Medical Tribune February 2015 RG

RESEARCH

REVIEWSAfIibercept effective in Japanese patients with wet AMD

RESEARCH

REVIEWSCatheter ablation beneficial for elderly patients with AF

NEWSAsthma associated with new-onset sleep apnea

FEATUREWhere there’s smoke

FEBRUARY 2015

New guideline recommends treating obesity before comorbidities

FEBRUARY 2015 2

ELVIRA MANZANO

A new pharmacotherapy guideline for man-

aging obesity recommends treating obesity

before obesity-related comorbidities, a move ex-

perts described as a shift in current practice.

“The old paradigm was to treat each comor-

bidity with medications, then manage obesity,”

said Dr. Caroline M. Apovian from Boston Medi-

cal Center, Boston, Massachusetts, US, and

chair of the taskforce that authored the guide-

line. “The new approach is for physicians to

target obesity first to diminish the associated

complications such as hyperglycemia, dyslipid-

emia and hypertension, rather than treating the

comorbidities caused by the excess weight.”

Use of approved weight-loss medications as

adjuncts to diet and exercise is recommended

in patients who have not been successful with

lifestyle modification alone. For patients with

diabetes, weight loss therapy is the primary ap-

proach to improve glycemic control and reduce

cardiovascular risk.

The guideline, released by The Endocrine

Society, with support from the European So-

ciety of Endocrinology and The Obesity Soci-

ety, also transitions patients off the drugs that

cause weight gain. [J Clin Endocrinol Metab 2015;doi:10.1210/jc.2014-3415]

Obese patients with type 2 diabetes (T2D),

for example, should be started on metformin,

and if necessary followed with glucagon-like

New guideline recommends treating obesity before comorbidities

peptide-1 (GLP-1) analogs or sodium-glucose-

linked transporter-2 (SGLT-2) inhibitors that have

the additional advantage of inducing weight

loss, the guideline said.

For obese diabetic patients with hyperten-

sion, angiotensin-converting enzyme (ACE) in-

hibitors, angiotensin receptor blockers (ARBs)

and calcium channel blockers are the recom-

mended first-line therapy. A weight loss of 5-10

percent generally lowers blood pressure where-

as 3 percent reduces blood glucose levels, said

Apovian.

Sympathomimetic agents (phentermine and

diethylpropion) should not be used in patients

with uncontrolled hypertension or a history of

heart disease.

For patients with chronic inflammatory dis-

eases (ie, rheumatoid arthritis), use of non-ste-

roidal anti-inflammatory drugs (NSAIDs) and dis-

ease-modifying antirheumatic drugs (DMARDs)

is advised as corticosteroids commonly cause

weight gain, the guideline said.

Ungraded best practice recommendation

meanwhile advised against off-label use of med-

ications approved for other diseases to promote

weight loss.

Professor Donna Ryan from the Pennington

Biomedical Research Center, Louisiana State

University, Louisiana, US, and member of the

panel said sweeping changes in obesity man-

agement can help physicians identify patients

who need additional support.

FEBRUARY 2015 3

ELVIRA MANZANO

The US Food and Drug Administration (FDA)

has approved the factor Xa inhibitor edoxa-

ban (Savaysa®, Daiichi Sankyo Co., Ltd) to low-

er the risk of stroke and systemic embolism in

patients with nonvalvular atrial fibrillation (AF).

Edoxaban, administered orally once daily,

is also approved to treat deep vein thrombosis

(DVT) and pulmonary embolism (PE) in patients

who have previously been given a parenteral an-

ticoagulant for 5-10 days.

Dr. Norman Stockbridge, director, division of

cardiovascular and renal products, FDA Center

for Drug Evaluation and Research, said it is im-

portant to have a variety of these types of drugs

available to patients. The approval was largely

based on a randomized double-blind trial com-

paring two different dosages of edoxaban (30

and 60 mg) with warfarin in 21,105 patients with

moderate-to-high-risk AF. Patients treated with

edoxaban had less major bleeding than those

receiving older anticoagulant warfarin. [N Engl J Med 2013; 369:2093-2104]

In the Hokusai VTE study, edoxaban was

noninferior to warfarin in terms of the primary

Edoxaban approved to reduce stroke risk in nonvalvular AF

efficacy endpoint of recurrent symptomatic ve-

nous thromboembolism (VTE, 3.2 vs 3.5 per-

cent, respectively) and caused less bleeding in

a broad spectrum of patients, including those

with severe PE. [N Engl J Med 2013; 369:1406-

1415]

The FDA however cautioned that edoxaban,

as with other anti-clotting drugs, may increase

the risk of bleeding and healthcare profession-

als should counsel patients taking the drug. The

agency also required edoxaban manufacturer

to carry a boxed warning that the drug is less

effective in AF patients with a creatinine clear-

ance (CrCL) of >95 mL/min. Physicians should

also measure CrCL before initiating edoxaban.

Patients with CrCL levels over 95 mL/min should

be administered a different anticoagulant.

Premature discontinuation of edoxaban also

increases the risk of stroke.

Edoxaban joins three other new oral antico-

agulants – dabigatran, rivaroxaban and apix-

aban – which are designed to overcome the

limitations of warfarin.

Warfarin requires extensive monitoring and

dose adjustment and interacts with food and

other drugs.

FEBRUARY 2015 FORUM 4

Beyond Haiyan: The challenges of maintaining the drug supply chain in catastrophes CHRISTINE AILEEN M CHING

T hink about medical workers flying in, but

upon arrival, the donated medicines have

been shipped to another storm-stricken prov-

ince. What should be done if the delivered box-

es contain drugs that are not useful in emer-

gency situations, such as chemotherapeutic

agents? What if the products have labels only in

Chinese? How can doctors manage infections

when amoxicillin is the only antibiotic avail-

able? These are just some of the things that

could happen when there is no proper drug

supply chain system set in place in preparation

for disasters.

Disaster-proneA year ago, news agencies all over the world

aired how typhoon Haiyan, one of the stron-

gest recorded typhoons to make landfall, rav-

aged central Philippines. As the government

and international community flew in to send

aid to the affected regions, the infrastructure

damage, manpower losses and downed com-

munication lines revealed gaps in preparation

and response procedures for disasters of this

magnitude. One particular area of concern in

providing medical support in this crisis is the

management of the drug supply chain, which

ideally enables better distribution, access, utili-

zation and health outcomes and reduced wast-

age of medicines resources.(1)

Being commonly exposed to natural calami-

ties, the country is in need of substantial prepa-

ration for catastrophes, especially with the threat

of climate change that is set to change the defi-

nition of normal environmental conditions in the

coming years.

