Ajd July-September 2013 by IJCP

www.ijcpgroup.com

RNI NO. - 71334/99

ISSN 0972-7043

The Asian Journal of

Diabetology January-March July-September 20132013

VOLUME VOLUME13, 16,NUMBER NUMBER23

xxxxxxxxxxxxxxxxxxxxxxxxx Newer Hypolipidemics on the Block xxxxxxxxxxxxxxxxxxxxxxxx

Age group

30-39 40-49 50-59 60-69

38.75

Prevalence

35 30 25 20 15 10 5 0

18.75 11.25 7.5 6.25 3.75

MS3

13.75 6.25

2.5

1.25

MS4

10 6.25 1.25

MS5

Total MS

7.5 3.75 1.25

No MS

xxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxx Gastrointestinal Complications of Diabetes xxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxx Patterns of Extended Lipid Profile Abnormalities in Freshly Diagnosed Myocardial Infarction Patients xxxxxxxxxxxxxxxxxxxxxxxxx of Bundelkhand Region

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xxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxx

Corneo-scleral Melting in a Diabetic Patient

Dr Vijay Viswanathan Editor

Dr KK KK Aggarwal Aggarwal Dr Group Editor-in-Chief Group Editor-in-Chief

The Asian Journal of

DIABETOLOGY

IJCP Group of Publications

Volume 16, Number 3, July-September 2013

Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor

FROM THE DESK OF GROUP EDITOR-IN-CHIEF

Dr Deepak Chopra Chief Editorial Advisor Padma Shri and Dr BC Roy National Awardee

Dr KK Aggarwal Group Editor-in-Chief

Elderly New-onset Diabetes: A New Sub Group of Diabetes

KK Aggarwal

Dr Veena Aggarwal MD, Group Executive Editor Anand Gopal Bhatnagar Editorial Anchor

IJCP Editorial Board

IJCP Editorial Board Obstetrics and Gynaecology Dr Alka Kriplani Dr Thankam Verma, Dr Kamala Selvaraj Cardiology Dr Praveen Chandra, Dr SK Parashar Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses, Dr Sidhartha Das Dr A Ramachandran, Dr Samith A Shetty ENT Dr Jasveer Singh Dr Chanchal Pal Dentistry Dr KMK Masthan Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar Dr Rajiv Khosla Dermatology Dr Hasmukh J Shroff Dr Pasricha Dr Koushik Lahiri Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan Dr Vineet Suri Journal of Applied Medicine & Surgery Dr SM Rajendran, Dr Jayakar Thomas Orthopedics Dr J Maheshwari Advisory Bodies Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

REVIEW ARTICLE 6

Newer Hypolipidemics on the Block

Princy Louis Palatty, Manasa M, Apoorva Naik, Archana Kaveri B, Bhavishya Kirthi Anna Walder, Manohar Prabu, Manjeshwar Shrinath Baliga

14 Gastrointestinal Complications of Diabetes

Amer Shakil, Robert J. Church, Shobha S. Rao

CLINICAL STUDY 20 Patterns of Extended Lipid Profile Abnormalities in Freshly Diagnosed Myocardial Infarction Patients of Bundelkhand Region

Deep Chandra Pant, Hema Pant

CASE REPORT

Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Ltd. and Published at E - 219, Greater Kailash, Part - 1 New Delhi - 110 048 E-mail: editorial@ijcp.com

27 Corneo-scleral Melting in a Diabetic Patient

Joginder Pal Chugh, Prachi Jain, Rajender Singh Chauhan, Ashok Rathi

Printed at New Edge Communications Pvt. Ltd., New Delhi E-mail: edgecommunications@gmail.com ÂŠ Copyright 2013 IJCP Publications Ltd. All rights reserved. The copyright for all the editorial material contained in this journal, in the form of layout, content including images and design, is held by IJCP Publications Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.

CLINICAL ALGORITHM 31 Algorithm for Management of Type 2 Diabetes Mellitus

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LIGHTER READING 32 Lighter Side of Medicine

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Elderly New-onset Diabetes: A New Sub Group of Diabetes

lderly patients with new-onset diabetes and poor sugar control (HbA1C of 7.5% or higher) are linked with increased mortality risk. There is no U-shaped risk pattern, unlike that reported for elderly patients with long-standing diabetes.

In a study published in July edition of Diabetes Care, patients with the highest levels of HbA1C also were least likely to undergo a coronary revascularization procedure. The findings are totally different from the results in elderly with long-standing diabetes. The researchers conducted a retrospective observational study of data from a cohort of 2,994 individuals (48% males) living in the Sharon-Shomron District, Israel, who were insured by a large provider. The study subjects were 65 years or older when they were newly diagnosed with diabetes in 2003 or 2004. The patients were assumed to have type 2 diabetes, since type 1 diabetes is very rare at this age and only 0.1-3% of the patients were receiving insulin therapy. The patients were followed for seven years or until they reached a study outcome: Coronary revascularization - percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) - or mortality. At baseline, patients had a mean age of 75.6 years. They were stratified into four groups, based on their average HbA1C levels during follow-up: < 6.5% (n = 1580), 6.5-6.99% (n = 611), 7-7.49% (n = 367), and â&#x2030;Ľ 7.5% (n = 436). During a mean follow-up of 5.54 years, 1,173 participants (39.17%) died. All-cause mortality rates were 41%, 32%, 36% and 46%, in the four groups. Compared with participants in the group at lowest risk of dying (those with an average HbA1C level of 6.5-6.99%), patients in the group with the highest HbA1C levels (>7.5%) had a significant increased mortality risk.

These findings differ from a previous large, retrospective cohort study of patients older than 50 who had longstanding diabetes and intensive hypoglycemic treatment, where researchers reported finding a U-shaped risk pattern and an HbA1C level of about 7.5% was associated with the lowest all-cause mortality (Lancet. 2010;375: 481-489). The difference in mortality patterns between our finding and the aforementioned study underscores the need to differentially treat elderly patients with new-onset (diabetes) and elderly patients with long-standing disease. During follow-up, 285 participants (9.51%) underwent PCI or CABG. The rate of coronary revascularization was highest in the patients with an average HbA1C level of 6.5-6.99% and lowest in the patients with an HbA1C level of 7.5% or higher. This inverse relationship may be the result of a protective effect of revascularization against mortality, or the patients with the highest levels of HbA1C may have received suboptimal medical treatment for various reasons. (Source: Medscape)

Asian Journal of Diabetology, Vol. 16, No. 3, July-September 2013

REVIEW ARTICLE

Newer Hypolipidemics on the Block PRINCY LOUIS PALATTY*, MANASA M**, APOORVA NAIK†, ARCHANA KAVERI B†, BHAVISHYA KIRTHI ANNA WALDER‡, MANOHAR PRABU‡, MANJESHWAR SHRINATH BALIGA¶

ABSTRACT Hypolipidemics, are much widely used in the present day scenario as the sure prophylactic to tackle cardiovascular diseases and stroke, which are leading causes of death across the world. Moreover, hyperlipidemia is not just a metabolic disorder, it also runs in families, making hypolipidemics more important and necessary. Hence, newer and more efficient drugs are being released. The statins and fibrates, especially rosuvastatin and fenofibrate are associated with much fewer complications then their early counterparts. Ezetemibe or orlistat reduce absorption of cholesterol, beclibrinic acid has a unique action. Chinese red yeast rice has a hyoplipidemic action. Our study has explored in detail the status of newer drugs like micronized fenofibrate, 1-methyl-4-piperidyl bis (chlorophenoxy) acetate, lentysine and gugulipid. Keywords: Hypolipidemia, hypercholesterolemia, triacylglycerols, phospholipids, apoproteins, ezetimibe

ardiovascular diseases (CVDs) are the commonest cause of death the world over (27%). Hyperlipidemia is the harbinger of myocardial infarction and stroke, which accounts for 33.6% in Indian diet.1 The incidence of hyperlipidemia is 42.9% in USA and similar in other countries also.2 Reducing incidence of hyperlipidemia would reduce the death followed by CVD. This review addresses the probable available agents that reduce cholesterol and triglyceride levels.

increasing intensity. Some of them include refined low polyunsaturated fatty acid (PUFA), increased use of egg and meat, ‘refined’ low fiber containing carbohydrate stuffs.4 Hyperlipoproteinemias or hyperlipidemias are included under metabolic disorders; vascular or cyclic vomiting syndrome (CVS) disorders are secondary to them.5 Hence, more importance has to be given to these disorders to prevent further complications.

Plasma lipids are transported in complexes called lipoproteins. Metabolic disorders that involve elevations in any lipoprotein species are termed hyperlipoproteinemias or hyperlipidemias. Hyperlipemia denotes increased levels of triglycerides.3

Plasma lipids consist of triacylglycerols (16%), phospholipids (30%), cholesterol (14%) and cholesteryl esters (36%) and a much smaller fraction of unesterified long-chain fatty acids (4%). This latter fraction, the free fatty acids (FFA), is metabolically the most active of the plasma lipids.6

Hyperlipidemia has become one of the most common problems in day-to-day’s life. The sedentary life today has particularly enhanced its risk. It has become a house-to-house disorder, especially in higher middle class and higher societies. Intake of fat and high carbohydrate rich diet style of India has also added to its

*Professor Dept. of Pharmacology **II MBBS †IV MBBS ‡III MBBS ¶Dept of Research and Development Fr. Muller Medical College, Kankanady, Mangalore Address for correspondence Dr Princy Louis Palatty Professor, Dept. of Pharmacology 302, Binany Homes, Kottara, Ashoknagar, Mangalore - 575 006 E-mail: drprincylouispalatty@yahoo.com, drprincylouispalatty@gmail.com

Asian Journal of Diabetology, Vol. 16, No. 3, July-September 2013

LIPID AND LIPOPROTEINS

Because fat is less dense than water, the density of a lipoprotein decreases as the proportion of lipid to protein increases (Table 1). Four major groups of lipoproteins have been identified that are important physiologically and in clinical diagnosis. These are: i) Chylomicrons, derived from intestinal absorption of triacylglycerol and other lipids; ii) very-lowdensity lipoproteins (VLDL or pre-b-lipoproteins), derived from the liver for the export of triacylglycerol; iii) low-density lipoproteins (LDL, or b-lipoproteins), representing a final stage in the catabolism of VLDL and iv) high-density lipoproteins (HDL, or b-lipoproteins), involved in cholesterol transport and also in VLDL and chylomicron metabolism.7 Triacylglycerol is the predominant lipid in chylomicrons and VLDL,

REVIEW ARTICLE Table 1. Composition of Lipoproteins in Human Plasma Lipoprotein

Source

Density (g/ml)

Protein (%)

Lipid (%)

Main lipid component

Apoproteins

Chylomicrons

Intestine

<0.95

1-2

98-99

Triacylglycerol

A-I, A-II, A-IV, B-48, C-I, C-II, C-III, E

VLDL

Liver (intestine)

0.95-1.006

7-10

90-93

Triacylglycerol

B-100, C-I, C-II, C-III

IDL

VLDL

1.006-1.019

Triacylglycerol, cholesterol

B-100, E

LDL

VLDL

1.019-1.063

Cholesterol

B-100

HDL

Liver, intestine, VLDL, chylomicrons

Phospholipids, cholesterol

A-I, A-II, A-IV, C-I, C-II, C-III, D, E

HDL1

1.019-1.063

HDL2

1.063-1.210

HDL3

1.125-1.210

Pre-β-HDL

>1.210

Alb/Free fatty acid Adipose tissue

>1.281

whereas cholesterol and phospholipids are the predominant lipids in LDL and HDL, respectively (Table 1). Lipoproteins may be separated according to their electrophoretic properties into α-, b- and pre-blipoproteins.8 The nonpolar lipid core consists mainly of triacylglycerol and cholesteryl ester and is surrounded by a single surface layer of amphipathic phospholipid and cholesterol molecules. These are oriented so that their polar groups face outward to the aqueous medium, as in the cell membrane.9 The protein moiety of a lipoprotein is known as an apolipoprotein or apoprotein, constituting nearly 70% of some HDL and as little as 1% of chylomicrons. Some apolipoproteins are integral and cannot be removed, whereas others are free to transfer to other lipoproteins.9 TYPES OF APOLIPOPROTEINS Lipids are transported in the plasma as lipoproteins. Apolipoproteins constitute one of the building blocks of lipoproteins, in turn fat. Some of them are A I-IV, B48, B100, CI, II, III… D and E.10 One or more apolipoproteins (proteins or polypeptides) are present in each lipoprotein. The major apolipoproteins of HDL (β-lipoprotein) are designated are described in Table 1. The main apolipoprotein of LDL (β-lipoprotein) is apolipoprotein B (B-100), which is found also in VLDL. Chylomicrons contain a truncated form of apo B (B-48) that is synthesized in the intestine, while B-100 is synthesized in the liver.

