemented by extensive literature search to collect the relevant evidences. An initial draft was prepared which was reviewed by the core committee. Inputs from other experts were also sought and an initial guideline version was formulated that was presented in a conference, discussed and debated among experts. The guidelines on PPHG were then finalized and published.

macro vascular complications.1,2 There is a close correlation between the risk of complications and the glycosylated hemoglobin (HbA1c) values, which depend upon both fasting and postprandial glucose

levels. Although pre-prandial and FPG concentrations are considered as the primary measures of daily g lucose contro l , postprandia l glucose (PPG) levels are equally important.3

Journal of The Association of Physicians of India ■ Vol. 63 ■ August 201546

PPG is an independent r isk factor for the development of m a c r o va s c u l a r c o m p l i c a t i o n s associated with type 1 and type 2 diabetes and impaired glucose tolerance (IGT) stage. PPG has been linked to cardiovascular morbidity and mortality despite of HbA1c values being in the non-diabetic range.4–6

Objective: To assess relationships of diabetes and asymptomatic hyperglycemia at baseline to the risk of cardiovascular disease (CVD. Elevated FPG concentrations are not independently associated with increased cardiovascular disease (CVD) risk hence management of PPG becomes important.7,8 That cardiovascular disease occurs more frequently in patients with Type II (non-insulin-dependent The associations between PPG and markers of cardiovascular disease such as oxidative stress, i n f l a m m a t i o n , e n d o t h e l i a l dysfunction, and Carotid Intima-Media Thickness (CIMT) underscore the significance of PPG. In addition, post meal hyperglycemia has a lso been connected with the i n c i d e n c e o f c a r c i n o m a s a n d cognitive dysfunction in elderly type 2 diabetic patients further providing reasons for strict PPHG management.9,10

Numerous studies have shown that normalizing post-prandial b l o o d g l u c o s e c a n b e m o r e challenging than maintaining a fasting glucose level. So, there is a need to employ intense measures for reducing PPG and excessive glycemic readings.

Objective

T h e o b j e c t i v e o f t h e s e guidelines is to provide India specific recommendations for the management of post-meal glycemia in patients with diabetes. These guidelines will present clinical data obtained from evidences to establish a crucial relationship between post-meal hyperglycemia and the development of diabetic

complications. Though logic and clinical judgment remain critical components o f d iabetes care , following recommendations will assist clinicians and organizations to understand and address questions concerning post-meal glycemia management. The objectives of these guidelines are:• To present clinical data on

the relationship of post-meal h y p e r g l y c e m i a a n d t h e d e v e l o p m e n t o f d i a b e t i c complications

• To explain the role of optimizing PPG management in reducing the burden of diabetes and its complications

• To identify and explain the m a n a g e m e n t a n d r o l e o f various therapies in controlling post-meal plasma glucose

Methodology

Guidelines on PPG and other aspects of management of diabetes were formulated in a step-wise manner with due consideration given to opinion of experts and published literature on the matter. A core committee comprising of experts (healthcare professionals/researchers/c l inic ians) having expertise in treating diabetes was formulated. It was decided by the committee members that there is a pressing need of diabetes management guidelines in the Indian context. A separate group compris ing of 6-7 individuals and one chairman was formed for each guideline. This group was responsible for formulating a draft version of a guideline. Extensive literature search was conducted o n o n l i n e d a t a b a s e s s u c h a s Medline, Cochrane, Embase etc. to identify the relevant subject matter. Evidences included randomized or nonrandomized clinical trials, meta-analyses, evidence based reviews, case studies, cohort studies and epidemiological studies. Opinion of expert panel was also taken into account. The grading of evidences was done as below:

Level Type of EvidenceA Meta-analyses or systematic review/

randomized controlled trialsB Controlled trials, no randomization/

randomized uncontrolled trialsC Observational trials/reviews/case

studiesD Opinion of expert panel

The initial draft of guidelines was presented to core committee who discussed all the aspects of guidelines and provided their inputs based on their c l inical experience. This draft was posted on Diabetes India website to seek opinion from global and regional experts. Draft guidelines were further modif ied on the basis of comments received and the refined version was presented at a conference attended by nearly 200 experts. Each guideline was discussed and further comments were obtained from the group which resulted in the second draft of the guidelines. This draft was again sent to the core committee for their closing remarks and approval.

Definition

• American Diabetes Association (ADA) 2013 defines post-meal hyperglycemia as a 2-h plasma glucose level of more than 200 mg/dl (11.1 mmol/l) during an oral glucose tolerance test (OGTT). It recommends the use of a glucose load equivalent of 75 g anhydrous glucose dissolved in water as prescribed by WHO.11

• A plasma glucose level of 7 .8 mmol/ l (140 mg/dl ) or m o r e , a f t e r 1 - 2 h o u r s o f food ingestion is defined as p o s t - m e a l h y p e r g l y c e m i a b y I n t e r n a t i o n a l D i a b e t e s Federation (IDF) 2011.12

PPG Epidemiology

Post-prandial hyperglycemia i s a widespread condi t ion in Asia and often underdiagnosed. Dickinson et al found that Asian Indians displayed a marked rise in prandial glucose excursion after


Table 1: Morbidity and mortality related to postchallenge and postprandial hyperglycemia

Study Patients Key FindingsDECODE study75 10 prospective studies among

15,388 men and 7126 women not previously diagnosed with diabetes

2-hour blood glucose levels following 75-gOGTTbetterpredictorofallcauseand cardiovascular deaths from FPG levels

Chicago Heart Association76

12,220 men with diabetes or asymptomatic hyperglycemia

Increased risk of CVD mortality with higher PPG (after 50-g-OGTT)

Temelkova-Kurktschiev et al5

582 men and women at risk for type 2 diabetes

2 hour blood glucose levels and spikes more strongly associated with CIMT than FPG or HbA1c

Diabetes Intervention Study6

1139 men women with newly diagnosed type 2diabetes

PPHGbutnotFPG,significantriskfactor for MI and mortality

Companion Postprandial Hyperglycemia Study47

93 men and 82 women with type 2 diabetes, not previously drug treated

Reduction of PPHG, but not FPG, associated with reductions in CIMT

consumption of 75-gm of bread meal.13 Another study conducted on 3,284 people with non-insulin-treated type 2 diabetes monitored dai ly plasma glucose prof i les over a one-week period. Results demonstrated that a post-prandial blood glucose value of more than 8 .89 mmol / l ( 160 mg/d l ) was recorded at least once in 84% of these patients8 even among patients in apparently good glycaemic control, and that simple clinical characteristics identify subsets of diabetic patients with frequent post-prandial hyperglycaemia.