WHO assessmentIn a rapid WHO-commissioned evaluation

of the medicines supply system in selected

Haiyan-affected areas, it was found out that the

policies on donated medicines were not prop-

erly implemented as evidenced by stock-outs,

expired medicines and wastages as a result of

the problems in procurement, storage and dis-

tribution, and utilization of both donated and

government-supplied medicines. The problems

MT(SG)FEB15-FINAL.indd 6 1/30/15 5:54 PM


with access, timeliness and appropriateness of

medicines immediately after Haiyan and in the

rehabilitation phase highlight the necessity for a

proper management system in national, provin-

cial and municipal levels of the devolved health

care system.(2)

Existing vertical programThe selection of medicines by the govern-

ment is based on the Philippine National Drug

Formulary (PNDF) while the procurement pro-

cess follows the Philippine Procurement Act (RA

9184). The Department of Health Package List

for Emergencies and Disasters managed by the

Health Emergency Management Staff, which

is similar to other vertical programs, centrally

procures and allocates health supplies during

emergencies and disasters to augment local

supplies The Department of Health is respon-

sible for coordinating and providing medicines

assistance to the local health facilities, and in

times of disaster, has the power to assume man-

agement of these local facilities.

Dr. Jean Michel-Cann, a WHO consultant,

explained the different challenges in the differ-

ent areas of the drug management cycle dur-

ing disasters.(1) In product selection, the dona-

tions are not always included in the PNDF. Local

prescribers would often not prescribe products

with other available dosage strengths or dosage

forms not in the PNDF, resulting in product un-

derutilization and wastage.

Push system vs. pull systemThe government follows a push system in

most of its vertical programs, including the

preparation for disasters, where allocation is

determined by the national level coordinators

in the supply chain. However, immediately af-

ter a disaster, the pull system is more reliable,

where quantities are requested based on the

available data on the affected areas. During di-

sasters, there is a high risk for loss of data, so a

contingency plan of preparing and retrieving a

backup data should be in place. There are also

significant losses of products especially if the

extent of damage is so grave that the storage

areas themselves have been damaged. In ad-

dition, a sudden unpredictable increase in de-

mand compounded by the need for timeliness

is very crucial. An efficient pull system helps

avoid over-stocking of slow-moving products

and optimizes the allocated storage spaces for

the products that are more commonly utilized,.

Inadequacy in the local supply usually results in

stock-outs and emergency purchases from oth-

er suppliers or pharmacies. However, for these

purchases, only products listed in the PNDF can

be reimbursed.

Expired medicinesAnother area of concern is the wastage of

medicines and supplies, which arises from

oversupply and underutilization of some drugs,

and the influx of medications that are expired or

near-expiry. Most of these medicines that are ex-

pired or near-expiry are donated medicines that

were delivered directly into the health care facili-

ties and were not checked or approved. These

medicines cannot be used due to their question-

able quality and may harm patients instead of

helping them.


Storage and distributionAn often overlooked issue during disasters is

the maintenance of the quality and efficacy of

medicines by proper storage and distribution.

Humidity levels, temperature, and direct sunlight

may contribute to the degradation of products,

significantly decreasing their shelf-life. The prob-

lems are due to the damage to available storage

areas, absence of electricity, or simply that the

health care facilities are not prepared to handle

the sudden arrival of medicines. With these con-

ditions, it is not uncommon to see the donated

medicines stacked in cartons along hallways, or

big rooms or outside buildings exposed to en-

vironmental forces.. Distribution channels are

also not coordinated and unplanned, resulting

in parallel channels that lead to duplication of

stocks or oversupply in one area and lack of sup-

plies in another. Transportation for medicines is

also a very big concern, in addition to human

resources knowledgeable on how to handle the

drug supplies.

Data collection Finally, during disasters, data collection is

given the least priority, and stocks are often not

properly monitored and accounted for. The uti-

lization data does not return to higher levels in

the drug supply chain management, resulting in

inappropriate procurement. The assessment of

the drug supply chain shows that even during

normal circumstances, many Rural Health Units

do not have the proper inventory management

and trained personnel to handle medicines.

Manual documentation is also being practiced

from regional to the rural health level, with no

feedback to the national government despite

the presence of a National Online Stock and In-

ventory Reporting System (NOSIRS).

In a nutshellThe problems with donated medicines are

mostly due to lack of coordination among gov-

ernment agencies and donors, unavailability

of proper transportation and storage facilities,

and an updated inventory system that will pro-

vide feedback to help meet the actual needs

on the ground. Despite existing protocols, gov-

ernance, which is key to implementation and

monitoring of these protocols in emergency

situations, are not given due attention. More-

over, greater integration of procedures should

be considered to facilitate efficient receipt and

delivery of donations. Finally, health personnel

at all levels of care must be made aware of the

considerations in accepting donated products.

The proper handling of supplies should be as-

signed to people who are well-trained in this

responsibility. (The author, who is assistant professor with the UP Manila College of Pharmacy, attended the recent National Stakeholders’ Meeting on Ensuring Drug Accessibility During Disasters and Health Emer-gencies.)

References(1) National Stakeholders’ Meeting on Ensuring Drug Accessibility During Disasters and Health Emergencies, November 11, 2014. Manila.(2) Robles, YR, Loquias, MM, and Capule, FR. Assessment of the medicines supply system in selected Haiyan-affected areas (Un-published; presented at the National Stakeholder’s Meeting).

MT(SG)FEB15-FINAL.indd 8 1/30/15 5:54 PM

FEBRUARY 2015 NEWS 9

Cooking with biogas rather than solid fuels may protect against CVDLIANNE COWIE

Poor households in low-and middle-income

countries often use solid fuels for cooking,

which increases their exposure to pollutants and

thus the risk of high blood pressure. However, a

recent study has reported that switching to alter-

native fuels such as biogas may protect against

such effects.

“More than two fifths of the world’s popula-

tion cooks with solid fuels... These fuels are of-

ten burnt in inefficient stoves inside poorly ven-

tilated houses producing high levels of several

health-damaging pollutants, in particular fine

particles of a diameter of up to 2.5 µm (PM2.5)

and mixture of other pollutants,” said the study

authors, led by Maniraj Neupane from the Cen-

ter of International Health, Ludwig-Maximilians-

Universitaet, Munich, Germany. In their cross-

sectional study, the researchers determined

whether sustained use of biogas fuel for at least

10 years altered blood pressure levels among

adult female cooks ≥30 years of age in rural

Nepal. Systolic and diastolic blood pressure

(BP) were compared among 219 and 300 cooks

from households that used biogas or firewood,

respectively. The cooks were matched by age,

body mass index, and socioeconomic status

and were stratified into two age groups to ac-

count for postmenopausal changes (30 to 50

years and >50 years). [Environmental Research

2015;136:343-351]

The results showed that biogas use was as-

sociated with a substantial reduction in 24-hour

kitchen carbon monoxide levels. In addition, a

mean 9.8 mmHg reduction in systolic BP (95%

confidence interval [CI], -20.4 – 0.8) and 6.5

mmHg reduction in diastolic BP (95% CI, -12.2 –

-0.8) were observed among women >50 years

of age from biogas households after adjusting

for smoking, kitchen characteristics, ventila-

tion status, and additional fuel use. The odds of

developing hypertension were reduced by 68

percent in this group (odds ratio 0.32, 95% CI,

0.14–0.71), but no such effects were observed

among younger women.