A-I Free fatty acid

Apo B-100 is one of the longest single polypeptide chains known, having 4,536 amino acids and a molecular mass of 5,50,000 Da. Apo B-48 (48% of B-100) is formed from the same mRNA as apo B-100 after the introduction of a stop signal by an RNA editing enzyme. Apo C-I, C-II and C-III are smaller polypeptides (molecular mass 7,000-9,000 Da) freely transferable between several different lipoproteins. Apo E is found in VLDL, HDL, chylomicrons and chylomicron remnants; it accounts for 5-10% of total VLDL apolipoproteins in normal subjects.10 Apolipoproteins carry out several roles: i) They can form part of the structure of the lipoprotein, e.g., apo B; ii) they are enzyme cofactors, e.g., C-II for lipoprotein lipase (LPL), A-I for lecithin: cholesterol acyltransferase (LCAT), or enzyme inhibitors, e.g., apo A-II and apo C-III for LPL, apo C-I for cholesteryl ester transfer protein and iii) they act as ligands for interaction with lipoprotein receptors in tissues, e.g., apo B-100 and apo E for the LDL receptor, apo E for the LDL-receptorrelated protein (LRP), which has been identified as the remnant receptor, and apo A-I for the HDL receptor. The functions of apo A-IV and apo D, however, are not yet clearly defined, although apo D is believed to be an important factor in human neurodegenerative disorders.6 FAMILIAL HYPERPROTEINEMIA Lipoproteins are metabolized in liver. Like all other nutrients defect of lipid metabolism also results in

Asian Journal of Diabetology, Vol. 16, No. 3, July-September 2013

REVIEW ARTICLE disorders. These are mainly classified as: i) Hypoor hyperlipoproteinemia ii) primary or secondary disorder. and iii) inherited or acquired. Primary disorders are usually inherited once, while acquired involve abnormal lipoprotein patterns secondary to diseases like diabetes mellitus, hypothyroidism, kidney diseases and atherosclerosis. Secondary patterns are very similar to primary inherited conditions. Virtually all primary conditions are defect at various stages in lipoprotein formation, transport or destruction. All abnormalities are not harmfull.11 FAMILIAL LPL DEFICIENCY (TYPE I) It is a condition of hypertriacylglycerolemia due to LPL deficiency, abnormal LPL or apo C-II deficiency causing inactive LPL (Table 2). Hence, type I is slow clearance of chylomicrons and VLDL, low levels of LDL and HDL and no increased risk of coronary disease.11 FAMILIAL HYPERCHOLESTEROLEMIA (TYPE IIA) Involves defective LDL receptors or mutation in ligand region of apo B-100, causing elevated LDL levels and hypercholesterolemia, resulting in atherosclerosis and coronary disease (Table 2).11 FAMILIAL TYPE III HYPERLIPOPROTEINEMIA It is also called broad-beta disease, or remnant removal disease also called ‘familial dysbetalipoproteinemia’

due to deficiency in remnant clearance by the liver as a result of abnormality in apo E. Patients lack isoforms E3 and E4 and have only E2, which does not react with the E receptor (Table 2).11 FAMILIAL HYPERTRIACYLGLYCEROLEMIA (TYPE IV) Condition with overproduction of VLDL often associated with glucose intolerance and hyperinsulinemia, resulting in rise of cholesterol level with VLDL (Table 2). LDL and HDL tend to be subnormal. This type of pattern is commonly associated with coronary heart disease (CHD), type 2 diabetes mellitus, obesity, alcoholism and administration of progestational hormones.11 OTHER HYPERLIPOPROTEINEMIAS Other hyperlipoproteinemias involve ‘hepatic lipase deficiency’ i.e., deficiency of the enzyme leading to accumulation of large triacylglycerol-rich HDL and VLDL remnants. Patients have xanthomas and CHD.12 ’Familial LCAT deficiency’ leading to block in reverse cholesterol transport. HDL remains as nascent disks incapable of taking up and esterifying cholesterol hence, plasma concentrations of cholesteryl esters and lysolecithin are low. An abnormal LDL fraction, lipoprotein X, is also found in patients with

Table 2. Frederickson’s Classification Hyperlipoproteinemias Type

Lipoprotein fraction elevated

Cholesterol level

TAG level

Metabolic effect

Features

Management

Chylomicrons

LPL deficiency

Eruptive xanthomas; hepatomegaly; pain abdomen

Restriction of fat

II A

LDL

LDL receptor defect; apo B+

Atherosclerosis, coronary artery disease, tuberous xanthoma

Low cholesterol and saturated fat. Give PUFA and drugs (statins)

II B

LDL and VLDL

Apo B + Apo C II+

Corneal arcus

(Do)

III

Broad-beta; VLDL and chylomicrons

Abnormal apo E; Palmar xanthoma. High apo CII + incidences of vascular disease

VLDL

Over production of VLDL; apo CII +

VLDL, chylomicrons

Secondary to other causes

N: Normal; +: Increased.

Asian Journal of Diabetology, Vol. 16, No. 3, July-September 2013

Reduction of weight, restriction of fat and cholesterol. Give PUFA and drugs

Reduction of body weight. Associated with Restrict carbohydrate and diabetes mellitus, cholesterol ischemic heart disease, obesity Ischemic heart diseases

High PUFA intake, hypolipidemic drugs

REVIEW ARTICLE cholestasis.11 VLDL is abnormal (β-VLDL). ‘Familial lipoprotein excess’, which may result in premature CHD due to atherosclerosis, plus thrombosis due to inhibition of fibrinolysis.12 ’Familial hyperalphalipoproteinemia’ is a defect of increased concentration of HDL. It is a rare condition apparently beneficial to health and longevity.11 COMPLICATIONS OF HYPERLIPOPROTEINEMIA Hyperlipoproteinemia results in further complication of which, a serious one is atherosclerosis. It is recognized that triacylglycerols are independent risk factor.10 Atherosclerosis is characterized by deposition of cholesterol and cholesterol ester into artery wall. Diseases with prolonged elevation of LDL, VLDL, chylomicron remnants, or LDL in blob are often accompanied by premature or more severe atherosclerosis. There is also an inverse relationship between HDL concentrations and CHD, making the LDL: HDL cholesterol as a good predictive parameter.12 GENETIC BASIS OF FAMILIAL DYSLIPIDEMIA AND HYPERTENSION The genetic and environmental determinants of hypertension, lipid abnormalities and coronary artery disease (CAD) were studied for 15 years in Utah in population-based multigenerational pedigrees (2,500 subjects among 98 pedigrees), twin pairs (74 monozygous and 78 dizygous), hypertensive siblings (131 sibships), siblings with CAD before age 55 (45 sibships), and anecdotally ascertained pedigrees with type 2 diabetes (271 subjects among 16 pedigrees), LPL deficiency (106 subjects in a single pedigree), and familial hypercholesterolemia (502 heterozygotes among 50 pedigrees). Estimates of heritability ranged from 20 to 75% for blood pressures and blood lipids. A strong positive family history predicts a future occurrence of hypertension (relative risk [RR] = 3.8) and CAD (RR = 12.7). Segregating single-gene effects were found for several ‘intermediate phenotypes’ associated with hypertension (erythrocyte sodium-lithium counter transport, intraerythrocytic sodium, a relative fat pattern, total urinary kallikrein excretion, and fasting insulin levels). Strong single-gene effects in segregation analysis were also found for LDL cholesterol, lipoprotein (a) (Lp[a]), low HDL cholesterol and high apolipoprotein (apo) B. Deoxyribonucleic acid (DNA) markers of lipid abnormalities or hypertension have included LDL-receptor defects, LPL deficiency, high

Lp(a), familial defective apo B, decreased quantitative levels of apo B, apo E phenotype, angiotensinogen and glucocorticoid remediable aldosteronism (GRA) hypertension.13 HYPERLIPIDEMIA, PREGNANCY AND PANCREATITIS Hypertriglyceridemia is a recognized complication of pregnancy. In patients with familial hypertriglyceridemia, the biochemical changes are greatly enhanced during pregnancy and may be associated with acute pancreatitis, a potentially fatal triad. Three patients were studied, in one of whom previously undiagnosed hyperlipidemia resulted in a fatal attack of fulminant acute pancreatitis. In the other two patients, this complication was avoided by close monitoring and restriction of dietary facts. A history of episodic abdominal cramps, often beginning in early childhood, or the presence of lipemic fasting plasma should alert the clinician to the presence of severe familial hypertriglyceridemia. Early diagnosis allows for the institution of relatively simple management strategies, which diminish the risk of pancreatitis.14 PHARMACOTHERAPY Treatment for hyperlipoproteinemias or hypolipidemias is very important. Hyperlipidemia needs to be controlled by means of diet mainly. Drugs serving this purpose are very useful and are the succour in familial disorders, which cannot be controlled by diet.15 Moreover, bringing down cholesterol levels is necessary to reduce risk of mortality and morbidity.15 Drugs are started after at least a trial of or 3-month period of low fat diet with exercise. Along with the use of drugs, dietary restriction is to be followed throughout (Table 3). Many drugs have been introduced over the years for the treatment of hyperlipidemia. These drugs are mainly involved in reducing body cholesterol by either decreasing the synthesis (statins), increasing its metabolism (fibrates) or by obstructing the absorption and increasing excretion (resins). The summary of these hyperlipidemics are in Table 4. EZETIMIBE CHD is the leading cause of death in United States. The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III recommends new lower cholesterol levels, particularly for patients at moderate

Asian Journal of Diabetology, Vol. 16, No. 3, July-September 2013

REVIEW ARTICLE Table 3. Classification HMG-CoA reductase inhibitor Levostatin Simvastatin Pravastatin Atovastatin Rosuvastatin Flustatin Fibric acid derivatives Gemfibrozil Clofibrate Colesevalam Fenofibrate Bezafibrate Ciprofibrate Bile acid binding resins Cholestyramine Colestipol Colesvalam Others Ezetemibe- sterol absorption inhibitor Beclobrinic acid- PG synthesis inhibitors Lentysine, Gugulipid- plant products

FIBRIC ACID DERIVATIVES: MICRONIZED FENOFIBRATE Fenofibrate reduces serum triglyceride, total cholesterol, and LDL cholesterol, and raises HDL cholesterol to clinically relevant degrees. Its spectrum of activity appears to exceed that recommended for types IV and V hyperlipidemia to encompass types IIa, IIb and III hyperlipidemias as well. To this extent, it may be considered a broad-spectrum fibrate than is indicated by its FDA approval. Adverse effects of fenofibrate appear to be similar to those of other fibrates and require routine monitoring (clinical, liver function). Long-term safety data are readily available from drug registries in many countries where the product has been available for nearly two decades. Cost-effectiveness studies comparing fenofibrate with other hypolipidemics demonstrate benefits of fenofibrate over simvastatin in types IIa and IIb hyperlipidemia. The need for dosage titration of the micronized preparation from 67 mg/day upward to a final dose of 200 mg/day is also not supported by peer-reviewed literature (except in the case of renal impairment). Although preliminary data on plaque regression are encouraging, published clinical studies evaluating the impact of fenofibrate on cardiovascular morbidity and mortality are awaited. Micronized fenofibrate is worthy of formulary inclusion.17