Subjects and Methods: Three self-assessed daily blood glucose profiles over a 1-week period, including 18 glucose readings before and 2 h after meals, were obtained from 3,284 unselected outpatients (men 51%; age 63±10 years.

S t u d i e s e x h i b i t t h a t patients with better control of fast ing glucose can a lso have postprandial hyperglycemia. This is called as isolated postprandial hyperglycemia and is found to be quite common.

One of the studies demonstrated t h e p r e v a l e n c e o f i s o l a t e d postprandial hyperglycemia in a cohort of 90 patients with type 2 diabetes . The pat ients were assessed with questionnaires, to obtain the demographic data as they visited the clinic for follow up. Result showed that isolated

postprandial hyperglycemia was prevalent in 24.4% of patients.14

Recommendations

• A 2-h plasma glucose levelo f m o r e t h a n 2 0 0 m g / d l (11.1mmol/l) during OGTT or with the use of 75 g anhydrous glucose wil l be def ined as pos t -mea l hyperg lycemia . (Level D)

Complications Associated with PPGCardiovascular diseases

PPG has been ident i f ied as an independent risk factor for cardiovascular disease (CVD) in patients with or without diagnosed diabetes , suggesting that PPG may be a be t te r pred ic tor o f cardiovascular risk than is FPG or HbA1c alone (Table 1). Levitan et al performed a meta-analysis of 38 prospective studies and concluded that PPG appears to have a linear relation with CVD. Hyperglycemia even across the non-diabetic range was found to be associated with CVD.15 In a study conducted on Hoorn population it was observed that an increase of 5.8 mmol/l in post-load glucose was associated w i t h h i g h e r c a r d i o v a s c u l a r mortality (RR 3.40) (p < 0.05).16

Studies reported PPG excursion to be associated with increase in systolic and diastolic blood pressure. Giugliano et al showed

that acute hyperglycemia in normal subjects significantly increases s y s t o l i c a n d d i a s t o l i c b l o o d pressure.17

Backgroun: Acute hyperglycemia may increase vascular tone in normal humans via a glutathione-sensitive, presumably free radical-mediated pathway. The objective of this study was to investigate whether or not the vascular effects of hyperglycemia are related to reduced availability of nitric oxide.

Methods and Results: Acute h y p e r g l y c e m i a ( 1 5 m m o l / L , 270 mg/dL Similar results were obtained from studies conducted on a smal l group of hea l thy , non-obese normotensive subjects. Pos t -prandia l b lood pressure changes were observed in these patients during a 24-h period. It was reported that ingestion of a carbohydrate-rich meal induced an increase in systolic blood pressure, irrespective of the timing of meal ingestion.18

It is thus evident that PPG is an independent risk factor associated wi th CVD and i s reported to b e a s s o c i a t e d w i t h s e v e r a l card iovascu lar compl i ca t ions inc luding postprandia l b lood pressure, myocardial infarction (MI), CIMT and cardiovascular mortality. It is underscored that PPG is a more important factor than FPG or A1c in determining cardiovascular risks. Nephropathy

Emerging evidence suggests t h a t P P G m a y a f f e c t t h e development of nephropathy. PPG displays a stronger correlation with the incidence of diabetic microangiopathy compared to HbA1c levels . 19 A study of 52 pat ients with Type 1 diabetes mel l i tus conducted be tween 1965 and 1983, showed a definite r e l a t i o n b e t we e n t h e a n n u a l medians of PPG, the time interval between the onset of diabetes and the development of diabetic nephropathy. 20 The respect ive rôles of arterial blood pressure


and metabolic control in different stages of diabetic nephropathy were analyzed retrospectively in 52 sequentially-followed Type 1 diabetes.

The inves t iga tors f rom the Kumamoto study performed a 8-year follow up of type 2 diabetic subjects and found PPG to be a strong predictor of both retinopathy and nephropathy . 21 An 8-year prospective study of Japanese patients with type 2 diabetes was performed.

Research Design and Methods: A total of 110 patients with type 2 diabetes (55 with no retinopathy [the primary prevention cohort] and 55 with simple retinopathy [the secondary intervention cohort] In an Indian study of complications in subjects with a history of type 2 diabetes for more than 25 years, p o s t p r a n d i a l h y p e r g l y c e m i a was found to be associated with both diabetic nephropathy and neuropathy.22

Retinopathy

Sufficient evidence suggests that postprandial hyperglycemia may lead to the development of retinopathy.

Data from the National Health and Nutrition Examination Survey showed that patients who had 2-hour postprandial glucose levels of 194 mg/dL had a threefold i n c r e a s e i n t h e i n c i d e n c e o f retinopathy, despite normal fasting glucose levels.23

Two observational prospective studies from Japan demonstrated that post-meal hyperglycemia is a better predictor of diabetic retinopathy than HbA1c. A multiple regression analysis revealed that not only PPHG independently correlates with the incidence of diabet ic ret inopathy, but a lso was a s trong predictor of the progression of this complication.19,24 Studies of Egyptian and Indian P i m a p o p u l a t i o n s r e ve a l e d a similar increase in the incidence of retinopathy in subjects with normal fasting glucose levels but

2-hour postprandial glucose values of >200 mg/dL.25 Neuropathy

In a population study, Beghi et al showed that elevated fasting and PPG levels in conjunction with prolonged disease duration were associated with an increased incidence of diabetic neuropathy.26

Other Morbidities

E p i d e m i o l o g i c s t u d i e s a n d meta-analyses show that type 2 d i a b e t e s i n c r e as es t h e r i sk and tumor-specific mortality of certain cancers. PPG has also been connected with the incidence of cognitive dysfunction in elderly type 2 diabetic patients. One study reported that significantly elevated PPG excursions (11.1 mmol; 200 mg/dl) were associated with a disturbance of global, executive and attention functioning.27

A study conducted in northern Sweden included 33,293 women and 31,304 men. 2,478 incident cases of cancer were identified. Relative risk (RR) of cancer for levels of both fasting and PPG was observed. Relative risk of cancer in women increased significantly by 1.26 in the highest quartile for fasting and 1.31 for post-load glucose compared with the lowest quartile. No significant association was found in men.28

A large, prospect ive cohort study of 35,658 adult men and w o m e n ( 5 5 ) f o u n d a s t r o n g correlation between pancreatic cancer mortality and PPG levels. The relative risk for developing pancreat ic cancer was 2 .15 in people with PPG levels more than 11.1 mmol/l (200 mg/dl) compared with people who maintained PPG less than 6.7 mmol/l (121 mg/dl). This association was stronger for men than women 29–31 however , on the association of postload plasma glucose concentration with pancreatic cancer, which could provide insight into the role of abnormal glucose metabolism in the etiology of pancreatic cancer.