“Sustained use of biogas for cooking for at least

[10] years is associated with lower systolic and dia-

stolic blood pressure as well as reduced risk of de-

veloping hypertension in female cooks older than

50 years,” concluded the authors. “Although the

findings of our study need to be confirmed by well-

designed longitudinal studies, our study suggests

that household biogas... could be an alternative en-

ergy source to improve cardiovascular health of mil-

lions of cooks exposed to household air pollution

[worldwide].”


Asthma associated with new-onset sleep apneaELVIRA MANZANO

Adults with asthma may be at increased

risk for new-onset obstructive sleep apnea

(OSA), according to new research.

OSA is characterized by repeated episodes

of complete or partial blockage of the upper

airway lasting 20 to 30 seconds during sleep,

which can reduce oxygen flow to vital organs.

“The longer the duration of asthma, the more

likely an individual is to develop OSA,” said

study author Dr. Mihaela Teodorescu from the

University of Wisconsin School of Medicine and

Public Health in Madison, Wisconsin, US. Left

untreated, OSA can lead to serious complica-

tions, including worsening asthma and cardio-

vascular disease.

The study involved a random sample of in-

dividuals participating in the population-based

prospective Wisconsin Sleep Cohort Study who

were recruited to undergo overnight polysom-

nography studies at 4-year intervals from 1988

through March 2013. Overall, there were 1,105

4-year follow-up intervals involving 547 individu-

als who were free of OSA (apnea-hypopnea in-

dex [AHI] of <5 events/hour) at baseline. [JAMA

2015;313:156-164]

Of 81 participants with asthma, 22 (27 per-

cent) developed incident OSA over the first

4-year follow-up interval, as compared to only

75 of 466 (16 percent) participants without asth-

ma. An analysis of all available 4-year intervals

showed there were 45 incident cases of OSA

among participants with asthma over the course

of 167 (27percent) 4-year intervals. By contrast,

there were 160 incident cases (17 percent) of

OSA among those without asthma (p difference

=0.007) over the course of 938 4-year intervals.

The differences in OSA risk were observed

despite the same average BMI changes in

patients with or without asthma during the

4-year follow-up intervals, said the authors.

Asthma was also associated with new-onset

OSA with habitual sleepiness (p=0.045).

In addition, asthma duration was related

to both incident OSA and OSA with habitual

sleepiness (p=0.01 and p=0.02, respective-

ly).

The findings lend further support to a po-

tential causal role of asthma in the devel-

opment of OSA, said the authors. However,

more studies investigating the mechanisms

underlying this association and the value of

periodic OSA evaluation in patients with asth-

ma are needed, they concluded.


Link between allergy and asthma clearELVIRA MANZANO

There is a clear connec tion between allergy

and asthma, and many patients have both

hay fever and asthma, says an allergy specialist.

Pharmacy assistants need to be aware that

patients coming in with allergic rhinitis may also

have undiagnosed asthma, said allergy special-

ist Vincent Crump of the Auckland Allergy Clinic

in Auckland New Zealand.

In atopic patients who have a genetic predis-

position to getting asthma, eczema or hay fever,

it is common to have both hay fever and asthma,

with one often being undiagnosed, Crump said.

“Many patients with allergic rhinitis related to

grass pollen will also get seasonal asthma when

their hay fever is very bad, and, because they

are more trou bled by their hay fever symptoms,

they might not seek help specifi cally for the

asthma symptoms.”

It is important that all patients with allergic

rhinitis are assessed by a doctor for asthma, he

said. How ever, asthma is not necessarily worse

in the spring months when pollen is abundant.

It also depends on what the allergic trigger for

the in dividual is, Crump said. “If they are allergic

to pollens, then their asthma could be worse in

spring or summer.

“However, if they are allergic to dust mites

or their pets, their symptoms could be worse in

win ter, when they spend more time locked up

indoors and wearing their woollen clothes which

har bor dust mites.”

Controlling both asthma and hay fever is

important if patients do have both diseases,

Crump said. “Patients with both hay fever and

asthma will have their asthma better controlled

when their rhi nitis is treated adequately, even

if their rhinitis symptoms are not their primary

concern.”

The role of pharmacistsPharmacists have a crucial role in educat-

ing asthma patients, said Jim Reid, deputy

dean of the University of Otago’s Dunedin

School of Medicine, Dunedin, New Zealand.

Reid did an informal study of asthma pa-

tients which found 30 percent could not tell

the dif ference between their reliever and pre-

venter inhalers. Many asthma patients do not

understand the importance of prophylaxis or

preventative medication, and commonly say

their blue reliever inhaler is the only one that

works. Another problem is poor inhaler tech-

nique, Reid said.

Pharmacists should be on the lookout for

asthmatics who regu larly pick up scripts for

reliever inhalers without any preventative

medication, he added.

All asthmat ics should have an “action

plan” which spells out when they need to

seek help, Crump said. Asthma patients

should be referred to a doctor if their reliever

inhaler is not reliev ing their symptoms, or

if they need to use their reliever more than

twice a week.


Certolizumab pegol improves productivity, social participation of patients with psoriatic arthritis LIANNE COWIE

Patients with psoriatic arthritis (PsA) can

benefit from treatment with certolizumab

pegol (CZP), which offers significant improve-

ments in productivity at home and at work and

also increases social participation, according to

a multinational group of researchers.

In their ongoing phase III, multicenter trial,

409 patients diagnosed with adult-onset active

psoriatic arthritis of ≥6 months’ duration were

randomized to placebo (n=136) or subcutane-

ous certolizumab pegol (400 mg loading dose

at weeks 0, 2, and 4 followed by 200 mg ev-

ery 2 weeks [n=138] or 400 mg every 4 weeks

[n=135]) for 24 weeks. The arthritis-specific

Work Productivity Survey was used to assess

the impact of psoriatic arthritis on paid work and

household productivity as well as participation

in social activities during the preceding month.

[Ann Rheum Dis 2015;74:44-51]

At baseline, 56.6 percent of placebo recipi-

ents were employed, compared with 60.1 per-

cent and 61.5 percent of patients who received

certolizumab pegol 200 mg or 400 mg, respec-

tively. At study end, the number of days of ab-

senteeism (full day of work missed) and pre-

senteeism (days where work productivity was

reduced by ≥50 percent due to arthritis) were

significantly reduced among employees who

received certolizumab

pegol, compared with

placebo (absenteeism

-1.0 – -1.8 vs -1.0 day,

respectively, and pre-

senteeism -3.0 – -3.8 vs

-0.3 days, respectively;

p<0.05). In addition, pa-

tients treated with certoli-

zumab pegol gained sig-

nificantly more household work days per month

(average 3.0–3.5 vs 1.0 day; p<0.05) and re-

ported greater participation in family, social, and

leisure activities.

“The rapid improvements seen in CZP-treat-

ed patients in paid work productivity, house-

hold productivity and participation in fam-

ily, social and leisure activities, alongside the

clinical improvements seen, suggest that CZP

is a potentially valuable treatment option for

PsA patients,” concluded the study authors,

led by Dr. A. Kavanaugh, Division of Rheuma-

tology, Allergy and Immunology, University of

California San Diego, California, US. “These

beneficial effects with respect to PsA patients’

workplace and household productivity could

ultimately result in gains in the quality of life

and in the economic burden of this chronic

inflammatory disease, particularly in those of

working age.”