Chinese red-yeast rice- genetically modified

PROSTAGLANDIN SYNTHESIS INHIBITORS and high-risk for coronary disease. LDL cholesterol is primarily the target of hypolipidemic drugs. The NCEP ATP III recommends an LDL cholesterol goal of <100 mg/dl in high-risk patients and an LDL cholesterol goal of <70 mg/dl as a therapeutic option, especially in patients with very high-risk of CHD. Statins are potent LDL cholesterol-lowering drugs, but they are not as effective as fibrates and niacin in improving levels of triglycerides or HDL cholesterol. Ezetimibe represents a new class of hypolipidemic drugs that inhibit cholesterol absorption in the small intestine. The combination of ezetimibe with statins has been more effective than monotherapy alone in many randomized trials. LDL cholesterol reduction with statin occurs mainly with the initial dose, with relatively smaller reductions seen at higher doses. Ezetimibe was also shown to be useful in various population subgroups such as African-Americans, men and women, elderly and aged, and also those with kidney disease.16

Asian Journal of Diabetology, Vol. 16, No. 3, July-September 2013

Beclobrinic Acid A new hypolipidemic agent - inhibits in vitro human platelet activation by blocking prostaglandin synthesis. Effects and the mechanism of the antiplatelet actions of beclobrinic acid, free acid form of a new hypolipidemic agent beclobrate [(+)-2-[d-(P-chlorophenyl)p-tolyl) oxy)-2-methyl-butyrate), were examined using human platelets. Platelet-rich plasma (PRP), which was prelabeled with (14C)-serotonin was incubated with beclobrinic acid (BBA) for one minute before the addition of various agonists. BBA (0.1-1.5 mM) inhibited platelet aggregation and serotonin secretion induced by ADP, epinephrine, arachidonic acid and collagen in a concentration-dependent manner. BBA also inhibited arachidonic acid-induced production of malondialdehyde (MDA), a byproduct of prostaglandins, in a concentration-dependent manner. However, upto 1.0 mM BBA did not inhibit platelet aggregation induced by U46619, a stable analog of prostaglandin H2. In other experiments, BBA also blocked

REVIEW ARTICLE Table 4. Summary of Activity and ARD of Hypolipidemics Subclass

Mechanism of action

Effects

Clinical applications

Pharmacokinetics, toxicities, interactions

Inhibit HMG-CoA reductase

Reduce cholesterol synthesis and upregulate LDL receptors on hepatocytes modest reduction in triglyceride

Atherosclerotic vascular disease (primary and secondary prevention) acute coronary syndromes

Oral duration 12-24 hours Toxicity: Myopathy, hepatic dysfunction Interactions: CYP-dependent metabolism (3A4, 2C9) interacts with CYP inhibitors

Statins Atorvastatin, simvastatin, rosuvastatin

Fluvastatin, pravastatin, lovastatin: Similar but somewhat less efficacious Fibrates Fenofibrate, gemfibrozil

Peroxisome proliferatoractivated receptor-a (PPAR-a) agonists

Decrease secretion of VLDL increase LPL activity increase HDL

Hypertriglyceridemia, low HDL

Oral duration 3-24 hours Toxicity: Myopathy, hepatic dysfunction

Decreases LDL

Elevated LDL, digitalis toxicity, pruritus

Oral taken with meals not absorbed, Toxicity: Constipation, bloating interferes with absorption of some drugs and vitamins

Bile acid sequestrants Colestipol

Binds bile acids in gut prevents reabsorption increases cholesterol catabolism upregulates LDL receptors

Cholestyramine, colesevalam: Similar to colestipol Sterol absorption inhibitor Ezetimibe

Blocks sterol transporter NPC1L1 in intestine brush border

Inhibits reabsorption of cholesterol excreted in bile decreases LDL and phytosterols

Elevated LDL, phytosterolemia

Oral duration 24 hours; Toxicity: Low incidence of hepatic dysfunction, myositis

Niacin

Decreases catabolism of apo AI reduces VLDL secretion from liver

Increases HDL decreases Lp(a), LDL, and triglycerides

Low HDL elevated VLDL, LDL, Lp(a)

Oral large doses; Toxicity: Gastric irritation, flushing, low incidence of hepatic toxicity may reduce glucose tolerance

thrombin-induced release of (3H)-arachidonic acid from platelet phospholipids. These findings suggest that: (a) BBA inhibits platelet aggregation and serotonin secretion by inhibiting prostaglandin synthesis at two steps. First by interfering in the release of arachidonic acid from platelet phospholipids and second by inhibiting its conversion into prostaglandins and (b) BBA does not inhibit the action of prostaglandins on human platelets.18

1-methyl-4-piperidyl bis (p-chlorophenoxy) acetate (SaH 42-348): A New Hypolipidemic Agent Animal studies have shown the hypolipidemic properties of (SaH-2-438), which is chemically 1-methyl4-piperidyle bis (p-chlorophenoxy) acetate. This agent is 8-9 times more active on a weight for weight basis than chlorophenoxy isobutyric acid ethyl ester (CPIB) (Atromid-S), and in common with CPIB lowers the level of all major classes of serum lipid. No increase

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REVIEW ARTICLE in liver lipid content was seen in animals treated with SaH 42-348, although hepatomegaly was seen after treatment with SaH 42-348 or with CPIB. Evidence suggests that the mechanism of action of SaH 42-348 in lowering serum cholesterol in the rat differs from that of CPIB. Thus, it was not possible to demonstrate that SaH 42-348 inhibited cholesterol biosynthesis in vivo, while the inhibitory effect of CPIB was readily demonstrated. In addition, n-propylthiouracil (PTU) inhibited the hypocholesterolemic activity of CPIB in both normolipemic and hyperlipemic rats, where as the activity of SaH 42-348 was unaffected by PTU.19 PLANT STEROLS AND STEROIDS Consumption of diet, which is low in saturated and trans-fats yet high in fibers, lowers the ‘bad cholesterol’ (LDL) and keeps the heart and blood vessels healthy. ‘Phytosterols’ in fruits, vegetables, vegetable oils, nuts and seeds amounts to ‘plant sterols’ and ‘plant stenols’ that reduce absorption of cholesterol. Source: Wheat, peanut, vegetable oil (corn, sesame, canola and olive oil), almonds, brussels sprouts, etc.

Mechanism of Action Sterols and stenols (similar chemically to cholesterol) Cholesterol absorbed in intestine LDL levels in blood Plant sterols and stenols resemble cholesterol in terms of chemical structure. They prevent intestinal cholesterol absorption, thus lowering LDL. Studies have shown that, sterols and stenols lower LDL cholesterol by average 6% and perhaps 14% in four weeks. Daily requirement: 2 g/day as by NCEP.

Adverse Effects Plant sterols and stenols have been studied for >50 years. They are both safe and effective in lowering cholesterol. However, large doses may cause nausea, indigestion, diarrhea and also interferes with absorption of fat-soluble vitamin. Pregnant and breastfeeding women should be cautious in consumption. Moreover, they cannot be a substitute for cholesterol-lowering medications and are advocated in combination, not as monotherapy.16

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These can be either obtained naturally from plants and their products (e.g., lentysine, gugulipid) or from genetically modified sources (e.g., red yeast rice). Few of plant hypolipidemidic agents are discussed below.16

Lentysine Lentysine is one of the naturally obtained hypolipidemic agent. It was recently discovered that few of the edible mushrooms contained a chemical named lentysine, which was found to act as a hypolipidemic agent. Hence, in patients with high fat diet consumption of these mushrooms were found to be useful. Its actions on serum and liver lipids in rats have been investigated. Lentysine markedly reduced serum cholesterol, phospholipids and triglycerides, both in intact rats and in animals fed a high fat diet. However, it showed no effect on liver lipid levels, and enlargement of liver was not observed in rats treated with lentysine.20

Gugulipid Gugulipid, the resin of the Commiphora mukul tree has been used in Ayurvedic medicine for more than 2,000 years to treat a variety of ailments. Studies in both animal models and humans have shown that this resin, termed gum guggul, can decrease elevated lipid levels. The stereoisomers E- and Z-guggulsterone have been identified as the active agents in this resin. Recent studies have shown that these compounds are antagonist ligands for the bile acid receptor farnesoid X receptor (FXR), which is an important regulator of cholesterol homeostasis. It is likely that this effect accounts for the hypolipidemic activity of these phytosteroids.21

Red-yeast-rice Red-yeast-rice is one of the genetically modified rice, which contains hypolipidemic agent from yeast. The cholesterol-lowering effects of a proprietary Chinese red-yeast-rice supplement was examined in an American population consuming a diet similar to the American Heart Association Step I diet using a doubleblind, placebo-controlled, prospectively randomized 12-week controlled trial at a university research center. Eighty-three healthy subjects with hyperlipidemia who were not being treated with lipid-lowering drugs participated. Subjects were treated with red-yeast-rice (2.4 g/d) or placebo and instructed to consume a diet providing 30% of energy from fat, <10% from saturated

REVIEW ARTICLE fat and <300 mg cholesterol daily. Main outcome measures were total cholesterol, total triacylglycerol, and HDL and LDL cholesterol measured at Weeks 8, 9, 11 and 12. Cholesterol concentrations decreased significantly between baseline and eight weeks in the red-yeast-rice-treated group compared with the placebo-treated group. LDL cholesterol and total triacylglycerol were also reduced with the supplement. HDL cholesterol did not change significantly. Hence, red-yeast-rice was proven to a new, novel, foodbased approach to lower cholesterol in the general population.22 REFERENCES 1. US census bureau population estimates. Available at: http:// www.census.gov/popest. 2. Centers for Disease Control and Prevention (CDC). Behavioral Risk Factor Surveillance System Survey Data. Atlanta, Georgia: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. 3. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al; American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112(17):2735-52. 4. Kromhout D, Menotti A, Kesteloot H, Sans S. Prevention of coronary heart disease by diet and lifestyle: evidence from prospective cross-cultural, cohort, and intervention studies. Circulation 2002;105(7):893-8. 5. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105(9):1135-43. 6. Goldberg IJ, Merkel M. Lipoprotein lipase: physiology, biochemistry, and molecular biology. Front Biosci 2001;6:D388-405. 7. Christi WW. Lipid analysis. 3rd edition, The Oily Press, 2003. 8. Gurr MI, Harwood JL, Frayn K. Lipid biochemistry. Blackwell Publishing, 2002. 9. Dowhan W, Bodanov H. Functional roles of lipid metabolism. In: Biochemistry of Lipids, Lipoproteins and Membranes. Vance DE, Vance JE (Eds), 4th edition.