O b j e c t i v e : T o d e t e r m i n e t h e i n d e p e n d e n t a s s o c i a t i o n between postload plasma glucose concentration and risk of pancreatic cancer mortality among persons without self-reported diabetes.

Des ign : Prospec t ive cohor t study.

S e t t i n g a n d P a r t i c i p a n t s : Employees of 84 Chicago-area organizations, with an average age of 40 years at baseline, were screened from 1963 to 1973 and followed up for an average of 25 years. A total of 96 men and 43 women died of pancreatic cancer among 20,475 men and 15,183 women, respectively.

M a i n O u t c o m e M e a s u r e s : Relationship of pancreatic cancer mortality with postload plasma glucose levels.

R e s u l t s : C o m p a r e d w i t h a postload plasma glucose level of 6.6 mmol/L (119 mg/dL).

Recommendations

• Measures should be taken to improve awareness, regarding CVD risk with PPG, among c l in ic ians and the general public. (Level D)

• Emerging evidence suggests that PPG affect the development of microvascular complications. (Level C)

• Limited evidence also link PPG to occurrence of carcinoma in type 2 diabetic patients. H o w e v e r w e l l d e s i g n e d , prospective, clinical studies w o u l d b e n e c e s s a r y t o differentiate and demonstrate t h e p o s s i b l e c o r r e l a t i o n be tween PPG and var ious treatment modalities to change of cancer risk in type 2 diabetes mellitus. (Level D)

PPG Goal

Various international bodies have proposed different optimal goals for post meal glucose. While IDF 2011 advocates a level of less than 9.0 mmol/l (160 mg/dl) (as


long as hypoglycemia is avoided), American College of Endocrinology Conference recommends 2-hour postprandial plasma glucose to be at a level lower than 140 mg/dl whereas ADA suggests more relaxed targets i.e lesser than 180 mg/dl. Similarly, according to European Association for the Study of Diabetes (EASD/IDF-Europe) postprandial target should be less than 7.5 mmol/l (135 mg/dl).11,12

Recommendations

Targets for glycemic control must be individualized (between 1 4 0 t o 1 8 0 m g / d l ) b a s e d o n each pat ient ’s c l in ica l s ta tus , which includes socioeconomic circumstances, cognitive abilities, level of motivation, and other factors. (Level D)

Management of Post-Prandial Glucose

Both pharmacological and non-pharmacological interventions are required to manage PPG. Control of PPG can be obtained through following approaches: I. Screening testsII. S e l f - m o n i t o r i n g o f b l o o d

glucose (SMBG)III. Non-pharmacological therapyIV. Pharmacological therapyV. Combination therapyVI. PPG control in gestat ional

d i a b e t e s m e l l i t u s ( G D M ) patients

I. Screening Tests

a. P o s t p r a n d i a l g l y c e m i c screening : Based on the latest ADA recommendations for the testing of asymptomatic individuals, screening for PPG should be implemented in all adults who are overweight (BMI ≥25kg/m2) and have additional r isk factors . 11 Screening of PPG is also recommended for individuals having following conditions:

• IGTorIFGorHbA1c≥5.7%• High risk for CVD

• Established coronary artery disease (CAD)

• History of GDM• Hypertension(≥140/90mmHg

or on therapy for hypertension)• Dyslipidaemia [triglyceride >

250 mg/dL (2.82 mmol/L) and/or high-density lipoprotein (HDL) cholesterol < 35 mg/dL (0.90 mmol/L)]

• Physical inactivity• Polycystic ovarian syndrome• Firs t -degree re la t ive wi th

diabetes• O t h e r c l i n i c a l c o n d i t i o n s

a s s o c i a t e d w i t h i n s u l i n resistance (e.g. severe obesity and acanthosis nigricans)

b. Screening of Individuals with prediabetes/IGT11,12 : Already exis t ing guidel ines of IDF (2011) and ADA (2013) provide following recommendations for PPG screening in Individuals with prediabetes.

• I t should be performed in individuals those have FBG level of 100 mg/dL (5.5 mmol/L).

• 2-h OGTT should be performed, using 140–199 mg/dL (7.8–11.0 mmol/L) as determinant of IGT

• If HbA1c is available, screening target should be 5.7–6.4%.

c. Screening of Individuals with type 2 diabetes: Ideally, PPG should be measured in al l patients with type 2 diabetes, but particularly in patients with the following conditions:

• Those with high risk or with existing CVD

• Those with unstable glycemic control

• Those taking hypoglycemic m e d i c a t i o n s ( s u c h a s sulphonylureas, glinides, or all types of insulin)

• Those with chronic liver disease or end-stage renal disease

• Patients whose medication has been modified, or who are inadequately controlled

• Patients of GDM

Recommendation

• PPHG should be routinely screened. (Level D)

• 2-hr glucose challenge shall be test of choice for screening. (Level D)

• F r e q u e n c y o f m e a l - b a s e d monitoring in patients with diabetes shall be individualized based upon the PPG control. (Level D)

II. Self monitoring of blood glucose (SMBG)

Meal-based SMBG may help the patients to monitor their meal choices and portion sizes according to the effect their food has on their glucose levels.

Postprandial SMBG values often yield the highest glucose readings of the day and may motivate patients to avoid foods with high glycemic levels, encourage them for optimal physical activity to manage hyperglycemic excursions, or evaluate and adjust insulin doses.32 SMBG may facilitate significant improvement in g l y c e m i c c o n t r o l b e s i d e s d e t e c t i n g p o s t p r a n d i a l excursion.

Schwedes et al investigated the effect of meal-related SMBG on HbA1c, compared to no SMBG in non–insulin-treated patients. In the 6- month study, patients in the intervention group achieved a significant reduction in HbA1c values compared with controls (1.0% vs 0.54%, P=.0086).33

S i m i l a r l y , a s t u d y b y Muchmore et al showed that meal-based SMBG (before and 2 hours after meals for the first month) combined with dietary carbohydrate counting led to a significant decrease in HbA1c values (1.54%, P<.05) from baseline over the 44-week study.34

Structured SMBG followed by therapeutic interventions r e s u l t s i n g r e a t e r H b A 1 c


r e d u c t i o n i n p e o p l e w i t h non-insulin-requiring type 2 d iabetes compared with programs without structured SMBG.35–37 noninsulin-treated type 2 diabetes.

Research Design and Methods: This 12-month, prospective, c l u s t e r - r a n d o m i z e d , multicenter study recruited 483 poorly controlled (A1C ≥7.5%).