FEBRUARY 2015 DRUG PROFILE 13

Lixisenatide: The latest GLP-1R agonist for glycemic control in type 2 diabetesThe advent of the incretin-based therapies, comprising two distinct classes – the

glucagon-like peptide 1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4

(DPP-4) inhibitors – have provided clinicians with a much-needed fresh approach to

controlling glucose in type 2 diabetes. This drug profile describes lixisenatide, the

newest addition to the GLP-1R agonist class. Lixisenatide became available in 2012

following extensive investigations within the GetGoal phase III clinical trial program,

which included many Asian sites.

Cathy Chow, PhD

IntroductionResearch into the pathophysiology of type

2 diabetes has led to significant advances in

pharmacotherapy for this chronic disease. Chief

among these has been the development of

agents that modify the incretin system.

In non-diabetic individuals, the incretin sys-

tem amplifies insulin biosynthesis and secretion

via the action of two hormones, glucagon-like

peptide 1 (GLP-1) and glucose-dependent insu-

linotropic polypeptide (GIP). [Mol Cell Endocri-nol 2009;297:127-136, Diabetes 2007;56:1951-

1959] GLP-1 and GIP are released from the

gastrointestinal tract in response to eating,

stimulating release of insulin from the pancreatic

beta cells. In type 2 diabetic individuals, how-

ever, the incretin system is dysregulated; spe-

cifically, release of GLP-1 and GIP in response

to oral food intake is decreased, which conse-

quently reduces insulin synthesis and secretion

and, ultimately, impairs the incretin effect. [Mol Cell Endocrinol 2009;297:127-136, Diabetes

2007;56:1951-1959]

Two distinct pharmacologic approaches

have evolved in type 2 diabetes targeting the

incretin system: GLP-1R agonism and DPP-4

inhibition. DPP-4 inhibitors block endogenous

DPP-4, the enzyme that mediates breakdown

of GLP-1 and GIP, thereby increasing levels of

these hormones. [Lancet 2006;368:1696-1705,

Clin Ther 2012;34:993-1005, Int J Clin Pract 2006;60:1454-1470] Meanwhile, the GLP-1R

agonists mimic the action of GLP-1, exerting a

direct, pharmacologic, intrinsic biologic effect at

the receptor. [Drug Des Devel Ther 2013;8:25-

38] Liraglutide, exenatide (twice daily or once

weekly) and lixisenatide are the currently avail-

able GLP-1R agonists. These agents have dem-

onstrated efficacy, safety and tolerability, with a

lower risk of hypoglycemia than that observed

with either insulin or sulfonylureas. [Diabetes Obes Metab 2014;16:588-601]


LixisenatideLixisenatide is a potent and selective GLP-1R

agonist. [Lyxumia Injection, Solution. Product

Information. March 2014] It is a 44-amino acid

chain peptide based on the structure of exen-

din-4, with the difference being that it is ami-

dated at the C terminal (proline removed and

replaced by six lysine residues). [Regul Pept 2010;164:58-64] Lixisenatide is indicated for

the treatment of adults with type 2 diabetes to

achieve glycemic control in combination with

metformin; metformin plus sulfonylurea; basal

insulin plus metformin; or basal insulin plus sul-

fonylurea; when these agents, together with diet

and exercise, do not provide adequate glycemic

control. [Lyxumia Injection, Solution. Product In-

formation. March 2014]

Pharmacology Mechanism of action

Lixisenatide has three main mechanisms of

action: (1) it stimulates insulin secretion when

there is increased blood glucose but not in nor-

moglycemia; (2) it suppresses glucagon secre-

tion without affecting the rescue mechanism of

glucagon secretion in hypoglycemia; and (3) it

may have insulinotropic activity based on ani-

mal studies, including enhancement of insulin

biosynthesis and stimulation of beta cell prolif-

eration. [Lyxumia Injection, Solution. Product

Information. March 2014]

Clinically, treatment with lixisenatide effec-

tively reduces glycated hemoglobin (HbA1c),

fasting plasma glucose and post-prandial glu-

cose levels. This last effect can be very pro-

nounced, differentiating lixisenatide from the

other GLP-1R agonists. [Core Evid 2011;6:67-

79] Interestingly, the loss of post-prandial glu-

cose control is thought to be a central factor for

the development of type 2 diabetes. [Diabetes

Care 2007;30:263-269, Diabetes Obes Metab

2013;15:642-649] Lixisenatide treatment may

also promote weight loss and reduce the need

for exogenous insulin. [Drug Des Devel Ther 2013;8:25-38]

Clinical efficacy

The GetGoal program of phase III random-

ized controlled clinical trials extensively investi-

gated the efficacy and safety of lixisenatide 20

µg once daily, either as monotherapy or add-on

therapy to basal insulin, metformin and/or sulfo-

nylurea, across the spectrum of type 2 diabetes

scenarios (Table). [Diabetes Ther 2014;5:367-

383, Diabetes Care 2013;36:2543-2550, Dia-betes Care 2011;54 Suppl 1:A784, Diabetes Care 2012;3:70-79, Diabetologia 2011;54 Suppl

1:A785, Poster 1010-P presented at the 72nd

Scientific Sessions of the American Diabetes

Table: GetGoal Phase III Clinical Trial Program

Study Lixisenatide intervention,

details

HbA1c (percent) FPG (mmol/L) PPG (mmol/L)

GetGoal-Mono (n=361)

monotherapy (1-step vs

2-step dose)-0.5*** to -0.7*** -0.9** to -1.1*** -3.1*** to -3.7***

GetGoal-F1 (n=482)

+ metformin (1-step vs

2-step dose)-0.4*** to -0.5** -0.56*** to -0.53** N/A

GetGoal-M (n=680)

+ metformin (evening vs

morning dose)-0.9*** to -0.8*** -0.81** to -1.19**

-4.5* (morning dose) NS

(evening dose)

GetGoal-S (n=855)

+ sulfonylurea ± metformin

-0.9*** -0.99*** -6.19***

GetGoal-P (n=484)

+ pioglitazone ±metformin

-0.9*** -1.16*** N/A

GetGoal-L-Asia (n=311)

+ basal insulin ± sulfonylurea

-0.8*** -0.4** -7.96***

GetGoal-L (n=496)

+ basal insulin ± metformin

-0.7** NS -5.54***

GetGoal-Duo-I (n=898)

+ optimally titrated basal insulin +

OAD-0.7*** +0.34 (NS) -3.09***

GetGoal-X (n=634)

versus exenatide ± metformin (non-

inferiority trial)-0.8 -1.22 (NS) N/A

All values are mean differences from baseline, significance level as compared with placebo. One-step dose increase was 10 to 20 μg; two-step dose increase was 10 to 15 to 20 μg. *p<0.05; **p<0.005; ***p<0.0005. Non-inferiority achieved at predefined margin of 0.4 percent. OAD, oral antidiabetic drug; FPG, fasting plasma glucose; PPG, post-prandial glucose; NS, not significant; N/A, not available. [Adapted from Diabetes Ther 2014;5:367-383]