10. Shelness GS, Sellers JA. Very-low-density lipoprotein assembly and secretion. Curr Opin Lipidol 2001;12(2): 151-7. 11. Arner P. Human fat cell lipolysis: biochemistry, regulation and clinical role. Best Pract Res Clin Endocrinol Metab 2005;19(4):471-82. 12. Russell DW. Cholesterol biosynthesis and metabolism. Cardiovasc Drugs Ther 1992;6(2):103-10. 13. Williams RR, Hunt SC, Hopkins PN, Wu LL, Hasstedt SJ, Berry TD, et al. Genetic basis of familial dyslipidemia and hypertension: 15-year results from Utah. Am J Hypertens 1993;6(11 Pt 2):319S-327S. 14. De Chalain TM, Michell WL, Berger GM. Hyperlipidemia, pregnancy and pancreatitis. Surg Gynecol Obstet 1988;167(6):469-73. 15. Kromhout D, Menotti A, Kesteloot H, Sans S. Prevention of coronary heart disease by diet and lifestyle: evidence from prospective cross-cultural, cohort, and intervention studies. Circulation 2002;105(7):893-8. 16. Katragadda S, Rai F, Arora R. Dual inhibition, newer paradigms for cholesterol lowering. Am J Ther 2010;17(4):e88-99. 17. Guay DR. Micronized fenofibrate: a new fibric acid hypolipidemic agent. Ann Pharmacother 1999;33(10): 1083-103. 18. Anwer K, Gabis J, Romstedt K, Gojer C, Huzoor-Akbar. Beclobrinic acid - a new hypolipidemic agent - inhibits in vitro human platelet activation by blocking prostaglandin synthesis. Life Sci 1985;37(1):63-70. 19. Timms AR, Kelly LA, Ho RS, Trapold JH. Laboratory studies of 1-methyl-4-piperidyl bis(p-chlorophenoxy) acetate (SaH 42-348)— A new hypolipidemic agent. Biochem Pharmacol 1969;18(8):1861-71. 20. Rokujo T, Kikuchi H, Tensho A, Tsukitani Y, Takenawa T, Yoshida K, et al. Lentysine: a new hypolipidemic agent from a mushroom. Life Sci 1970;9(7):379-85. 21. Urizar NL, Moore DD. Gugulipid: a natural cholesterollowering agent. Annu Rev Nutr 2003;23:303-13. 22. Heber D, Yip I, Ashley JM, Elashoff DA, Elashoff RM, Go VL. Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement. Am J Clin Nutr 1999;69(2):231-6.

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India Poised to Revoke Pioglitazone Ban The Drug Technical Advisory Board (DTAB) has advised the Government to revoke the suspension of the diabetes drug pioglitazone. The DTAB met on July 19 and recommended that pioglitazone be put back in the market in India with a box warning about bladder cancer. The DTAB is an advisory body and the government may or may not accept its advice but it is likely that the recommendations may be accepted.

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REVIEW ARTICLE

Gastrointestinal Complications of Diabetes AMER SHAKIL, ROBERT J. CHURCH, SHOBHA S. RAO

ABSTRACT Gastrointestinal complications of diabetes include gastroparesis, intestinal enteropathy (which can cause diarrhea, constipation and fecal incontinence) and nonalcoholic fatty liver disease. Patients with gastroparesis may present with early satiety, nausea, vomiting, bloating, postprandial fullness, or upper abdominal pain. The diagnosis of diabetic gastroparesis is made when other causes are excluded and postprandial gastric stasis is confirmed by gastric emptying scintigraphy. Whenever possible, patients should discontinue medications that exacerbate gastric dysmotility; control blood glucose levels; increase the liquid content of their diet; eat smaller meals more often; discontinue the use of tobacco products and reduce the intake of insoluble dietary fiber, foods high in fat and alcohol. Prokinetic agents (e.g., metoclopramide, erythromycin) may be helpful in controlling symptoms of gastroparesis. Treatment of diabetes related constipation and diarrhea is aimed at supportive measures and symptom control. Nonalcoholic fatty liver disease is common in persons who are obese and who have diabetes. In persons with diabetes who have elevated hepatic transaminase levels, it is important to search for other causes of liver disease, including hepatitis and hemochromatosis. Gradual weight loss, control of blood glucose levels, and use of medications (e.g., pioglitazone, metformin) may normalize hepatic transaminase levels, but the clinical benefit of aggressively treating nonalcoholic fatty liver disease is unknown. Controlling blood glucose levels is important for managing most gastrointestinal complications. Keywords: Gastrointestinal complications, diabetes, gastroparesis, intestinal enteropathy and nonalcoholic fatty liver disease

astrointestinal (GI) complications of diabetes have become more common as the rate of diabetes has increased. These complications and their symptoms are often caused by abnormal GI motility, which is a consequence of diabetic autonomic neuropathy involving the GI tract. Although some studies have indicated that diabetic autonomic neuropathy is linked to the duration of diabetes, the Diabetes Control and Complications Trial suggested that, at least in persons with type 1 diabetes, neuropathy and other GI complications are associated with poor blood glucose control and not necessarily the duration of diabetes.1-3

AMER SHAKIL, MD, FAAFP, is an associate professor in the Department of Family and Community Medicine at the University of Texas (UT) Southwestern Medical Center at Dallas. He received his medical degree from the Punjab University, Rawalpindi Medical College in Islamabad, Pakistan. Dr. Shakil completed a family medicine residency at the University of Illinois at Chicago, Christ Hospital, and a faculty development fellowship at the University of Illinois at Chicago. ROBERT J. CHURCH, MD, is a family physician at Texoma Medical Center in Denison, Tex. At the time of writing this article, he was a third-year family medicine resident at UT Southwestern Medical Center at Dallas. Dr. Church received his medical degree from American University of the Caribbean School of Medicine in St. Maarten. SHOBHA S. RAO, MD, is an associate professor at the UT Southwestern Medical Center Family Medicine Residency Program. She received her medical degree from Sri Venkateswara Medical College in Tirupati, India. Dr. Rao completed a family practice residency at the UT Health Science Center in San Antonio and a geriatric medicine fellowship at the University of Pennsylvania School of Medicine in Philadelphia. Source: Adapted from Am Fam Physician. 2008;77(12):1697-1702, 1703-1704.

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GI conditions caused by diabetes include gastroparesis, intestinal enteropathy (which can cause diarrhea, constipation and fecal incontinence) and nonalcoholic fatty liver disease. ESOPHAGEAL INVOLVEMENT Esophageal manifestations of diabetic neuropathy, including abnormal peristalsis, spontaneous contractions and impaired lower esophageal sphincter tone, result in heartburn and dysphagia.4,5 The relationship between hyperglycemia and dysmotility is not well established. Although many patients may have objective evidence of esophageal dysmotility or reflux, symptoms only occur in a minority of patients with diabetes.6 Other possible factors contributing to diabetes-associated reflux include obesity, hyperglycemia and decreased secretion of bicarbonate from parotid glands. Treatment consists of controlling blood glucose levels and using medication to manage reflux. GASTROPARESIS Approximately 5-12 percent of patients with diabetes report having symptoms consistent with gastroparesis.7 Gastroparesis is more common in women and can present as early satiety, nausea, vomiting, bloating, postprandial fullness, or upper abdominal pain.

REVIEW ARTICLE Delayed gastric emptying contributes to poor blood glucose control and may be the first indication that a patient is developing gastroparesis.4

Pathophysiology The delayed gastric emptying in patients with gastroparesis is thought to be caused primarily by impaired vagal control.8 Other contributing factors include the impairment of inhibitory nitric oxide– containing nerves, damage to the interstitial cells of Cajal and underlying smooth muscle dysfunction.9

Evaluation A technical review from the American Gastroenterological Association (AGA) recommends performing an initial evaluation consisting of a patient history and physical examination, complete blood count, thyroid-stimulating hormone test, metabolic panel, amylase test (if the patient has abdominal pain), and pregnancy test (if appropriate).10 This should be followed by upper endoscopy or an optional upper GI series with small bowel follow-through to rule out mechanical obstruction or other GI conditions, and ultrasonography if the patient has biliary tract symptoms or significant abdominal pain (Figure 1).10 Gastric emptying scintigraphy is recommended to confirm the diagnosis of gastroparesis.10 With scintigraphy, the patient will usually ingest technetiumlabeled egg meal and gastric emptying will be measured by scintiscanning at 15-minute intervals for four hours. A simplified scanning of four images versus 13 images has shown comparable results. Retention of more than 10 percent of the meal at the end of four hours is consistent with gastroparesis.11 Table 1 lists tests for the evaluation of diabetic gastroparesis.5,12

Treatment Management of diabetic gastroparesis should focus on excluding other causes, assessing the severity of the disorder, correcting any nutritional deficiencies, and reducing symptoms.12 A grading system (Table 2) can be helpful in assessing severity and guiding management.13 Medications and substances that exacerbate underlying dysmotility should be eliminated when possible. Medications that delay gastric emptying include aluminum hydroxide antacids; anticholinergic agents; beta-adrenergic receptor agonists; calcium channel blockers; diphenhydramine; histamine H2 antagonists; interferon alfa; levodopa; opioid analgesics;

Evaluation of Suspected Gastroparesis Initial Evaluation • History and physical examination • Laboratory studies: Complete blood count (to evaluate for infection or cancer) Thyroid-stimulating hormone test (to evaluate for hypothyroidism) Metabolic panel (to evaluate for diabetes and electrolyte imbalance) Amylase test (if the patient has abdominal pain—to rule out pancreatitis) Pregnancy test (if appropriate) Initial evaluation suggestive of underlying cause? Yes

Treat underlying cause and consider further work-up if incomplete response

Further testing with upper endoscopy or an optional upper gastrointestinal series with small bowel followthrough (to rule out mechanical obstruction or other gastrointestinal conditions) and ultrasonography (if patient has biliary tract symptoms or significant abdominal pain) Evaluation suggestive of underlying cause? Yes

Treat underlying cause Positive Diagnosis of gastroparesis

No Gastric emptying scintigraphy Negative Further work-up as indicated

Figure 1. Algorithm for the evaluation of suspected gastroparesis. Information from reference 10.

proton pump inhibitors; sucralfate; and tricyclic antidepressants. Medications that accelerate gastric emptying include beta-adrenergic receptor antagonists and prokinetic agents.10 High blood glucose levels can cause gastric dysrhythmias and delayed emptying; therefore, it is important to control blood glucose levels.14 For mild disease, dietary modifications and a low-dose antiemetic or a prokinetic agent can help manage symptoms. Increasing the liquid content of the patient’s diet is helpful because liquid emptying is usually preserved in patients with gastroparesis who have delayed solid emptying. To minimize postprandial fullness, it is reasonable to recommend eating small meals more often. The use of tobacco products should be discontinued. Fiber supplements, foods that contain

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REVIEW ARTICLE Table 1. Tests for the Evaluation of Diabetic Gastroparesis Test Antroduodenal manometry

Comments Can be useful in patients with unexplained vomiting; can assess fasting and postprandial phases; invasive procedure requiring expertise to perform and interpret Breath test Breath tests using a nonradioactive isotope carbon-13 bound to a digestible substance have been validated for measuring gastric emptying; noninvasive but requires normal small intestinal absorption, liver metabolism, and pulmonary excretion functions Electrogastrography Noninvasive adjunct to gastric emptying scintigraphy as part of a comprehensive evaluation of patients with refractory symptoms Gastric emptying Recommended test for diagnosis of scintigraphy gastroparesis; quantifies the emptying of a physiologic caloric meal; able to assess liquid and solid emptying; minimal radiation exposure Magnetic Noninvasive; primarily measures resonance imaging emptying of liquids; expensive and time consuming Ultrasonography Noninvasive; operator dependent Upper Greatest value is the ability to exclude gastrointestinal mucosal lesions and mechanical outlet series obstruction; moderate radiation exposure Information from references 5 and 12.

insoluble fiber or that are high in fat, and alcohol can impair gastric emptying, and their intake should be reduced if possible.10,15 Metoclopramide has central antiemetic effects and is useful for improving symptoms of postprandial fullness and nausea. It also elevates lower esophageal sphincter pressure and improves antropyloroduodenal coordination. Approximately 20-30 percent of patients taking metoclopramide will experience adverse effects, and because it crosses the blood-brain barrier, some of the effects may be neurologic (e.g., drowsiness, irritability, extrapyramidal symptoms, dystonic reactions).4 Tardive dyskinesia, which is characterized by involuntary movement of the face and tongue, is a rare, dose-related adverse effect that may be irreversible. A technical review from the AGA identified four small, randomized, double-blind, crossover trials that found varying degrees of improvement in gastroparesis symptoms among patients taking metoclopramide.10 Erythromycin is a motilin agonist and potent prokinetic