T h e r e a r e n o a d e q u a t e randomized clinical trial data, but the fo l lowing c l in ica l s i t u a t i o n s d e m a n d P P G monitoring:

• Gestational diabetes• I n p a t i e n t s w h o a c h i e v e

t h e i r p r e - m e a l g l u c o s e targets , but whose HbA1c is inappropriately high and postprandial hyperglycemia is suspected.

• In patients with type 1 or type 2 diabetes treated with glucose-lowering agents aimed mainly to reduce PPG. PPG monitoring may be useful for dose titration of these medications. In these patients monitoring also helps to confirm patients’ response to the drug.

• Monitoring helps to evaluate the effect of changes in nutrition or exercise patterns.

Recommendations

• SMBGwithappropriatepatiente d u c a t i o n i s e f f e c t i ve f o r detecting and managing PPHG. (Level C).

III. Non-pharmacological Therapy

Apart from pharmacological a p p r o a c h e s f o r a c h i e v i n g better control of PPG, few non-pharmacological strategies are also beneficial. Regular physical exercise and proper dietary measures are associated with optimal control of post-prandial glucose levels. Evidences exist to support the significance of these approaches in diabetes management.

a. Physical Activity: Physical

e x e r c i s e h e l p s t o a t t a i n glycemic control by virtue of its sensitization effect on insulin. Exercise also affects the glucose uptake stimulation regardless of the insulin action. There is evidence that postprandial exercising has a more potent effect in reducing glucose levels while the effect of exercise performed in the fasting state is relatively insignificant on fasting glycemia.

Effect of exercise was studied in 10 sedentary men wi th type 2 diabetes treated with oral agents. Their fasting and post-meal plasma glucose was not significantly different at the beginning of exercise (12.4 ± 1 .3 vs 11.1 ± 1 .1 mmol/L respectively). However, post meal plasma glucose levels reduced signif icantly after exercise (7.6 ± 1.1 mmol/L) compared with the fasting state (10.0 ± 1.0 mmol/L; P = 0.009). Insulin levels were higher at the beginning of the exercise bout performed in the fed state (177 ± 26 vs 108 ± 19 pmol/L; P < 0.05) and during exercise. Increased levels of insulin after meal probably suppressed glucose production resulting in beneficial post-meal glucose levels in the fed state unlike the fasted state where insulin levels did not increase.38

Postprandial high intensity exercise reduces both glucose concentrat ions and insulin secretion. The beneficial effects of exercise on PPG homeostasis are more related to the total energy expenditure than to the peak of exercise intensity.394 min at 98.3 ± 5.1 % V.(O2

T h e p h y s i c a l a c t i v i t y i s c o n s i d e r e d a s o n e o f t h e mainstays in type 2 diabetes mellitus treatment. Appreciable amount of energy expenditure with one hour aerobic exercise after meal helps to control post-prandial hyperglycemia.

b. D i e t a r y M o d i f i c a t i o n : C a r b o h y d r a t e s a r e t h e m o s t c o m m o n d i e t a r y component in postprandial g lycemic excurs ion. Other m a c r o n u t r i e n t s c a n a l s o i n f l u e n c e t h e g l y c e m i c excursion, such as dietary fiber content and fats, which decrease glucose absorption. The postprandial glycemia d e p e n d s o n t h e a m o u n t and type of carbohydrates ingested.40 Most of the modern s t a r c h - r i c h f o o d s h a v e a relatively high glycemic index (GI), including potatoes, white and brown bread, r ice and breakfast cereals.41 Foods with a lower GI (legumes, and most fruits) contain starches and sugars those are less glycemic by nature (e.g. fructose, lactose) and take more t ime to get digested and absorbed. The product of the carbohydrate content of the diet and i ts average GI is termed as dietary glycemic load (GL). GL has been applied as a “global” estimate of post-meal glycemia and insulin demand. The GI and GL of individual foods have been reliable measures to predict how a mixed meal would af fec t postprandia l glucose and insulin levels.42,43 The use of GI can provide a n a d d i t i o n a l b e n e f i t f o r diabetes control apart from carbohydrate counting.44

Traditional Indian diets are carbohydrate-rich; sometimes, a s h i g h a s 8 0 % o f t h e macronutrient composition comes from this proximate p r i n c i p l e . T h e h i g h e r glucose load in the Indian diet leads to greater prandial glycemic excursion, increased g l u c o s i d a s e a n d i n c r e t i n activity in the gut which leads to higher lipemic peaks and a s s o c i a t e d c a r d i o va s c u l a r disease.45

An Indian trial was conducted upon T2DM patients. These


were treated with low glycemic diet and acarbose 50 mg thrice daily which was reduced to a maintenance dose of 25 mg thrice daily. An average decline of 4.7 mmol/l was reported in post-prandial blood sugar (PPBS) in 85% of cases. Thus the low glycemic diet apparently promotes the decline in PPBS in larger number of cases with lower dosage of acarbose.46

D i e t s r i c h i n h i g h G I c a r b o h y d r a t e s p r o d u c e postprandial hyperglycemia and assoc ia ted CVD. Low carbohydrate diet accompanied w i t h p h a r m a c o l o g i c a l intervention reduces post-meal glucose levels.

Recommendations

• F o r i n d i v i d u a l s w i t h I G T or type 2 diabetes, lifestyle modification should form the basis of PPHG management strategy. (Level D)

• Medica l nutr i t ion therapy ( M N T ) , p h y s i c a l a c t i v i t y and weigh t reduc t ion are t h e c o r n e r s t o n e s o f n o n -pharmacolog ic therapy in patients with type 2 diabetes. (Level D)

• M N T s h o u l d i n c l u d e t h e following

• D iabe t i c pa t i en t mus tingest 45-65% of their total caloric intake in the form of carbohydrates, with a minimum of 130 g/day for adults. (Level D)

• Increase in take o f lowglycemic index foods such as hand pounded brown rice. (Level D)

• Substitution of saturatedfat for unsaturated fat (for instance, cold water fish, olive oil, etc). (Level D)

• I n c r e a s e i n t a k e o fs o l u b l e a n d i n s o l u b l e f iber consumption, and c o n s u m p t i o n o f f r u i t and vegetables instead

of refined carbohydrates. (Level D)

• Modificationofthepopularand staple food items to provide adequate calories, proteins, fiber etc. (Level D)

• Encourageintakeofpulsessuch as Bengal gram (Cicer arietinum) or channa dal, urad, moong, masur, matar because of the presence of complex carbohydrates, having in general relatively low GI and conta ining substantial protein, fibre and calorie content. (Level D)

• Pulsesneedtobeacceptablycooked in the form of chapattis or parathas which the patients are habituated to take during principal meals instead of wheat and rice preparations. (Level D)

• P a t i e n t s s h o u l d b eencouraged to increase physical activity. (Level D)

• Patients should be instructed,supported, and motivated to make the necessary changes to successful ly implement a n a p p r o p r i a t e l i f e s t y l e intervention. (Level D)

IV. Pharmacotherapy

Drugs target ing post-meal hyperglycemia are essential to control the post prandial glucose level. These drugs may be used in combination or as a monotherapy.47 Repaglinide and glyburide are known to have di f ferent e f f i cacy on postprandial hyperglycemia, o n c a r o t i d i n t i m a - m e d i a thickness (CIMT).