Association, June 8–12, 2012, Philadelphia,

PA, USA, Diabetes Obes Metab 2012;14:910-

917, Diabetes Care 2013;36:2489-2496, Dia-betes Care 2013;36:2497-2503, Diabetes Care

2013;36:2945-2951] These data collectively

demonstrated significant reductions in HbA1c,

fasting plasma glucose and post-prandial glu-

cose levels with lixisenatide monotherapy or

combination therapy, with either weight loss

or no weight gain. [Diabetes Obes Metab

2014;16:588-601]

Of note, the GetGoal-L-Asia trial was con-

ducted exclusively in patients from Japan, Ko-

rea, Taiwan and the Philippines. [Diabetes Obes Metab 2012;14:910-917] This was based on the

rationale that drugs targeting the incretin system

appear to be particularly effective in Asian pa-

tients as they tend to have a pathophysiology of

insulin deficiency more than insulin resistance,

with some evidence for a profound underly-

ing GLP-1 insufficiency. [Diabetes Obes Metab

2012;14:910-917, J Diabetes Invest 2010;1:8-23,

J Diabetes Invest 2010;1:56-59, J Diabetes In-vest 2012;3:70-79]

Dosing and administration

Lixisenatide is injected subcutaneously in the

thigh, abdomen or upper arm. It is administered

once daily within the hour prior to the first meal

of the day or the evening meal. The starting dose

is 10 µg once daily for 14 days, which is then in-

creased to 20 µg once daily as the maintenance

dose. If a dose is missed, lixisenatide should be

injected within the hour prior to the next meal.

When added to metformin, the metformin dose

should not require adjustment. When added to

basal insulin or sulfonylurea, however, a reduc-

tion in these existing therapies may be consid-

ered to reduce the risk of hypoglycemia, de-

pending on the individual response. [Lyxumia

Injection, Solution. Product Information. March

2014]

Adverse events

Lixisenatide was generally well tolerated in

clinical trials, with gastrointestinal events (nau-

sea and vomiting) being the most frequently re-

ported, which were mostly mild and transient.

[Lyxumia Injection, Solution. Product Informa-

tion. March 2014] Severe symptomatic hypogly-

cemia was uncommon.

Future directions Lixisenatide is the first once-daily prandial

GLP-1R agonist, and the latest GLP-1R ago-

nist, to become available. It is the most stud-

ied agent in its class in combination with basal

insulin and, given its effectiveness, tolerability

and safety as add-on therapy to basal insulin

or oral antidiabetic drugs, it represents an im-

portant, new pharmacologic option for type 2

diabetes.

PPI Therapy: Safety Considerations

Professor Prateek Sharma

Associate Professor of Medicine, Division of Gastroenterology and Hepatology, University of Kansas School of Medicine, Kansas City, Missouri, USA

Proton-pump inhibitors (PPI) are generally safe drugs. However, some PPIs do have a few important safety considerations.

The first safety consideration is with regard to the use of PPIs in patients receiving clopidogrel. The efficacy of clopidogrel is dependent on its conversion to active metabolites via cytochrome P2C19. It has been hypothesized that PPIs competitively inhibit clopidogrel activation. The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation (PRINCIPLE) – Thrombolysis in Myocardial Infarction (TIMI) 44 study showed that in patients undergoing elective percutaneous coronary intervention, clopidogrel-receiving patients on PPIs showed significantly lower inhibition of platelet aggregation (23.2%) compared with those not on PPI (35.2%; p=0.02).1 However, other TIMI trials suggested that PPIs should not be withheld from patients on clopidogrel or prasugrel when it is clinically indicated.1

It should also be emphasized that PPI-related attenuation of clopidogrel efficacy is not a class effect. For example, dexlansoprazole has no clinically significant effect on clopidogrel active metabolite pharmacodynamics as measured by inhibition of platelet aggregation and inhibition of platelet reactivity index (Figure 3).2 As a result, the US Food and Drug Administration (FDA) has differentiated the PPIs in the updated label of clopidogrel: “Avoid concomitant use of [clopidogrel] with omeprazole or esomeprazole … Dexlansoprazole, lansoprazole and pantoprazole had less effect on the antiplatelet activity of [clopidogrel] than did omeprazole or esomeprazole.3

The US FDA also warns that PPIs may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine, especially in patients who received high-dose, long-term PPI therapy (a year or longer).4 In addition, PPIs may also be associated with an increased risk of Clostridium difficile-associated diarrhea, especially in hospitalized patients.5 Hence, the US FDA recommended that patients

should use the lowest PPI dose and the shortest duration of therapy required to treat the underlying condition.

Overall, some safety concerns have been raised regarding the use of PPIs. While literature does support some of these risks, serious adverse events are quite rare. Like any medical intervention, the clinical risk/benefit of PPI therapy should be evaluated, and should not be withheld when benefits outweigh risks. Further minimize risks of PPI therapy by making rational decisions in PPI choice and administration. REFERENCES:1. Ho PM, et al. JAMA 2009;301:937-944.2. Frelinger AL III et al. J Am Coll Cardiol. 2012;59:1304-1311.3. Plavix® (clopidogrel) prescribing information. Bridgewater, New Jersy, USA: Sanofi-Aventis; 2013.4. US Food and Drug Administration. FDA Drug Safety Communication: Possible increased risk of fractures of the hip, wrist,

and spine with the use of proton pump inhibitors. Maryland: US Food and Drug Administration; 2011.5. US Food and Drug Administration. FDA Drug Safety Communication: Clostridium difficile-associated diarrhea can

be associated with stomach acid drugs known as proton pump inhibitors (PPIs). Maryland: US Food and Drug Administration; 2012.

〉 Figure 3. Effect of dexlansoprazole vs omeprazole on clopidogrel platelet inhibition2

Discussion with Professors Peura & Sharma

0.24.7

35.2

Dexlansoprazole 60 mgb

Positive control (Omeprazole 80 mg)b

IPA = Inhibition of PlateletAggregation; PRI = PlateletReactivity Index.aADP 5 µM.bN=40 randomized per arm.

0

20

40

% Decrease in IPAa

With Clopidogrel and PPICoadministration for 9 Days

% Decrease in Inhibition of PRIWith Clopidogrel and PPI

Coadministration for 9 Days

Ch

ang

e, %

22.5

Sponsored as a service to the medical profession by Takeda Pharmaceuticals (Asia Pacific) Pte. Ltd. For Healthcare Professionals Only.

Editorial development by MIMS MedComms. The opinions expressed in this publication are not necessarily those of the editor, publisher or sponsor. Any liability or obligation for loss or damage however so arising is hereby disclaimed. © 2015 MIMS. All rights reserved. No part of this publication may be reproduced by any process in any language without the written permission of the publisher.

MIMS Pte Ltd, 6 Shenton Way, #15-08, OUE Downtown 2, Singapore 068809. Tel: +65-6290 7400 Fax: +65-6290 7401 Email: [email protected] Website: www.mims.com D

EX-F

PA-1

2201

4-20

Q What is the basis of the 25%-75% ratio of drug release with dexlansoprazole capsule?