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Table 2. Proposed Classification of Gastroparesis Grade 1: mild Symptoms relatively easy to control Ability to maintain weight and nutrition on a regular diet or with minor dietary modifications Patients with diabetes should strive for optimal blood glucose control to minimize effects of hyperglycemia on gastric function Grade 2: compensated Moderate symptoms with partial control using pharmacologic agents (typically involving a combination of antiemetic and prokinetic medications given at regularly scheduled intervals) Ability to maintain nutrition with dietary and lifestyle adjustments Rare hospital admissions Grade 3: gastric failure Refractory symptoms despite medical therapy Inability to maintain nutrition orally Aggressive treatments, including hospitalization for intravenous hydration, insulin administration, and intravenous antiemetic and prokinetic agents, are considered Chronic care may include total enteral or parenteral nutrition with endoscopic and/or surgical intervention

agent that stimulates antral contractility and increases the rate of gastric emptying by acting directly on motilin receptors, smooth muscles, and enteric nerves.16 Research on erythromycin for gastroparesis consists primarily of case reports and open-label trials with 10 or fewer patients. Although most studies found a modest symptomatic benefit with erythromycin, the poor design of these studies would bias results in favor of the intervention. Nevertheless, given its good safety profile, erythromycin is a reasonable treatment option for symptomatic patients.10 Tegaserod has some promotility effects. Studies in healthy participants without gastroparesis have shown that tegaserod increases gastric emptying, but clinical trials in patients with gastroparesis are lacking. Because of its high cost and potential for adverse effects, tegaserod is not routinely recommended.17 Bethanechol has been shown to enhance the amplitude of contractions throughout the GI tract, but evidence is lacking regarding its effects on the symptoms of gastroparesis when used alone or in combination with other drugs.7 Antiemetics, such as promethazine and ondansetron, may be prescribed for symptomatic relief of persistent nausea. Gastric electric stimulation has been approved for the treatment of refractory gastroparesis; however, clinical trials have shown mixed results, with some showing

REVIEW ARTICLE Table 3. Treatment Options for Gastroparesis Treatment Mechanism Metoclopramide, Serotonin (5-HT3) receptor 10 mg four times daily antagonist, central dopamine (D2) receptor antagonist Normalize gastric slow-wave dysrhythmias by inhibiting gastric smooth muscle relaxation produced by dopamine Erythromycin, 250 mg Motilin receptor agonist three times daily Prokinetic effects via action on gastroduodenal motilin receptors Bethanechol, 25 mg Nonspecific cholinergic muscarinic four times daily receptor agonist Botulinum toxin type A Inhibits acetylcholine release from synaptic vesicles in pylorus Surgery Gastric decompression, partial gastrectomy with Roux-en-Y gastrojejunostomy Gastric electric stimulation

Electric stimulation with high-energy, long-duration pulses

Adverse effects Evidence comments Dystonic reactions, tardive Symptoms improved in 25 to 62 dyskinesia, extrapyramidal percent of patients10 symptoms, hyperprolactinemia Physicians should discuss the risk of tardive dyskinesia with their patients and document this discussion in the medical records Nausea, vomiting, abdominal Most studies are open-label pain, antibiotic resistance design10,20 Salivation, blurred vision, abdominal cramps, and bladder spasm â&#x2C6;&#x2019; â&#x2C6;&#x2019;

Possible infection, gastric erosion

Not a true prokinetic agent Most studies are open-label design10 No well-designed studies for diabetic gastroparesis; most studies are nonrandomized, unblended, or case series10,19 No well-designed studies; more data are needed

Note: Treatments are listed in order from most to least likely to be used. Information from references 10, 19 and 20.

no benefit. Complications, such as gastric erosion or infection, occur in 5 to 10 percent of patients.10 A longterm, uncontrolled, open-label follow-up study of 156 patients with an implanted electric stimulation device showed significant reductions in symptoms of drugrefractory gastroparesis.18

drug-related causes (e.g., metformin, lactulose) should be considered.

INTESTINAL ENTEROPATHY

Treatment of diabetic diarrhea is mainly empiric and directed toward symptomatic relief, such as correcting fluid and electrolyte imbalances, improving nutrition and blood glucose control, and managing any underlying causes.21 Antidiarrheals can be used for symptomatic relief, but should be used with caution because of their potential to cause toxic megacolon. Broad-spectrum antibiotics have been used for the treatment of diarrhea, but there are no well-designed studies to support their use. In one small, prospective study, six of the eight patients who were positive for bacterial overgrowth on hydrogen breath testing were given amoxicillin/clavulanic acid for 10 days and experienced significant improvement of diarrhea.21

Intestinal enteropathy in patients with diabetes may present as diarrhea, constipation, or fecal incontinence. The prevalence of diarrhea in patients with diabetes is between 4 and 22 percent.4,5 Impaired motility in the small bowel can lead to stasis syndrome, which can result in diarrhea. In addition, hypermotility caused by decreased sympathetic inhibition, pancreatic insufficiency, steatorrhea, and malabsorption of bile salts can further contribute to diarrhea. Abnormal internal and external anal sphincter function caused by neuropathy can lead to fecal incontinence. When evaluating a patient with diabetes who has diarrhea,

Constipation, which may alternate with diarrhea, is one of the most common complications of diabetes. A population-based study found that 20 to 44 percent of patients with diabetes reported symptoms of constipation or increased use of laxatives.22 Neuronal dysfunction in the large bowel, along with impairment of the gastrocolic reflex, results in constipation. It is important to rule out other causes of constipation such as hypothyroidism or medications. A thorough history and physical examination, including a rectal examination, should be performed. Treatment includes good hydration, regular physical activity, and increased

For patients who are refractory to pharmacotherapy and gastric electric stimulation, total parenteral nutrition, placement of a gastrostomy or jejunostomy tube, botulinum toxin type A injection into the pylorus, or surgery can be considered; however, data from clinical trials are lacking.10,19 Table 3 lists treatment options for gastroparesis.10,19,20

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REVIEW ARTICLE fiber intake. Sorbitol or lactulose can also be used to treat constipation; saline or osmotic laxatives may be needed in more severe cases.4 DIABETES AND NONALCOHOLIC FATTY LIVER DISEASE Nonalcoholic fatty liver disease is the term used to describe a liver condition in patients who have a pathology resembling alcohol-induced liver injury but lack a history of significant alcohol consumption. The etiology is unknown, but the disease is often associated with type 2 diabetes and obesity. In some cases, nonalcoholic fatty liver disease may progress to nonalcoholic steatohepatitis with varying degrees of inflammation and fibrosis. In very rare cases, it can lead to cirrhosis. All patients who are severely obese and who have diabetes have some degree of steatosis, with one half having steatohepatitis.5,23 Nonalcoholic fatty liver disease is generally diagnosed because of persistent elevation in hepatic transaminase levels. Patients with elevated levels should have serologic testing to exclude hepatitis, an antinuclear antibody test to exclude autoimmune hepatitis, and a transferrin saturation test to exclude hemochromatosis. Ultrasonography or computed tomography showing characteristic changes in a patient who uses little or no alcohol confirms the diagnosis.24

Clinical Features, Course, and Prognosis Most patients with nonalcoholic fatty liver disease are asymptomatic. Although some may experience malaise or right upper-quadrant fullness, it is unclear whether this is caused by the disease or by comorbidities (e.g., obesity, diabetes).5 Clinical disease in patients with nonalcoholic fatty liver disease ranges from mild elevation of liver enzymes to rare cases of severe liver disease with fibrosis and nodular regeneration. A longitudinal study was conducted to evaluate the histologic course of 103 patients with nonalcoholic fatty liver disease who underwent serial liver biopsies. Researchers found that fibrosis stage remained stable in 34 percent, progressed in 37 percent, and regressed in 29 percent of patients. Changes in aminotransferase levels did not parallel changes in fibrosis stage. However, patients with diabetes, an elevated body mass index, and fibrosis were at risk of higher rates of progression.25

Treatment Gradual weight loss (approximately 1 to 2 lb [0.5 to 0.9 kg] per week) and good control of blood glucose levels (A1C of less than 7 percent) are recommended for patients

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with nonalcoholic steatohepatitis.24 Pharmacologic interventions, including metformin26 and gemfibrozil,27 have shown benefit in lowering hepatic transaminase levels and improving ultrasound findings in patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis; however, there is no evidence that longterm use of these agents improves clinical outcomes. A statistically significant improvement of nonalcoholic steatohepatitis histology was seen in one small study of pioglitazone,26 but this drug is not approved by the U.S. Food and Drug Administration (FDA) for use in patients with liver disease. Because good evidence is lacking, routine use of these drugs simply to normalize hepatic transaminase levels is not recommended. ASSOCIATION BETWEEN DIABETES AND OTHER GI DISEASES

Diabetes and Hepatitis C Diabetes is more common in patients with hepatitis C infection than in the general population. In one study, the estimated prevalence of diabetes in patients with hepatitis C was found to be 14.5 percent compared with 7.8 percent in the general population and 7.3 percent in a matched control group with nonhepatitis C liver disease.28 Among patients with hepatitis C infection, older age, obesity, severe liver fibrosis, and family history of diabetes are associated with the development of diabetes.29 The use of interferon alfa for treating hepatitis C infection has also been associated with the development of diabetes.30

Cirrhosis and Diabetes Causes of cirrhosis linked to diabetes include nonalcoholic fatty liver disease, hemochromatosis, and hepatitis C infection. Patients with cirrhosis and diabetes may show signs of increased insulin resistance and may require high doses of insulin to control their blood glucose levels.31 If patients with cirrhosis and diabetes develop hemolysis because of hypersplenism or blood loss, their A1C levels may be falsely low; therefore, they should not be prescribed dietary restrictions because they are already malnourished.

Oral Hypoglycemics and Liver Disease Troglitazone, a thiazolidinedione, was withdrawn from the market because of hepatotoxicity. Therefore, the FDA recommends not using thiazolidinediones in patients with liver disease. In rare cases, sulfonylureas (e.g., chlorpropamide, glyburide, glipizide, tolbutamide) can cause hepatotoxicity, and acarbose can cause mild elevations in liver function tests.5

REVIEW ARTICLE Diabetes and Hemochromatosis The prevalence of idiopathic hemochromatosis is 9.6 per 1,000 in persons with diabetes versus 4 per 1,000 persons in the general population.32 Patients with diabetes who also have abnormal liver function tests, arthritis, or a family history of iron overload should be screened for hemochromatosis by checking transferrin saturation levels. REFERENCES 1. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977-986. 2. Bytzer P, Talley NJ, Leemon M, et al. Prevalence of gastrointestinal symptoms associated with diabetes mellitus: a population-based survey of 15,000 adults. Arch Intern Med. 2001;161(16):1989-1996. 3. Bytzer P, Talley NJ, Hammer J, Young LJ, Jones MP, Horowitz M. GI symptoms in diabetes mellitus are associated with both poor glycemic control and diabetic complications. Am J Gastroenterol. 2002;97(3):604-611. 4. Rayner CK, et al. Relationships of upper gastrointestinal motor and sensory function with glycemic control. Diabetes Care. 2001;24(2):371-381. 5. Ebert EC. Gastrointestinal complications of diabetes mellitus. Dis Mon. 2005;51(12):620-663. 6. Lluch I, Ascaso JF, Mora F, et al. Gastroesophageal reflux in diabetes mellitus. Am J Gastroenterol. 1999;94(4): 919-924. 7. Camilleri M. Clinical practice. Diabetic gastroparesis [published correction appears in N Engl J Med. 2007;357(4):427]. N Engl J Med. 2007;356(8):820-829. 8. Yoshida MM, Schuffler MD, Sumi SM. There are no morphologic abnormalities of the gastric wall or abdominal vagus in patients with diabetic gastroparesis. Gastroenterology. 1988;94(4):907-914. 9. Ordรถg T, Takayama I, Cheung WK, Ward SM, Sanders KM. Remodeling of networks of interstitial cells of Cajal in a murine model of diabetic gastroparesis. Diabetes. 2000;49(10):1731-1739. 10. Parkman HP, Hasler WL, Fisher RS, et al. American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology. 2004;127(5):1592-1622. 11. Tougas G, Chen Y, Coates G, et al. Standardization of a simplified scintigraphic methodology for the assessment of gastric emptying in a multicenter setting. Am J Gastroenterol. 2000;95(1):78-86. 12. Quigley EM, Hasler W, Parkman HP. AGA technical review on nausea and vomiting. Gastroenterology. 2001;120(1):263-286. 13. Abell TL, Bernstein RK, Cutts T, et al. Treatment of gastroparesis: a multidisciplinary clinical review. Neurogastroenterol Motil. 2006;18(4):263-283. 14. Jebbink RJ, Samsom M, Bruijs PP, et al. Hyperglycemia induces abnormalities of gastric myoelectrical activity in patients with type 1 diabetes mellitus. Gastroenterology. 1994;107(5):1390-1397.