Therapies which are available for managing PPG include alpha-glucosidase inhibitor (AGI), Glinides, short-acting sulfonylureas (SU), rapidly acting human insulins or insulin analogues and biphasic (pre-mixed) insulins or analogues, dipeptidyl peptidase-4 (DPP4)

inhibitors, and glucagon-like peptide (GLP -1) derivatives.

Oral Antidiabetic Drugs (OADs) and Control of PPHG

i. M e t f o r m i n : E f f e c t o f m e t f o r m i n w a s s t u d i e d against prandial secretagougue repaglinide in non-obese T2DM patients. Metformin reduced postprandial levels of glycemia, triglycerides and free fatty acids (FFA) similarly compared to repaglinide. Furthermore, metformin reduced fasting and postprandial cholesterolaemia and insulinaemia compared with repaglinide.48

M e t f o r m i n c a n p l a y a n important role in non-obese patients with T2DM targeting f a s t i n g a n d p o s t p r a n d i a l glucose and lipid metabolism.

ii. S u l f o n y l u r e a s ( S U s ) a n d glinides: Use of traditional secretagogue SUs is associated with unwanted hypoglycemia in diabetic patients especially i n e l d e r l y . H y p o g l y c e m i a occurs due to lengthy plasma half-lives, prolonged drug-receptor in terac t ions , and active metabolites or due to insufficient renal clearance. R e p a g l i n i d e b e l o n g s t o m e g l i t i n i d e g r o u p , w h i l e nateglinide is an amino acid derivative of phenylalanine. They stimulate a rapid but short-lived (for 1-2 hours) release of insul in from pancreat ic ß-ce l l s . Sul fonylureas and glinides are effective in the stages of type 2 diabetes when β-cellmassisstillsufficienttosecrete appropriate amounts of insulin. Due to their short-lived secretogogue property they do not produce hypoglycemia.

G l i n i d e s h a v e a m u c h s h o r t e r a c t i o n o f o n l y a few hours compared wi th sulfonylureas because of their pharmacokinetic properties. Hypoglycemia occurs with the glinides, but some studies report a lower incidence of


hypoglycemia compared with sulfonylurea therapy.49

These agents secrete less insulin several hours after the meal. When taken at meal t imes , t h e y a t t e n u a t e p o s t - m e a l plasma glucose excursions and decrease the risk of post-meal hypoglycemia.

iii. Alpha-Glucosidase Inhibitor ( AG I ) : A G I s d e l a y t h e absorption of carbohydrates from the gastrointestinal tract, thereby l imiting post-meal plasma glucose excursions. S p e c i f i c a l l y , t h e y i n h i b i t α-glucosidases located in thebrush border of the proximal small intestine that breaks d o w n d i s a c c h a r i d e s a n d more complex carbohydrates. A c a r b o s e , m i g l i t o l a n d voglibose are commercially available AGIs.

AGIs have favorable effect on PPG, FBG and HbA1c which reflect the overall improvement i n g l u c o s e c o n t r o l o f t h e patients AGIs could be used effectively to control PPHG and provide additional benefits. Evidences exist in favour of two of the AGIs: Acarbose and Voglibose to support their benefits in PPG control.

Acarbose The Cochrane Library lists 143

published placebo-controlled trials that have evaluated the efficacy of acarbose on HbA1c, fasting and postprandial blood glucose. In this meta-analysis, acarbose specifically reduced postprandial hyperglycemia with an average reduction of HbA1c by 0.8%50 uncontrolled b y d i e t a r y i n t e r v e n t i o n

alone, increase around the world. Therapeut ic agents that target the early stages of type 2 diabetes, such as the α-glucosidaseenzymeinhibitora c a r b o s e , w h i c h r e d u c e s postprandial hyperglycaemia and hyperinsulinaemia, now have a more prominent role to play in diabetes management in view of increasing evidence that the postprandial state is an important contributing factor to the development of atherosclerosis. This review provides an update on the role of acarbose in present-day diabetes care. Acarbose is a first-line treatment for newly d iagnosed pa t ien ts with type 2 diabetes, those who have high postprandial blood glucose and for patients where dietary treatment alone provides inadequate glycaemic control. Acarbose lowers blood glucose when administered a s m o n o t h e r a p y a n d i n combination with other oral antidiabetic drugs. It reliably reduces levels of g lycated haemoglobin (HbA1c).

A d d i t i o n o f a c a r b o s e t o metformin, sulphonylurea, or insulin shows significant benefit on HbA1c (Table 2) and body weight reduction.

An open-labeled, multicenter s tudy compared the ef fect of acarbose in combination t h e r a p y w i t h m e t f o r m i n . Combination group exhibited a decrease of 91.43 ± 28.65 mg/dl in PPBG from baseline compared to 48 .20 ± 32 .72 mg/dl decrease in metformin group. Combination reduced

the HbA1c by almost 1.76% while metformin alone reduced it by around 1.06%. FBG was decreased by 45.30 ± 15.30 mg/dl from baseline in acarbose plus metformin group while metformin alone reported a reduction of decrease of 27.76 ± 22.91 mg/dl in PPBG.51

Miglitol M i g l i t o l i s a f i r s t

p s e u d o m o n o s a c c h a r i d e alpha-glucosidase inhibitor. It effectively lowers postprandial peak plasma glucose levels thus improves glycemic control. In a systemic review conducted by Scott et al, it was shown that miglitol significantly reduce post prandial glucose levels. In a study, it was observed that miglitol and sitagliptin treatment resulted in similar glycemic control.52 Another study provided the evidence of beneficial effect of miglitol o n e n d o t h e l i a l f u n c t i o n established by postprandial RHI improvement (p=0.007) as a result of control of PPHG. Significant inverse correlation w a s f o u n d b e t w e e n t h e postprandial change in RHI and postprandial fasting-to-60-minutes surge in glucose (r =−0.382,p=0.009).53