A Several studies were conducted to determine the optimal regimen for this unique drug delivery system, and the 25%-75% ratio was found to be the most efficient in prolonging the area under the curve of dexlansoprazole.

Q Can dexlansoprazole be given via nasogastric tube (NGT)?

A The capsule can be opened and the granules administered with water via a French 16 NGT or larger.

Q Will a prokinetic affect the pharmacokinetics of dexlansoprazole?

A The effect of a prokinetic on dexlansoprazole has not been studied. However, the release of dexlanso-prazole from the microgranules is not time-dependent, but pH dependent. Hence, the second peak of drug release will occur once the microgranules reach the appropriate site in the intestines, regardless of time. A prokinetic may increase this by only a few seconds.

Q How do you manage a patient with non-erosive reflux disease that does not respond to high-dose proton-pump inhibitors (PPI), in the setting where pH monitoring is not available, as in the case in most of Asia?

A Ideally, these patients should undergo pH monitoring. However, in the absence of this modality, you may presume that the patient has a non-acid disease. You may

want to consider giving a prokinetic or agents that decrease visceral hypersensitivity,

such as tricyclic antidepressants.

Q What is the role of PPIs in the treatment of extra-esophageal reflux disease?

A The management of extra-esophageal reflux disease is directed at

relieving symptoms. In this context, remember that it is also multifactorial.

Hoarseness, chronic cough, or asthma, may be due to reflux, smoking,

angiotensin-converting enzyme inhibitors, voice overuse, post-nasal

drip or allergies. Reflux may be treated with PPIs, but other causes

should also be identified and treated as well.

Q When should dexlansoprazole be given in relation to clopidogrel to minimize

drug interaction?

A There is currently no data evaluating how timing of administration of

dexlansoprazole affects interaction with clopidogrel. However, considering that

dexlansoprazole has minimal impact on platelet aggregation, you can probably give

it at any time in relation to clopidogrel.

Q From 15% to 30% of Asians are poor metabolizers of PPIs and other substrates

of CYP2C19. Does this affect the safety of PPIs?

A In poor metabolizers, there may be an increase in PPI effect, with a corresponding increase in adverse events (AE). In these patients, AEs should be monitored. Further minimize risks by using PPIs that are less likely to cause drug interactions.

Q Should acid suppressive therapy to prevent or treat gastrointestinal (GI) bleeding be given to patients who just underwent percutaneous cardiac intervention?

A Patients at high risk of GI bleeding due to age, history of gastric ulcers, or history of gastric ulcer bleed, should receive gastroprotection, and a PPI should be considered. Many of these patients would be receiving clopidogrel. Based on the recommendation of the US Food and Drug Administration, it is best not to take risks, and choose PPIs that are less likely to interact with clopidogrel (eg, dexlansoprazole, lansoprazole, or pantoprazole) may be used.

Patients with high-risk, active bleeding should be treated with endoscopic haemostasis and intravenous PPI for 72 hours followed by oral PPI.

The decision to discontinue clopidogrel depends on how long the stent has been in place. If the stent has been deployed over a year ago, clopidogrel may be safely discontinued. If it has been in place from 6 to 12 months, discuss the safety of discontinuing clopidogrel with the patient’s cardiologist.

FEBRUARY 2015 RESEARCH REVIEWS 17

Zonisamide an effective treatment for alcohol dependence

Zonisamide appears to have similar efficacy

to topiramate in the treatment of patients

with alcohol dependence, but may be better tol-

erated, according to a recent study.

Under double-blind placebo-controlled con-

ditions, zonisamide was compared to two anti-

convulsant drugs, topiramate and levetiracetam

(positive controls), in 85 alcohol-dependent

patients (37 women) aged 21–65 years. Alco-

hol dependence was defined as consuming

≥35 standard drinks (for men) or ≥28 standard

drinks (for women) per week consecutively

for at least 4 weeks. [J Clin Psychopharmacol 2015;35:34-42]

The patients were randomized to levetirace-

tam 2000 mg/day (n=21), topiramate 300 mg/

day (n=21), zonisamide 400 mg/day (n=19),

or placebo (n=24) for 14 weeks (including a

2-week taper period). Neuropsychological eval-

uations were performed at week 1 (before drug

therapy) and at week 12 (at the end of mainte-

nance therapy) to evaluate cognitive function-

ing, including working memory, language func-

tion, executive function, visual processing, and

psychomotor performance.

At study end, both zonisamide and topiramate

significantly reduced the number of drinks con-

sumed per day, the percent days drinking, and

the percent days heavy drinking. Levetiracetam

only reduced the percent days heavy drinking.

Topiramate was found to increase mental slow-

ing, while both topiramate and zonisamide were

associated with modest reductions in verbal flu-

ency and working memory.


Catheter ablation beneficial for elderly patients with AF

Catheter ablation maintains normal sinus

rhythm and lowers stroke risk and mortal-

ity among elderly patients with atrial fibrillation

(AF).

Researchers determined the long-term safety

and efficacy of the procedure in 261 patients

aged ≥75 years who had AF; they compared

observed outcomes between these patients and

an additional 63 patients who were eligible for

the study, but who either declined or were un-

suitable for ablation. All patients were followed-

up every 3 months. The primary endpoints for

analysis were maintenance of normal sinus

rhythm and the incidence of stroke, death, and

major bleeding. [Heart Rhythm 2015;12:44-51]

After a mean follow-up of 3 ± 2.5 years, 216

(83 percent) patients who underwent catheter

ablation remained in normal sinus rhythm com-

pared with 14 (22 percent) patients who did not

(p<0.0001). The 1- and 5-year survival rates

among the patients with normal sinus rhythm

following ablation were 98 percent and 87 per-

cent, respectively. Among patients who under-

went ablation but did not maintain normal sinus

rhythm, the survival rates were 86 percent and

52 percent, respectively. The 1- and 5-year sur-

vival rates among the patients who did not un-

dergo ablation were 97 percent and 42 percent.

Normal sinus rhythm was identified as an in-

dependent parameter favoring survival (hazard

ratio [HR], 0.36, 95% confidence interval [CI],

0.2–0.63; p=0.0005). In contrast, older age

(HR, 1.09, 95% CI 1.01–1.16, p=0.02) and an

ejection fraction <40 percent (HR, 2.38, 95%

CI, 1.28–4.4; p=0.006) were found to be unfa-

vorable parameters.


Sufentanil sublingual tablet system a safe, effective option for postoperative pain

The novel sufentanil sublingual tablet system

(SSTS) is both safe and effective for man-

aging postoperative pain, according to a recent

US-based study.