15. Bujanda L. The effects of alcohol consumption upon the gastrointestinal tract. Am J Gastroenterol. 2000;95(12):3374-3382. 16. Galligan JJ, Vanner S. Basic and clinical pharmacology of new motility promoting agents. Neurogastroenterol Motil. 2005;17(5):643-653. 17. Degen L, Matzinger D, Merz M, et al. Tegaserod, a 5-HT4 receptor partial agonist, accelerates gastric emptying and gastrointestinal transit in healthy male subjects. Aliment Pharmacol Ther. 2001;15(11):1745-1751. 18. Anand C, Al-Juburi A, Familoni B, et al. Gastric electrical stimulation is safe and effective: a long-term study in patients with drug-refractory gastroparesis in three regional centers. Digestion. 2007;75(2-3):83-89. 19. Jones MP, Maganti K. A systematic review of surgical therapy for gastroparesis. Am J Gastroenterol. 2003;98(10):2122-2129. 20. Maganti K, et al. Oral erythromycin and symptomatic relief of gastroparesis: a systematic review. Am J Gastroenterol. 2003;98(2):259-263. 21. Virally-Monod M, Tielmans D, Kevorkian JP, et al. Chronic diarrhoea and diabetes mellitus: prevalence of small intestinal bacterial overgrowth. Diabetes Metab. 1998;24(6):530-536. 22. Maleki D, et al. Pilot study of pathophysiology of constipation among community diabetics. Dig Dis Sci. 1998;43(11):2373-2378. 23. Angulo P, et al. Nonalcoholic fatty liver disease. N Engl J Med. 2002; 346(16):1221-1231. 24. American Gastroenterological Association. American Gastroenterological Association medical position statement: nonalcoholic fatty liver disease. Gastroenterology. 2002;123(5):1702-1704. 25. Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 2005;42(1):132-138. 26. Angelico F, Burattin M, Alessandri C, Del Ben M, Lirussi F. Drugs improving insulin resistance for non-alcoholic fatty liver disease and/or non-alcoholic steatohepatitis. Cochrane Database Syst Rev. 2007;(1):CD005166. 27. Basaranoglu M, et al. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol. 1999;31(2):384. 28. Zein CO, et al. Chronic hepatitis C and type II diabetes mellitus: a prospective cross-sectional study. Am J Gastroenterol. 2005;100(1):48-55. 29. Petit JM, et al. Risk factors for diabetes mellitus and early insulin resistance in chronic hepatitis C. J Hepatol. 2001;35(2):279-283. 30. Fabris P, et al. Insulin-dependent diabetes mellitus during alpha-interferon therapy for chronic viral hepatitis. J Hepatol. 1998;28(3):514-517. 31. Vidal J, Ferrer JP, Esmatjes E, et al. Diabetes mellitus in patients with liver cirrhosis. Diabetes Res Clin Pract. 1994;25(1):19-25. 32. Phelps G, Chapman I, Hall P, et al. Prevalence of genetic haemochromatosis in diabetic patients. Lancet. 1989;2(8657):233-234.

Asian Journal of Diabetology, Vol. 16, No. 3, July-September 2013

CLINICAL STUDY

Patterns of Extended Lipid Profile Abnormalities in Freshly Diagnosed Myocardial Infarction Patients of Bundelkhand Region DEEP CHANDRA PANT*, HEMA PANT**

ABSTRACT Introduction: Coronary artery disease (CAD) in Indian population occurs a decade earlier, is more advanced at presentation and have different patterns of dyslipidemia compared to western population.1,2 Role of nonconventional lipid markers like apolipoprotein A (ApoA), apolipoprotein B (ApoB), lipoprotein a (Lpa) were studied in the present study. Material and methods: Thirty-six consecutive patients of acute myocardial infarction (AMI) were included in the study. Patients with risk factors for dyslipidemia like diabetes mellitus, hypothyroidism, liver failure, renal failure or those already on lipid-lowering therapy were excluded from study. Extended lipid profile in fasting state was studied for all patients including apolipoproteins and Lpa within 12 hours of chest pain. The study was duly approved by hospital ethics committee. Results: Total cholesterol and LDL cholesterol values were within normal range for most of the patients (average value 155 ± 21 mg% and 90 ± 16.7, respectively). The major abnormality found in lipid profile was high triglyceride (164 ± 51 mg%), low HDL (33 ± 6.5 mg%), high Lpa (mean value 25 ± 10.3 mg%) and high incidence of unfavorable ApoA/ApoB ratio (i.e. ratio <1.00). 41.7% (15/36) patients had high Lpa value (i.e. >30 mg%). Percentage of patients having unfavorable ApoA1/ApoB ratio was 92%. Comprehensive lipid tetrad index was 19,286. Percentage of patients with truncal obesity (i.e. waist-hip ratio >1.00) was 36% (13/36). Percentage of current smokers in study was 42% (15/36). Conclusion: We observed high incidence of elevated Lpa and unfavorable ApoA/ApoB ratio in AMI patients of this region. The role of these additional lipid markers needs to be studied in detail especially in subsets who have normal conventional lipid profile. Keywords: Coronary artery disease, extended lipid profile, myocardial infarction, apolipoprotein A, apolipoprotein B, lipoprotein (a), HDL cholesterol, LDL cholesterol, waist-hip ratio

bnormalities in plasma lipoproteins and derangements in lipid metabolism are one of the best established risk-factors for atherosclerosis and coronary artery disease (CAD). Studies have shown that apolipoprotein A1 (ApoA1): Apolipoprotein B (ApoB) ratio distinguishes unequivocally between patients with and without CAD.3 Role of other lipid parameters like lipoprotein a (Lpa) in causation of atherosclerosis and CAD is yet to be established clearly. It is a known fact that CAD in Indians occurs at levels of dyslipidemia much lower than western populations and many Indian patients with coronary

*Associate Professor Dept. of Cardiology **Assistant Professor Dept. of Pathology UFHT Medical College, Haldwani Nainital, Uttarakhand

Asian Journal of Diabetology, Vol. 16, No. 3, July-September 2013

artery have lipid parameters that are much lower then their western counterparts.1,4-6 Asian Indians tend to have higher levels of triglycerides, lower high-density lipoprotein (HDL) levels and higher Lpa.8-11 The role of studying nontraditional lipid risk factors like ApoA1:ApoB ratio and Lpa in Indian CAD patients especially in patients with normal lipid parameters is not clear. Studies are needed in Indian patients to evaluate the role of extended lipid profile parameters including the above nontraditional risk factors described above, especially when the patterns of dyslipidemias in Indian patients are different from their western counterparts. AIMS AND OBJECTIVES To study the patterns of extended lipid profile abnormalities in CAD patients of Bundelkhand region.

CLINICAL STUDY MATERIAL AND METHODS This study has been conducted on 36 freshly diagnosed CAD patients presenting on first instance with first episode of freshly diagnosed acute myocardial infarction (AMI). Inclusion criteria were: ÂÂ

All patients of AMI were not previously known case of CAD.

ÂÂ

Patients found to have confounding factors for dyslipidemia were excluded from the study (confounding factors included presence of systemic hypertension, diabetes mellitus, hypothyroidism, liver diseases, kidney disease and those on statins).

ÂÂ

The diagnosis of MI was made by combination of history, physical examination, ECG, troponin bedside test, cardiac enzymes. Patients with evidence of old MI on ECG were also excluded from the study.

Examination History: Name, age, sex, weight, height, body mass index (BMI), waist-hip ratio, history of smoking and detailed medical and treatment history was taken. Physical examination: Patient full general examination was done to look for any signs of hyperlipidemia, thyroid swelling, pulse rate, blood pressure and detailed cardiovascular examination was done. Body weight, hei ght, BMI, waist-hip ratio was taken.

parameters: Total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, HDL cholesterol, VLDL, LAa, ApoA1, ApoB, ApoA/ApoB ratio. The blood samples received were sent with due precautions to Lal’s Laboratory Pvt. Ltd., New Delhi, immediately for analysis. This Lab is approved by WHO and Center for Disease Control, Atlanta, Georgia, USA and is a laboratory of international repute Analysis The results of extended lipid profile was pooled and patterns of lipid abnormalities studied using relevant statistical methods. RESULTS

Age-wise Distribution of Patients The average age of the patient was 55.86 years (25-78 years). Percentage of patients with age <60 years was 75% (27/36); percentage of patients with age <30 years was 2.77% (1/36). Maximum clustering of AMI was seen in the age group 40-59 years, which included 70.22% patients (26/36).

Total Cholesterol Levels

Investigations

The average total cholesterol in the study group was 155 ± 21 mg%. Maximum clustering of total cholesterol levels were seen in the range group 140-159 mg% (16/36; 44.4%). Only one patient had total cholesterol value of >200 mg%. The range of total cholesterol was 106-207 mg%.

General Routine Investigations

LDL Cholesterol

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Hemogram, total and differential count

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Fasting and 2-hour postprandial blood glucose measurements to rule out diabetes mellitus.

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Liver function tests (serum glutamic pyruvic transaminase [SGPT], serum glutamic oxaloacetic transaminase [SGOT] serum bilirubin and serum alkaline phosphate) to rule out liver disease.

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Renal function tests including blood urea and serum creatinine to rule out renal disease.

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Routine urine microscopy was also done for all patients.

The average value of LDL cholesterol in the study group was 90.4 ± 16.7 mg%. Only 25% patients of the study group had LDL cholesterol value >200% (9/36). The range of LDL cholesterol value was 56.4-141 mg%.

Triglycerides The average value of triglyceride in the study group was 164 ± 52 mg%; 18 patients (50%) had triglycerides >150 mg%. The range of triglyceride value was 67-354 mg%.

HDL Cholesterol Extended Lipid Profile Fasting venous sample was taken for all patients within 12 hours of onset of chest pain for following lipid

Mean value of HDL cholesterol in the study group was 33.0 ± 6.5 mg%; 32/36 (90%) patients had HDL cholesterol value <40 mg%.

Asian Journal of Diabetology, Vol. 16, No. 3, July-September 2013

CLINICAL STUDY VLDL Cholesterol

Comprehensive Lipid Tetrad Index

The average value of VLDL cholesterol in the study group was 32.6 ± 10.9 mg%; percentage of patients having unfavorable VLDL levels >41 mg% was 18.4% (7/36). The range of VLDL cholesterol was 14.42-58.2 mg%.

Proposed by Enas as the best estimate of total burden of dyslipidemia. It is derived as follows: Total cholesterol × triglycerides × Lpa/HDL (all in mg%) = 24.9 × 164 × 155.9/33.01 = 19286.

Lipoprotein A

Rural/Urban Classification

The average Lpa for the patients in the study group was 24.9 ± 10.29 mg%. Percentage of patients having high Lpa levels (i.e. >30 mg%) was 41.67% (15/36). The range of Lpa was 10.3-45.0 mg%.