Voglibose 1780 patients with impaired

g l u c o s e t o l e r a n c e w e r e randomly assigned to oral voglibose 0.2 mg thrice daily or placebo in a multicentre, double-blind, parallel group trial . Patients treated with voglibose had a lower risk of progression to type 2 diabetes than placebo (50 of 897 vs 106 of 881; hazard ratio 0.595, 95% CI 0.433-0.818; p=0.0014). More people in the voglibose group achieved normoglycemia than those in the placebo group (599 of 897 vs 454 of 881; 1.539, 1.357-1.746; p<0.0001).54

Of all three clinically used A G I s , a c a r b o s e p r o d u c e d

Table 2: Reduction of HbA1c and PPBG in long-term studies with acarbose in combination with oral hypoglycemic agents (OA), sulphonylureas (SU) or metformin (MF)

Study Combination N HbA1c PPBGReduction p-value Reduction

(mg/dl)p-value

Halimi et al77 MF 152 0.90 <0.0001 45 <0.0001Lindstrom et al53 OA 72 0.90 <0.002 48.6 <0.001Holman et al78 MF/SU/Insulin 1,946 0.50 <0.001


most favourable results for cardiovascular benef i t s in controlled studies and long-term clinical investigations. Indian diet has a more carbohydrate load thereby increasing the odds of post-meal glucose and lipid excursions. So the roles of AGIs that inhibit carbohydrate absorption from gut become even more crucial in Indian settings.

iv. GLP-1-based Therapy

GLP-1 is an incretin hormone secreted from the gut that lowers glucose through its ability to stimulate insulin secretion, inhibit glucagon secretion, decelerate gastric emptying and induce satiety. Patients with type 2 diabetes have diminished abil i ty of insulin secretion in response to meal which is called as the incret in effect . This defect c a n b e a t t e n u a t e d b y t h e administration of exogenous GLP-1 analogues or GLP-1 r e c e p t o r a g o n i s t s . G L P - 1 derivatives diminish post-meal glucose excursions with a low risk of hypoglycemic episodes. GLP-1 receptor agonists are peptides that use GLP-1 action and can be used as an injectable therapy in type 2 diabetes. Exenat ide and l i rag lu t ide are currently commercially available GLP-1 analogues.

Exenatide Exenatide has been effective in

lowering A1C in patients failing oral therapy with metformin and/or sulfonylurea.55 There may be enhancement of post-prandial glucose control and some diminution of fasting glucose control with shorter a c t i n g G L P - 1 r e c e p t o r agonist (exenatide twice daily) compared to longer-act ing a g o n i s t ( e x e n a t i d e o n c e - weekly, liraglutide).56

Exenatide can be advantageous f o r p a t i e n t s w h e r e hypoglycemic episodes and

insul in therapy associated increase in body weight is not desirable.57,58

Liraglutide In the LEAD trials, treatment

with liraglutide was associated with substantial improvements i n g l y c e m i c c o n t r o l a n d low r isk of hypoglycemia. Liraglutide was also shown to be effect ive at reducing postprandial glucose (PPG); consistent reductions were observed in peak PPG (across all three meals) in the LEAD-1-5 studies). In addition liraglutide significantly improved β-cellfunct ion, reduced systo l ic blood pressure and induced weight loss. Overall, liraglutide was well tolerated.59

G L P - 1 a n a l o g u e s c o n t r o l postmeal hyperglycemia by stimulating insulin secretion in response to meals. They are not associated with risk of hypoglycemia or insulin associated increase in body weight.

v. DPP-4 inhibitor

D P P - 4 i n h i b i t o r s a c t b y inhibiting the DPP-4 enzyme which degrades GLP-1, thereby increasing the act ive form of the hormone. This in turn stimulates glucose-dependent i n s u l i n s e c r e t i o n a n d suppresses glucagon release. DPP-4 inhib i tors decrease post-meal glucose and improve H b A 1 c w i t h o u t c a u s i n g h y p o g l y c e m i a . C u r r e n t l y , l i n a g l i p t i n , s a x a g l i p t i n , sitagliptin and vildagliptin are commercially available DPP-4 inhibi tors in India . DPP-4 inhib i tors are e f fec t ive in early stages of type 2 diabetes, either as monotherapy or in combination with metformin or other oral agents for type 2 diabetes. They do not change the body weight and have no intrinsic risk for hypoglycemic episodes.

Sitagliptin

E f f i c a c y a n d s a f e t y o f sitagliptin as an add-on to metformin therapy in patients w i t h m o d e r a t e l y s e v e r e type 2 diabetes mellitus was s t u d i e d i n a r a n d o m i z e d controlled trial . Sitagliptin was administered as 100 mg once daily dose for 18 weeks. The combination significantly reduced HbA1c, FPG, and 2 - h P P G , c o m p a r e d w i t h placebo. HbA1c was reduced by 1.0% in the combination group. 22.1% patients in the t rea tment group achieved HbA1c levels of lesser than 7.0% compared to only 3.3% in placebo. No change in body weight, neither hypoglycemic nor gastrointestinal episodes were reported.60

Saxagliptin In a similar 24-week safety

and efficacy study, saxagliptin was used as 2.5, 5, or 10 mg once dai ly in combinat ion with metformin. Combination therapy significantly decreased HbA1c, FPG and PPG. PPG AUC was reduced by 8,891, 9,586, and 8,137 from baseline, with three doses respectively. Metformin alone demonstrated a m e a n c h a n g e o f - 3 , 2 9 1 mg.min/dl). β-Cell functionand postprandial C-peptide, insulin, and glucagon AUCs improved in all saxagliptin treatment groups at week 24. Effects on body weight and incidences of hypoglycemia w i t h s a x a g l i p t i n w e r e comparable to placebo group.61

Objective: This 24-week trial assessed the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes wi th inadequate g lycemic control with metformin alone.

Research Design and Methods: This was a randomized, double-blind, placebo-controlled study of saxagliptin (2.5, 5, or 10 mg once daily).

Linagliptin


T o a s s e s s t h e e f f e c t o f linagliptin on PPG, 67 patients were treated with linagliptin and were compared against p l a c e b o g r o u p . A m e a l tolerance test was performed 30 minutes after study drug dosing administration. After 24 weeks, treatment group showed a placebo adjusted mean change of -3.2 mmol/l in 2-h postprandial glucose from baseline62 randomized, parallel group, phase III study compared linagliptin treatment (5 mg once daily, n = 336).