In the phase III double-blind trial, which was

conducted at 13 hospitals in the US between

March 2012 and January 2013, 178 male and

female patients with moderate-to-severe post-

operative pain were randomized to the SSTS

(n=128) or placebo (n=50) after undergoing

open abdominal surgery. The SSTS dispensed

a 15 µg sufentanil tablet with a 20-minute lock-

out, and an identical system was used to dis-

pense the placebo. Pain intensity scores were

recorded at baseline and up to 72 hours after

treatment initiation. Patient and health care pro-

vider global assessments of the method of pain

control were also recorded. [Reg Anesth Pain Med 2015;40:22-30]

The mean summed pain intensity differ-

ence (SPID) over 48 hours was significantly

higher among patients in the SSTS group com-

pared with placebo recipients (105.60 vs 55.58;

p=0.001). Moreover, significantly higher mean

SPID and total pain relief scores were observed

among patients in the SSTS group at all time-

points from 1 or 2 hours up to 72 hours after

treatment initiation. Significantly more “good”

or “excellent” ratings of pain relief were also

recorded by patients and health care providers

for the SSTS compared with placebo at all time-

points (p<0.001). Safety parameters were simi-

lar between the two groups.


Rice consumption not associated with CVD risk

Publicity surrounding the possible associa-

tion between rice consumption and arsenic

exposure has raised concerns that habitual rice

consumption may increase the risk of developing

cardiovascular disease, but there is no evidence

of any such association in the US population.

The study investigators prospectively exam-

ined the association between consumption of

white and brown rice and cardiovascular dis-

ease risk among 207,556 women and men

who were free of cardiovascular disease and

cancer at baseline. A total of 73,228 women

were participants in the Nurses’ Health Study

(1984-2010), 92,158 women were participants

in the Nurses’ Health Study II (1991-2011), and

42,170 men were participants in the Health

Professionals Follow-Up Study (1986-2010).

Rice consumption was assessed using food-

frequency questionnaires and the incidence

of fatal and non-fatal cardiovascular events

(including coronary artery disease and stroke)

was recorded from self-reports or obtained

from patient medical records. [Am J Clin Nutr 2015;101:164-172]

A total of 12,391 cases of cardiovascular dis-

ease (7,719 coronary artery disease and 4,672

stroke) were observed over 4,393,130 person-

years of follow-up. After adjusting for major

cardiovascular risk factors, consumption of ≥5

servings of rice per week compared with <1

serving per week did not lead to a remarkable

increase in the risk of developing cardiovascular

disease, regardless of whether individuals con-

sumed white rice (hazard ratio [HR], 0.98, 95%

confidence interval [CI], 0.84–1.14) or brown

rice (HR, 1.01, 95% CI, 0.79–1.28).


AfIibercept effective in Japanese patients with wet AMD

Aflibercept, a novel anti-vascular endothelial

growth factor agent, has been found to be

both safe and effective in the treatment of Japa-

nese patients with wet age-related macular de-

generation (AMD).

In the double-masked, multicenter VIEW 2

trial, 1,240 patients from 172 sites in Europe,

the Middle East, Asia Pacific, and Latin America

were randomized to intravitreal aflibercept 0.5

mg every 4 weeks, 2 mg every 4 weeks, 2 mg

every 8 weeks after 3 monthly injections, or ra-

nibizumab 0.5 mg every 4 weeks. Vision mainte-

nance and best corrected visual acuity (BCVA)

were assessed at week 52. The present report

relates to a subgroup analysis that was per-

formed using data obtained from 101 Japanese

patients included in the trial. [Br J Ophthalmol 2015;99:92-97]

All of the Japanese patients treated with in-

travitreal aflibercept (n=70) maintained their vi-

sion at week 52, compared with 96 percent of

the Japanese patients treated with ranibizumab.

BCVA was improved in all treatment groups,

with decreases in central retinal thickness and in

the mean area of choroidal neovascularization

present in all treated patients. The incidence

of adverse events was also similar among the

treatment groups.

The researchers note that outcomes from the

Japanese population were consistent with those

from the total VIEW 2 population.


Exercise therapy can reduce need for total hip replacement in patients with hip OA

Patients with radiographic hip osteoarthritis

(OA) who have mild-to-moderate symp-

toms may find that exercise therapy can reduce

the need for total hip replacement, according

to a recent study.

The analysis was based on data collected

from the long-term follow-up of 109 patients

aged 40–80 years with OA who participated

in a randomized trial investigating the effi-

cacy of exercise therapy plus patient educa-

tion or patient education alone for maintain-

ing the native hip. Patient education consisted

of three group sessions while the exercise

therapy program was designed for patients

with hip OA and included strengthening, flex-

ibility, and functional exercises performed 2–3

times a week for 12 weeks. [Ann Rheum Dis

2015;74:164-169]

During the 3.6–6.1-year follow-up period,

22 patients in the exercise therapy group un-

derwent total hip replacement compared with

31 patients who only participated in the edu-

cation sessions. The 6-year cumulative sur-

vival of the native hip was 41 percent and 25

percent, respectively (p=0.034). Participation

in the exercise program had a protective effect

(hazard ratio 0.56, 95% confidence interval

0.32–0.96). Although self-reported hip func-

tion was better among patients in the exercise

group, pain and stiffness were not significant-

ly different between the groups.

The researchers concluded that their find-

ings support offering exercise therapy as a

first-line treatment for hip OA in patients with

mild-to-moderate symptoms.

FEBRUARY 2015 FEATURE 23

Where there’s smokeA haze has periodically wafted over Southeast Asia for 20 years. But despite rising

public health concern, the problem remains as opaque as the smoke itself, Mike Ives

reports.

At the age of 13, Tan Yi Han could not see the

edge of his schoolyard. It was 1998 in Sin-

gapore, the wealthy city-state known for its tidy

streets and clean, green image. But for much

of that particular school year, clouds of smoke

shrouded the skyline. The record-setting air pol-

lution, which had begun in 1997 and lasted for

months, caused a 30 percent spike in hospital

visits. It would later be remembered as one of

Southeast Asia’s worst-ever “haze episodes”.

Haze episodes have occurred in Southeast

Asia nearly every year since. Back in 1998, and

for years afterwards, Tan didn’t think too deeply

about them. Yet at some point in his late 20s,

he began to wonder: where did the haze come

from? And why did it keep coming back?

Air pollution kills around 7 million people

every year, according to the World Health Or-

ganization (WHO), accounting for one in eight

deaths worldwide in 2012. The main causes of

death were stroke and heart disease, followed

by chronic obstructive pulmonary disease

(COPD), lung cancer, and respiratory infections

among children.

It is especially bad in the Asia-Pacific region,

which has a population of over 4.2 billion and

high population density. China and India alone,

with a combined population of around 2.7 bil-

lion, are both enormous sources and victims of

air pollution.

In 2010, 40 percent of the world’s premature

deaths caused by air pollution were in China,

the world’s largest emitter of carbon dioxide,

according to a survey published in the Lancet. The University of Hong Kong’s School of Pub-

lic Health reported more than 3,000 premature

deaths in the city in 2013, and the situation in

many mainland Chinese cities is reckoned to

be far worse. A poll by the US Pew Research

Center found that 47 percent of Chinese citizens

thought air pollution to be a “very big” problem

in 2013 (up from 31 percent in 2008). It is now

a central focus for many Chinese environmental

groups and a growing source of anxiety for the

country’s leadership.