Of the study group, 23 patients were from rural background and 13 from urban background. Percentage of patients of: Rural background (63.88%) and urban background (36.11%).

Apolipoprotein A1

Waist-hip Ratio

The average ApoA1 levels in the study group was 85 ± 14.62 mg%. The desirable ApoA1 level is in the range 104-202 mg%. Percentage of patients having ApoA1 <104 mg% (i.e. desirable levels) was 86.11% (31/36). The range of ApoA1 is 59-110 mg%.

The waist-hip ratio of the patient varied between 0.9-1.16. The average waist-hip ratio of the group was 0.99. Percentage of patient having unfavorable waisthip ratio (i.e. >1.00) was 36.1% (13/36).

Apolipoprotein B The average ApoB in the study group was 89 ± 14.09 mg%. The desirable range of ApoB is 66-133 mg%. The range of ApoB was 59-118 mg% in our study group.

ApoA1/ApoB1 Ratio Percentage of patients having unfavorable ApoA1/ApoB ratio (ratio <1.00) was 49.44% (16/36). The ApoA1/ApoB ratio varied between 0.61-1.52.

Total Cholesterol/HDL Ratio Total cholesterol/HDL ratio should be <5.00. For our study group this ratio varied between 2.75-9.0. Percentage of patients having undesirable total cholesterol/HDL ratio (i.e. >5.00) was 36.11% (13/36).

LDL/HDL Cholesterol Ratio The desirable LDL/HDL ratio should be <3.55. For our study group, this ratio varied between 1.55-6.13. Percentage of patients having unfavorable ratio (i.e. ≥3.55) was 11.11% (4/36).

BMI The BMI of the study group varied between 19.7-31.25. The average BMI of the study group was 23.72. Percentage of patients who were overweight were (i.e. BMI >25) 22.2% (8/36). Percentage of patients who were obese was (i.e. BMI >30) were 2.78% (1/36).

Asian Journal of Diabetology, Vol. 16, No. 3, July-September 2013

DISCUSSION The present study has shown that conventional lipid parameters were normal for majority of patients in the study group. The main abnormalities found in the extended lipid profile of the patients with freshly diagnosed MI were high triglyceride, low HDL, high Lpa and high incidence of unfavorable ApoA1:ApoB ratio (<1.00). A study5 by Gupta et al at Monilek Hospital and Research Centre, Jaipur, found out that total cholesterol levels were not significantly higher in CAD patients compared to healthy age-matched controls. This finding in our study is in conformity with our observation of near normal cholesterol levels (mean = 155.9 ± 21 mg%) for most of the patients. Another study at Louisiana State University Medical College Center, New Orleans, evaluating risk factors for CAD and levels of Lp a in Asian Indians of USA found average total cholesterol to be 218.9 ± 39.0 mg% compared to 155.9 ± 21 mg% for our study. 1,4 Percentage of patients of MI patients having LDL cholesterol >100 mg% was only 25%. This value is in agreement with study by Gupta et al, which found out that level of LDL cholesterol was not significantly higher in CAD patients when compared to normal healthy age-matched controls. However, another study,4,7 of risk factor for CAD in Asian Indians of USA found average LDL cholesterol to be 117.8 ± 35.1 mg% compared to 90.4 ± 16.7 mg%

CLINICAL STUDY in our study. This study was conducted on 110 Asian Indian physicians residing in United States. However, it is pertinent to mention here that study subject’s profile was different in our study, because all patients were freshly diagnosed MI patients and who did not have any confounding factors for dyslipidemia so that a direct link of fresh MI without previous known CAD with dyslipidemia could be studied. A study by Austin2 et al recently described atherogenic lipoprotein phenotype B characterized by moderate hypertriglyceridemia, a high proportion of smalldense LDL, a high level of ApoA1 and HDL. It can inherited as a single gene trait. Atherogenic phenotype B can be differentiated from benign phenotype A by simple measurements of serum triglycerides and HDL. A triglyceride value of 95 mg/dl discriminates the two phenotypes in 83% cases, whereas an HDL value of 39 mg/dl separates the two groups in 72% of cases. When a triglyceride level of >95 mg/dl was used; 75% of Asian Indian men in the CAD among Indians study demonstrated this phenotype. This figure when using serum triglyceride >95% with HDL cholesterol <35 mg% to identify atherogenic phenotype B was found to be 91.8% in our study. The role of newer lipid parameter Lpa in atherogenesis is still to be proven; Lpa levels may be related to both atherogenesis and thrombosis and may be a key link between lipids and thrombosis.12 The levels of Lpa were found to be three times higher in the Asian Indians than among whites in United States in the CAD among Indians Study.7,13 A study12 of Lpa levels of 110 Asians physicians residing in United States found average value of Lpa to be 18.5 ± 20.0 mg%. This value is close to Lpa levels found in our study (24.9 ± 10.29 mg%). In the same study, levels of Lpa (mean = 20.0 mg%) among Indians were comparable to findings of Lpa values of Asian Indians in Singapore (20.1 mg%). The Lpa levels and high Lpa levels (>30 mg%) in males from this study (18.5 mg% and 20%) were also comparable to findings from male Indian physicians who migrated to US (19.6 mg% and 24%, respectively). In our study group, 49.44% (16/36) patients had unfavorable ApoA1/ApoB ratio (i.e. <1.00). One important observation was that none of the patients had this ratio in the high-risk range of 0.00-0.50. Studies15 have shown that ApoA1:ApoB ratio distinguishes unequivocally between persons with

and without CAD. Therefore, ApoA1 and B studies are superior to conventional total cholesterol, HDL and LDL cholesterol studies for predicting risk for atherosclerosis. A study4 of 110 Asian physicians residing in USA for risk factors for CAD found average level of ApoAI and B to be 131 ± 24 mg% and 147 ± 28%, respectively. The composite ApoA1/ApoB ratio for this population group was 0.89 which is comparable to ApoA1 by ApoB ratio obtained in our study (i.e. 0.95). A study13 conducted on lipid profile of patients with microvascular angina in Greece, found the average level of ApoB to be 146 ± 32 mg/dl in patients of CAD vs 89 ± 14.1 mg% in our study. Hence, we conclude by saying that although the absolute values of ApoA1 and ApoB were not comparable in above two studies the more important discriminator of severity of atherosclerosis i.e ApoA1/ApoB ratio was comparable to value found in our study. CONCLUSION Following conclusion can be derived from our study: ÂÂ

Total cholesterol and LDL cholesterol values were within normal range for most of the patients (average 155.9 ± 21.05 mg% and 90.4 ± 16.7 mg%, respectively).

ÂÂ

The major abnormality found in the extended lipid profile of MI patients was high triglyceride, low HDL, high Lpa and high incidence of unfavorable ApoA1 by ApoB ratio (i.e. ratio <1.00).

ÂÂ

Patient having atherogenic phenotype B as described by Austin and defined as serum triglyceride >95 mg% and HDL cholesterol values <35% was found in 60.1% patients (22/36).

ÂÂ

Percentage of patient having high Lpa values was 41.66%.

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Percentage of patient having unfavorable ApoA1/ ApoB ratio (i.e. <1.00) was 91.8.

ÂÂ

Comprehensive lipid-tetrad index as defined by Enas was 1928.6

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Unfavorable total cholesterol by HDL ratio (i.e. >5.00) was found in 36.11%(13/36) of patients.

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Unfavorable LDL cholesterol by HDL cholesterol ratio (i.e. >3.55) was found in 11.11% (4/36) patients.

ÂÂ

Percentage of patients who were overweight (BMI >25) was 25% (9/36).

Asian Journal of Diabetology, Vol. 16, No. 3, July-September 2013

CLINICAL STUDY ÂÂ

Percentage of patients who had objective evidence of truncal obesity (i.e. waist-hip ratio >1.00) was 36.11% (13/36).

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Percentage of female patients was 16.6% (6/36).

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Patients of MI had average age of 55.86 years. Percentage of patients who were <50 years was 25 (9/36). Maximum percentage of MI patients was seen in the age group 40-59 years, which included 70.22% patients (26/36).

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Rural urban division of the patients was as follows: Rural background - 63.88% (23/36), urban background - 36.11% (13/36).

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Percentage of smokers in the study group was 41.7% and percentage of tobacco chewers were 5.6%.

SUGGESTED READING 1. Enas A, Yusuf S, Mehta JL. Prevalence of coronary artery disease in Asian Indians. Am J Cardiol 1992;70(9): 945-9. 2. McKeigue PM, Miller GJ, Marmot MG. Coronary heart disease in south Asian’s: a review. J Clin Epidemiol 198942(7):597-609. 3. Stamler J, Wentworth D, Neaton JD. Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continuously graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 1986;256(20): 2823-8. 4. Enas EA, Mehta J; CADI Study. Malignant coronary artery disease in young Asian Indians: thoughts on pathogenesis, prevention, and therapy Clin Cardiol 1995;18(3): 131-5. 5. Gupta R, Kaul V. Prakash H, Saran M, Gupta VP. Lipid abnormalities in coronary heart disease: a populationbased case-control studies. Indian Heart J 2001;52(3): 332-6. 6. Chuang CJ, Subramaniam PN, Legardeur BY, Lopez A. Risk factors for coronary artery disease and levels

of lipoprotein(a) and fat-soluble antioxidant vitamins in Asian Indians of USA. Indian Heart J 1998;50(3): 285-91. 7. Mishra A, Reddy RB, Reddy KS, Muhan A, Bajaj JS. Clustering of impaired glucose tolerance, hyperinsulinemia and dyslipidemia in young North Indian patients with coronary heart disease: a preliminary case-control study. Ind Heart J 1995;51:275-89. 8. Gupta R, Gupta VP, Sarna M, Bhatnagar AS, Thanvi J, Sharma V, et al. Prevalence of coronary heart disease and risk factors in an urban Indian population: Jaipur Heart Watch. Indian Heart J 2002;54(1):59-66. 9. Anand S, Yusuf S, Vuksan V, Devanesen S, Teo K, Montague AA, et al. Differences in risk factors, atherosclerosis and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic Groups (SHARE). Lancet 2000;356: 279-84. 10. Haffner SM, D’Agostino R Jr, Goff D, Howard B, Festa A, Saad MF, et al. LDL size in African Americans, Hispanics and non-Hispanic whites: the insulin resistance atheroslerosis study. Arterioscler Thromb Vasc Biol 1999;19(9):2234-40. 11. Enas EA, Jacob S. Coronary artery disease in Indians in the USA. In: Coronary Artery Disease in Indians: A Global Perspective. Sethik (Ed.), Cardiological Society of India; Mumbai 1998:p.32-43. 12. Misra A, Luthra K, Srivastava LM. Lipoprotein (a): biology and role in atherosclerotic vascular diseases. Curr Sci 1999;76:1553-60. 13. Stadmpfer MJ, Saxcks FM, Simonetta S. A prospective study of cholesterol, apolipoprotein and risk of myocardial infarction. N Engl J Med 1998;47:2008-111. 14. Joseph A, Kutty AR, Soman CR. High risk for coronary heart disease in Thiruvanthapuram city: a study of serum lipids and other risk factors. Indian Heart J 2000;52(1):29-35. 15. Bahl VK, Vaswani M, Tlatadi D, Wasir HS. Plasma level of apolipoprotein A1 and B in Indian patients with angiographically defined CAD. Int J Cardiol 1994;46(2):143-9.