Vildagliptin Vildagliptin has been examined

when used in monotherapy (50 mg once daily) for 52 weeks in subjects with type 2 diabetes w i t h m i l d h y p e r g l y c e m i a ( H b A 1 c 6 . 2 – 7 . 2 % ) . W h e n a d j u s t e d f o r p l a c e b o , vildagliptin reduced HbA1c by 0.3%. The study was followed by a 52-week extension period in 131 patients. Following the 2-year period in these patients, HbA1c was reduced by 0.5% by the use of vi ldaglipt in. F i n a l l y , i n s u b j e c t s w i t h impaired glucose tolerance (IGT), treated for 12 weeks with vildagliptin at 50 mg once daily (n = 90) versus placebo (n = 89), vildagliptin improved glycemia as was evident by the reduced prandial glycemia fo l lowing a tes t meal . 63 A subgroup analysis by Bosi et. al in 2009 demonstrated a HbA1c reduction of 1.1.% (p<0.01 vs. placebo) from a baseline HbA1c of 8.7% with vildagliptin 50mg BID 64 randomized, double-blind, active-controlled study. Treatment-naive patients with T2DM who had a glycated haemoglobin (HbA(1c

D P P - 4 i n h i b i t o r s w h e n used in combinat ion wi th m e t f o r m i n e x h i b i t b e t t e r post-meal glycemic control without causing hypoglycemic episodes, body weight gain or gastrointestinal complications.

vi. Insulin

The goal of insulin therapy in both type 1 and type 2 DM is to mimic endogenous insulin as closely as possible thereby reaching the target HbA1c levels. Insulin therapy also aims to avoid the common side effects of antidiabetic therapies like hypoglycemia and gain in body weight. Genetically engineered human insulin is a new class of therapeutic agents known as insulin analogues. More than 300 short, moderate or long-acting analogues have been studied but few are used clinically. Evidences suggest that those analogues provide several benefits over traditional h u m a n i n s u l i n i n c l u d i n g improved physiologic profile, reduced risk of hypoglycemia and less weight gain. Analogues support physiological insulin profile more effectively than does the conventional insulin therapy.65

Rapid-acting Insulin Analogues T h e f a s t - a c t i n g i n s u l i n

analogues were developed to mimic the physiological insulin response after a meal with a better action profile than regular human insulin a n d c a n a l s o b e u s e d f o r prandial insulin therapy.66the new insulin analogues aim to eliminate these limitations. Five insulin analogues are commercially available and approved for individuals with type 1 diabetes: three rapid-acting (insulin lispro, insulin aspart and insulin glulisine Tw o r a p i d - a c t i n g i n s u l i n analogues, insulin Lispro and insulin Aspart, are already in the market, while a third one, insulin Glulisine, has recently obtained approval from the FDA. Rapid-act ing insul in a n a l o g u e s c l o s e l y m a t c h normal insulin patterns. Rapid acting analogues have faster absorption after subcutaneous administration and reach a

peak concentration about 1 h after injection. There are various advantages of using Rapid-acting Insulin analogues for PPG control.

• Faster onset of action• H i g h e r p e a k i n s u l i n

concentrat ion around high PPG values

• Mimic physiologic insul in profile (1st and 2nd Phase)

• Improved PPG control• Improved HbA1c• Lower weight gain• Lower risk of late hypoglycemia T h e r a p i d - a c t i n g i n s u l i n

analogues should be injected 5 to 15 minutes before a meal. However , in in fants or in older adults with dementia who both have unpredictable eating patterns, rapid-acting analogues can be administered after the meal without excessive d e t e r i o r a t i o n o f g l y c e m i c control.

Insulin Aspart E f f e c t o f a n i m m e d i a t e l y

pre-meal injection of insulin Aspart on postprandial glucose was studied against human insulin injected immediately or 30 minutes before a test meal in insulin-treated type 2 diabetic pat ients . Pat ients t reated with Aspart demonstrated a s i g n i f i c a n t l y i m p r o v e d postprandial glucose control and a significantly smaller postprandial blood glucose excurs ion (899 ± 609 (SD) mmol/l min) versus (1102 ± 497 mmol/l. min) in patients treated with human insulin. Immediate pre-meal administration of insul in Aspart resul ted in i m p r o v e d p o s t p r a n d i a l glucose control compared to regular human insulin injected immediately before the meal, with no concerns about safety.67

D o u b l e d u m m y c r o s s o ve r d e s i g n , p a t i e n t s a t t e n d e d three study days where the following insulin injections in


combination with placebo were given in a random order: IAsp (0.15 IU/kg body weight).

Insulin Lispro I n s u l i n l i s p r o i m p r o v e s

postprandial control, reduces hypoglycemic episodes, and improves patient convenience, compared with regular human insulin, in IDDM patients . Anderson et al . found that m e a l t i m e t h e r a p y w i t h lispro reduced postprandial hyperglycemia compared with regular human insulin therapy, and that it may decrease the rate of mild hypoglycemic episodes in patients with type 2 diabetes.68 An insulin analog recently developed particularly for meal t ime therapy, has a fast absorption rate and a short duration of action. We compared insulin lispro and regular human insulin in the mealtime treatment of 1,008 patients with IDDM. The study was a 6-month randomized multinational (17 countries).

Feinglos et al showed that using insulin lispro in combination w i t h a s u l f o n y l u r e a a t mealtime, not only reduced 2 - h p o s t p r a n d i a l g l u c o s e excursions, but also reduced both fasting glucose and A1C levels. 2-hour PPG was reduced from 18.6 to 14.2 mmol/l in combination group compared w i th su l fonylureas a lone . FPG levels were decreased from 10.9 to 8.5 mmol/l, and HbA1c values were reduced from 9.0 to 7.1%. Subjects in the lispro group also benefited from significantly decreased total cholesterol levels and improved HDL cholesterol concentrations.69

Insulin Glulisine C o m p a r e d w i t h r e g u l a r

h u m a n i n s u l i n , g l u l i s i n e has a more rapid onset of action and shorter duration of effect , affording greater flexibility in the timing and

content of meals. In a single-d o s e , r a n d o m i z e d , s t u d y , subjects received subcutaneous inject ions of ei ther insulin glulisine or human insulin p r e m e a l . P o s t p r a n d i a l baseline-subtracted maximum blood glucose excursion was reported in glulisine as 65 mg/dl compared with 89 mg/dl in human insulin. Postprandial baseline-subtracted maximum blood glucose concentration was 180 vs. 209 mg/dl.70

v. Combination therapy

Many oral agents successfully lower both FPG and PPG levels but may lose their effectiveness over time. Thus combinations of agents with complementary mechanisms of act ion may p r o v i d e b e t t e r c o n t r o l o f FPG and PPG levels. These combinations include agents that specifically target PPG including AGIs, short-acting insulinotropic agents, amylin analogues, GLP-1 analogues, DPP-4 inhibitors, and rapid-acting insulin analogues.