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Asian Journal of Diabetology, Vol. 16, No. 3, July-September 2013

CASE REPORT

Corneo-scleral Melting in a Diabetic Patient JOGINDER PAL CHUGH, PRACHI JAIN, RAJENDER SINGH CHAUHAN, ASHOK RATHI

ABSTRACT Scleritis is a rare, usually painful inflammation of sclera causing scleral melt and exposure of underlying uveal tissue. Although, idiopathic in 50% cases, systemic vasculitides, collagen vascular disorders and autoimmune diseases are well-established causes in remaining cases. Diabetes mellitus as an underlying cause of scleritis has not been reported in literature to the best of our knowledge. Microvasculopathy is a well-known complication of diabetes mellitus. We are presenting a case report of a painless scleral melting along with involvement of adjacent cornea in a known diabetic patient without any other systemic cause of scleritis. Keywords: Scleritis, diabetes mellitus, microvasculopathy

CASE HISTORY A 48-year-old male presented to us with an approximately 5 x 7 mm well-defined localized area of scleral thinning with prolapsed underlying uveal tissue involving inferotemporal region of left eye, which was painless and gradually progressing for last two months. About 2 mm of cornea near the limbus was also involved (Fig. 1). Recorded Snellenâ&#x20AC;&#x2122;s acuity was 6/6 OD and 6/9 OS. Ocular examination revealed mild pupillary distortion in the affected eye and moderate nonproliferative diabetic retinopathy in both eyes. Gonioscopy was not attempted due to corneal involvement. Ultrasound biomicroscopic examination of the affected eye did not reveal any mass lesion underlying the diseased area. There was no evidence of infection in the vicinity of the lesion. There was no history of ocular trauma, topical medication or any ocular surgery. Patient was a known case of diabetes for past 12 years. No history of any other systemic ailment was there. Hematological investigations revealed erythrocyte sedimentation rate (ESR) - 20 mm at the end of first hour, total leukocyte count (TLC) and differential leukocyte count (DLC) were within normal limits, Rh factor negative, antinuclear antibodies (ANA) and c-ANCA were negative. Fasting and postprandial blood sugar was 120 and 210 mg% with patient on

Regional Institute of Ophthalmology PGIMS, Rohtak, Haryana Address for correspondence Dr J oginder Pal Chugh 172-R, Model Town Rohtak, Haryana - 124 001 E-mail: chughjoginder@yahoo.co.in

Figure 1. Showing well-defined area of sclero-corneal melting in a quiescent eye.

oral hypoglycemic agents. Glycosylated hemoglobin (HbA1C) was 7.3. Renal function tests were within normal limits and no evidence of diabetic nephropathy was there. Patient was advised corneo-scleral patch grafting, which he deferred. DISCUSSION Systemic cause of scleritis can be identified in only 50% cases.1 Scleritis is usually noninfectious and associated with systemic vasculitides, connective tissue disorders and autoimmune diseases. Rheumatoid arthritis is the most common disease associated with scleritis.2 Other conditions associated with scleritis are Wegenerâ&#x20AC;&#x2122;s granulomatosis, polyarteritis nodosa, systemic lupus erythematosus, relapsing polychondritis, ankylosing spondylitis and inflammatory bowel

Asian Journal of Diabetology, Vol. 16, No. 3, July-September 2013

CASE REPORT diseases. Scleritis is also reported after ocular surgery.3 It is often complicated by involvement of adjacent structures. All patients with active scleritis require treatment. Treatment options include oral corticosteroids, nonsteroidal anti-inflammatory agents, intravenous pulsed steroid therapy, cytotoxic agents and surgical reinforcement. Oral corticosteroids are often the firstline agents. Refractory and progressive cases require cytotoxic therapy. Cyclophosphamide in a dose of 2 mg/kg is a drug of choice.4 Surgical reinforcement can be done in patients with severe thinning involving larger area in a quiescent eye. Surgical options include amniotic membrane transplantation, conjunctival flap, scleral and lamellar corneal patch graft. Kim et al reported a series of 16 cases of scleral necrosis in which 13 patients underwent lamellar scleral patch graft along with conjunctival flap and three patients underwent only conjunctival flap reinforcement.5 All cases showed excellent surface restoration except one case of graft melting. In our case, scleritis was painless and no systemic association was found on investigations except for

long-standing diabetes mellitus with poor control. A case of fungal scleritis in diabetic patients has been reported in the past.6 Diabetes mellitus per se as a cause of scleritis has not been reported to the best of our knowledge. Considering the fact that diabetes can lead to microvasculopathy, it could be the underlying factor responsible for scleral necrosis in our case. REFERENCES 1. Watson PG, Hayreh SS. Scleritis and episcleritis. Br J Ophthalmol 1976;60(3):163-91. 2. Afshari NA, Afshari MA, Foster CS. Inflammatory conditions of the eye associated with rheumatic diseases. Curr Rheumatol Rep 2001;3(5):453-8. 3. Joseph A, Biswas J, Sitalakshmi G, Gopal L, Badrinath SS. Surgically induced necrotizing scleritis (SINS) - Report of two cases. Indian J Ophthalmol 1997;45(1):43-5. 4. Hemady R, Tander J, Foster CS. Immunosuppressive drugs in immune and inflammatory ocular disease. Surv Ophthalmol 1991;35(5):369-85. 5. Kim SY, Chung WS, Hahn DK. Surgical management of scleral necrosis. J Korean Ophthalmol Soc 1995;36(1):7-12. 6. Locher D, Adesina A, Wolf TC, Imes CB, Chodosh J. Postoperative Rhizopus scleritis in a diabetic man. J Cataract Refract Surg 1998;24(4):562-5.

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High Blood Glucose Linked to Dementia Even without Diabetes Higher blood glucose levels, shy of the diabetic range, increase the risk for dementia in adults, new data from the longitudinal Adult Changes in Thought (ACT) study suggest by Paul K. Crane, MD, associate professor of medicine at the University of Washington School of Medicine, Seattle. The study is published in the August 8 issue of the New England Journal of Medicine. Among participants without diabetes, higher average glucose levels within the preceding 5 years were associated with increased risk for dementia. At a glucose level of 115 mg/dL, as compared with 100 mg/dL, the adjusted hazard ratio for dementia was 1.18. Higher average glucose levels were also related to an increased risk for dementia in those with diabetes. At a glucose level of 190 mg/dL, as compared with 160 mg/dL, the adjusted hazard ratio for dementia risk was 1.40.

Type 2 Diabetics can Reduce Weight by WAIT Program A short-term lifestyle modification program for overweight diabetic patients can lead to long-term benefits, said Padma Shri and Dr BC Roy National Awardee Dr KK Aggarwal President Heart Care Foundation of India and National President, Elect IMA. In a study conducted by Dr Osama Hamdy at the Joslin Clinic in Boston, patients who had a mean A1C of 7.6% at baseline were able to lower their A1C to 6.6% after 12 weeks of the intensive program and remained at 7% after three years. The name of the program is Why WAIT (Weight Achievement and Intensive Treatment) and it has been incorporated into regular practice at the clinic.

Asian Journal of Diabetology, Vol. 16, No. 3, July-September 2013

CLINICAL ALGORITHM

Algorithm for Management of Type 2 Diabetes Mellitus Type 2 diabetes mellitus Fasting glucose â&#x2030;Ľ 126 mg per dL (7.00 mmol per L)

Impaired fasting gluclose (100 to 125 mg per dL [5.55, 55 to 6.95 mmol per L]) or

Impaired glucose tolerance (two-hour post-glucose load; 140 to 199 mg per dL [7.75 to 11.05 mmol per L])

Random or two-hour postglucose load â&#x2030;Ľ 200 mg per dL (11.10 mmol per L)

Lifestyle intervention: Weight loss Decrease fat intake Calorie restriction Increase physical activity Reinforce at every visit

Fasting blood glucose < 250 mg per dL (13.90 mmol per L) and Random blood glucose < 300 mg per dL (16.65 mmol per L)

Postprandial glucose > 140 mg per dL

Lifestyle intervention: Weight loss Decrease fat intake Calorie restriction Increase physical activity Reinforce at every visit

Consider metformin therapy

Fasting blood glucose > 250 mg per dL or Random blood glucose persistently > 300 mg per dL or A1C > 10 percent Lifestyle intervention: Weight loss Decrease fat intake Calorie restriction Increase physical activity Reinforce at every visit

Blood glucose not controlled Begin metformin therapy Blood glucose not controlled

Sulfonylureas Less expensive, risk of hypoglycemia

Thiazolidinediones Expensive no risk of hypoglycemia

Blood glucose not controlled Alpha glucosidase inhibitors Nonsulfonylurea secretagogues Exenatide (approved for use with metfromin and/or sulfonylureas) Sitagliptin (approved for use with metformin and/or thiazolidinediones)

Begin insulin therapy Long- or intermediate-acting insulin at 10 units per day or 0.2 units per kg per day; increase by 2 units every three days Add short-acting premeal insulin as needed to normalize postprandial blood glucose

Transition back to oral agents as appropriate

Control not achieved with oral medications

Source: Adapted from Am Fam Physician. 2009;79(1):29-36.

Asian Journal of Diabetology, Vol. 16, No. 3, July-September 2013

LIGHTER READING

Testing for Gossip

“Triple filter?” “That’s right”, Socrates continued. “Before you talk to me about my friend, it might be a good idea to take a moment and filter what you’re going to say. That’s why I call it the Triple Filter Test. The first filter is truth. Have you made absolutely sure that what you are about to tell me is true?” “No,” the man said, “Actually I just heard about it and …” “All right”, said Socrates. “So you don’t really know if it’s true or not. Now let’s try the second filter, the filter of Goodness. Is what you are about to tell me about my friend something good?” “No, on the contrary.” “So”, Socrates continued, “you want to tell me something bad about him, but you’re not certain it’s true. You may still pass the test though, because there’s one filter left: the filter of Usefulness. Is what you want to tell me about my friend going to be useful to me?” “No, not really.” “Well”, concluded Socrates, “if what you want to tell me is neither true nor good nor even useful, why tells it to me at all?” …

‘Really? What happened?’ asked the doctor.

LAUGH A WHILE

In ancient Greece, Socrates was reputed to hold knowledge in high esteem. One day an acquaintance met the great philosopher and said, “Do you know what I just heard about your friend?” “Hold on a minute”, Socrates replied. “Before telling me anything I’d like you to pass a little test. It’s called the Triple Filter Test.”

dear exclaimed, ‘Oh, faith, bejaysus and begorrah! T’was horrid! Just terrible, doctor!’ ‘Well, I did as you advised and slipped it in his coffee and the effect was almost immediate. He jumped straight up, with a twinkle in his eye! With one swoop of his arm, he sent me cups and tablecloth flying, ripped me clothes to tatters and …! It was a nightmare, I tell you, an absolute nightmare!’ ‘Why so terrible?’ asked the doctor. ‘Freakin’, T’ was wonderful! But sure as I’m sittin’ here, I’ll never be able to show me face in Starbucks again.

“Happy is the man who can do only one thing; in doing it, he fulfills his destiny.

QUOTE

AN INSPIRATIONAL STORY

Lighter Side of Medicine

—Joseph Joubert

If you’re not using your smile, you’re like a man with a million dollars in the bank and no checkbook. —Les Giblin

Dr. Good and Dr. Bad SITUATION: A patient with COPD was put on oral steroid.

An Irish Woman Take it for five days

‘What about trying Viagra?’ asked the doctor. ‘Not a chance’, she said. ‘He won’t even take an aspirin.’ ‘Not a problem,’ replied the doctor. ‘Give him an “Irish Viagra”. It’s when you drop the Viagra tablet into his coffee. He won’t even taste it. Give it a try and call me in a week to let me know how things went.’ It wasn’t a week later when she called the doctor, who directly inquired as to her progress. The poor

Take it for 19 days

Asian Journal of Diabetology, Vol. 16, No. 3, July-September 2013

©IJCP Academy

LAUGH A WHILE

An Irish woman of advanced age visited her physician to ask his advice on reviving her husband’s libido.

LESSON: A five day’s course of steroid in COPD is not

inferior to the traditional 10-14 days course.

JAMA 2013;309:2223. Dr KK Aggarwal

The Asian Journal of

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Asian Journal of Diabetology, Vol. 16, No. 3, July-September 2013

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Asian Journal of Diabetology, Vol. 16, No. 3, July-September 2013

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Asian Journal of Diabetology

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