Proposed Recommendations

• In view of its myriad benefits and its relatively benign side e f f e c t p r o f i l e , m e t f o r m i n remains the first-line therapy for most cases of type 2 diabetes irrespective of its effect on PPHG. (Level A)

• A l l a n t i d i a b e t i c d r u g r e g i m e n s s h o u l d i n c l u d e metformin unless specifically contraindicated. (Level A)

• G l i n i d e u s e i s n o w limited to the treatment of PPHG if sulfonylureas are contraindicated and in patients who cannot afford or are not otherwise candidates for the newer agents.

• AGIs can be used as first-line drug in early type 2 diabetes, as well as in combination with nearly a l l establ ished oral antidiabetic and insulin. (Level A)

• Advice to patients to overcome difficulties with AGIs

• Startlow,goslow • P r e f e r nu t r i en t s w i t h

complex carbohydrates (r ice, pasta, ful l bread, vegetables, fruits)

• A v o i d r e f i n e dc a r b o h y d r a t e s ( s u g a r , sweets)

• Takeonlythreemeals • Avoid laxatives, such as

sugar alcohols (sorbitol) • I n m o s t c a s e s

g a s t r o i n t e s t i n a l s i d e -effects are transient

• RapidactinginsulinAnalogues • P r o v i d e g r e a t e r

convenience due to flexible t iming of injections, so these are very useful in sick and hospitalised patients. (Level A)

vi. PPG management in pregnancy

In diabetic pregnant women t h o s e r e q u i r e i n s u l i n ; controlling PPG has resulted in bet ter g lycemic control t h a n c o n t r o l l i n g F P G . C o n t r o l l i n g p o s t p r a n d i a l blood glucose values further reduces chances of neonatal hypoglycemia, macrosomia, and cesarean delivery. A 2 hours post-meal blood glucose m o n i t o r i n g i s s u g g e s t e d by Seshiah et a l , a l though di f ferent s tudies advocate varied intervals of 1 hour, 1.5 hours and 2 hours. Indian guidelines further recommend that management of GDM should encompass MNT, OHDs and insulin.71

In a s tudy that compared preprandial and postprandial monitoring of glycemic control in women with gestational diabetes, 33 women those who had PPG control indicated by lower HbA1c levels, gave birth to babies with lower weights, lower risk of neonatal hypoglycemia, and were less


l ikely to undergo cesarean section compared to other 33 women randomly assigned to FPG control.72 Weight gain during pregnancy, gestational age at the diagnosis of diabetes and at del ivery, degree of compliance with therapy, and degree of achievement of target blood glucose concentrations w e r e s i m i l a r i n t h e t w o groups. The Diabetes in Early Pregnancy Study showed that high birth-weight was closely c o r r e l a t e d w i t h t h e t h i r d trimester postprandial glucose levels.73 It recruited insulin-dependent diabetic and control women before concept ion, p r o v i d e d a n o p p o r t u n i t y to address the relationship between maternal glycemia and percentile birth-weight. D a t a we r e a n a l y z e d f r o m 323 diabetic and 361 control women. Fasting and nonfasting venous plasma glucose were measured on alternate weeks in the first trimester and monthly t h e r e a f t e r . G l y c o s y l a t e d hemoglobin was measured weekly in the first trimester and monthly thereafter. More infants of the diabetic women were at or above the 90th percenti le for birth-weight than infants of control women (28.5% versus 13.1%, p less than 0.001

Bet ter g lycemic control in p a t i e n t s w i t h G D M w a s associated with reduced risk of neonatal hypoglycemia. Demarini et al studied two groups of pregnant women with different target levels o f p o s t p r a n d i a l g l u c o s e . In 68 women the target 1.5 hour PPG level was less than 120 mg/dL (s t r ic t control ) a n d l e s s t h a n 1 4 0 m g / d l (customary control). Infants in the str ict control group had a significantly lower rate of hypocalcemia than infants in the customary control group.74

Physical activity in pregnant

women wi th d iabe tes has shown to assist in achieving better PPG levels. The ADA r e c o m m e n d s wa l k i n g f o r 10 minutes after each meal t o i m p r o v e P P G c o n t r o l significantly in such patients.

Evidences suggest that strict postprandial glycemic control in patients with GDM correlates with lower risk of macrosomia, n e o n a t a l h y p o g l y c e m i a , neonatal hypocalcemia and w i t h r e d u c e d c h a n c e s t o undergo cesarean surgery. Strict control in third trimester has the most potent effect on fetal body weight. Furthermore, physical activity also helps to reduce PPG levels.

Proposed Recommendation

• PPGratherthanFPGshouldbeused to guide management in pregnant women with GDM, requir ing insul in therapy. (Level D)

• Post-mealmonitoring shouldbe performed 2 hours after meal intake. (Level D)

• Al l GDM pa t i en t s shou ldreceive nutritional counseling. (Level D)

• Me t fo rmin a l one o r w i thsupplementation with insulin is preferred. (Level D).

• Premix insulin (30/70) to bein i t ia ted at 4 uni ts before breakfast and to be increased by 2 units till 10 units. (Level D)

• Rapidactinginsulinanaloguesshould be considered if PPG is still uncontrolled. (Level D)

Conclusion

PPG is an independent risk factor of cardiovascular complications in diabetes patients and a better predictor of glycemic control than the FPG. Patients who are seemingly well controlled with diet, exercise, and medical therapy, even those with normal FPG and HbA1c could have uncontrolled PPHG. The combinat ion of improved

detection and monitoring of PPG along with effective medications may help to establish optimal glycemic control thereby reducing diabet ic complicat ions. SMBG provides information on glucose excursions in response to daily e v e n t s , m e a l s , m e d i c a t i o n s , exercise, and illness hence it may complement information provided by HbA1c. To real ize the ful l potential of SMBG, patients must be educated on how and when to monitor and what steps to take in response to high or low blood sugar levels. Severe hypoglycemia is a challenge in primary care settings. It can however be managed in most patients with type 2 diabetes t h r o u g h s t r a t e g i c a l l y u s e d therapeutic options, in combination with appropriate blood glucose m o n i t o r i n g r e g i m e n s a n d comprehensive patient education. Therefore, the ideal treatment for patients with type 2 diabetes should include a combination of agents that lower basal plasma glucose levels and agents that control meal-related glucose excursions. The success in maintaining the glycemic and perhaps, the lipid excursion must be acknowledged as the therapy target. Most available treatments reduce fasting glycemia, but have a lesser effect on the postprandial glucose excursions. The availability of new agents directed at the postprandial state as the aforementioned ones, leads to the possibility of better long-term management of patients with type 2 diabetes, aiding in the prevention of the high morbidity-mortality associated to diabetes, especially cardiovascular disease.Acknowledgement

We thank WorkSure for their suppor t and medica l wr i t ing a s s i s t a n c e i n d e ve l o p i n g t h e guideline.

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