Similar health concerns are building in India,

where air pollution is now the fifth-leading cause

of death. Between 2000 and 2010, the annual

number of premature deaths linked to air pol-

lution across India rose six-fold to 620,000, ac-

cording to the Centre for Science and Environ-


ment, a public-interest research and advocacy

group in New Delhi. In May 2014, the WHO said

that New Delhi had the worst air of 1,600 cities

surveyed worldwide and that rising air pollution

had increased the risk of strokes, cancers and

heart disease. Another 2014 study has linked a

significant drop in India’s wheat and rice crop

yields to rising levels of two air pollutants – black

carbon from rural cooking stoves and ground-

level ozone formed from motor vehicle exhausts,

industrial emissions, and chemical solvents –

between 1980 and 2010.

In both China and India, air pollution is one

consequence of a massive exodus from farm to

city that has occurred in recent decades. The

change has contributed to rising emissions from

both vehicles and factories, especially coal-fired

power plants, and an emerging middle class

that increasingly desires a range of consumer

goods that are common in Europe and the US.

Southeast Asia has encountered similar

problems in recent decades as its economies

and populations have boomed. In fact, accord-

ing to the WHO, nearly one million of the 3.7 mil-

lion people who died from ambient air pollution

in 2012 lived in Southeast Asia.

But on top of smokestacks and tailpipes, the

region faces an added burden: smoke haze pro-

duced in Indonesia that is a by-product of the

world’s US$50 billion palm-oil industry.

In the summer of 2013, a plane carried Tan Yi

Han over the Straits of Malacca to Pekanbaru,

the capital of Riau province, the largest palm-

oil production region in Indonesia. Tan, then a

28-year-old financial consultant, was volunteer-

ing with the Global Environment Centre, a Ma-

laysian group that has worked for years to pre-

vent and mitigate haze. He travelled to the heart

of neighbouring Indonesia, just after a record-

breaking haze episode hit peninsular Malaysia.

On a driving tour in Riau, he saw endless

acres of burned-out landscapes. Fires had turned

swampy peat bogs, the area’s natural vegeta-

tion, into land whose parched surface resembled

charcoal. These fires are to dry out the peatlands

for agricultural uses, mainly the cultivation of oil

palms. But in some villages, fires had even de-

stroyed existing oil palm trees that belonged to

multinational companies or local farmers.

Tan had a memorable encounter in the village

of Rantau Bais. A couple there plied him with tea

and snacks, then quietly asked if he could spare

any of his own food for them. Their daughter

had developed a respiratory problem because

of the haze. The surprise medical bill, coupled

with the fire destroying their oil palm crops, had

left the family penniless and hungry.

Until that moment, he had mostly thought of

peat blazes as “forest fires,” as they are often

called in media reports. But here was a visceral

reminder that the fires affect working land and

real people. “It really touched me,” said Tan. “I

made a promise to myself that I’d do my best

to prevent them from suffering from fires again.”

It was an issue, he felt, that required far more

public discussion – and when the time was right,

action. “I must get more people involved,” he

had thought, “and turn this into a movement.”

Hazy skies may all look similar, but the emis-

sions from any particular source are unique. A

factory smokestack in Beijing releases a differ-

ent mix of chemical compounds into the atmo-


sphere than an automobile tailpipe in New Delhi

does. And the extent of pollution in a given city

will depend on how carefully emissions are con-

trolled, and how easily they can be dispersed.

Vehicle and factory emissions have been

analysed for decades in high-income countries,

but haze smoke, and its impact on health, is not

well understood. “Not many people have in-

vestigated it even though it’s a very important

phenomenon,” said Mikinori Kuwata, an atmo-

spheric chemist at Singapore’s Nanyang Tech-

nological University.

Unlike factory and vehicle emissions, wildfire

smoke is not regulated by tailpipe scrubbers,

catalytic converters or other pollution-mitigating

applications. The composition of the smoke also

varies widely according to the type of material

that is burning. Peatlands, for example, typically

take a longer time to burn than drier matter – just

as a damp piece of wood takes longer to burn

in a campfire. According to the US Environmen-

tal Protection Agency, peat fires burn at lower

temperatures and produce smoke that is more

harmful, and in larger quantities, than the aver-

age forest fire or grassland fire does.

The emissions from a given peat fire will large-

ly depend on the peat’s composition, its burning

temperature and how far below the ground the

fire occurs. But such details aren’t yet available

in Indonesia, whose peatlands cover an area

roughly the size of the UK. As a result, Kuwata

told me, “We do not have a very reliable inven-

tory” of the country’s peatland fire data. Kuwata

burns Indonesian peat in his Singapore labo-

ratory to study its chemical properties, but his

work is limited, he said, because he can never

be sure whether his experiments mirror reality.

Indonesia has an enormous repository of

tropical peatlands – and, for a generation, areas

of these have been burned to prepare the land

for the cultivation of oil palms. Peat smoke now

contributes around 40 percent of Indonesia’s

overall greenhouse gas emissions. Palm oil is

an ingredient in a range of consumer products,

from lipstick to ice cream. Yet it has also helped

to give its source country the dubious distinction

of being the world’s third-largest greenhouse

gas emitter after China and the US – as well as a

leading source of hazardous smoke haze.

On a summer afternoon, the skies were a

milky white in Riau, the Indonesian province that

produces about a quarter of Indonesia’s palm

oil. My first stop was the headquarters of WALHI,

an NGO in the city of Pekanbaru that lobbies the

Indonesian government for action on haze and

other environmental problems.

I arrived at WALHI’s headquarters, a low-rise

residential building near the Pekanbaru airport,

just as a group of farmers and environmental

activists were discussing haze, over coffee and

cigarettes, with Sri Nurhayati Qodriyatun, a re-

searcher for the Secretary General of Indone-

sia’s parliament.


Qodriyatun said her boss had dispatched her

to Riau to compile a report on haze. At the meet-

ing, she explained that, according to govern-

ment estimates, forest fires were generally not

occurring in areas owned by large plantations.

The crowd stirred.“Government statements about haze are

false!” shouted an activist from a local NGO,

Forest Rescue Riau Network. “And there’s no

coordination between ministers – they just pass

the blame around!”

The exchange underscored the long-running

debate across Southeast Asia about who, ex-

actly, is responsible for Indonesia’s peat fires.

Farmers and environmental groups often ac-

cuse companies, many of which are headquar-

tered in Singapore or Malaysia, of malfeasance.

But many companies say such criticism is over-

blown, and that they have largely reformed their

destructive land-clearing practices in recent

years through voluntary reform initiatives like the

Roundtable on Sustainable Palm Oil, an indus-

try-led consortium.

Whoever is right, said Qodriyatun, the fires

have damaged Indonesia’s international reputa-

tion, and the Indonesian government pays little

attention to their health implications in Riau and

beyond.

“Personally, I don’t think the government is

managing this well,” she told me after the meet-

ing. “Usually they just react after the fires start,

but they should think more about prevention.”

Peat fires, though, are notoriously hard to

predict and extinguish. They start and spread

easily, and sometimes uncontrollably, depend-

ing on conditions like wind speed, the depth of

the soil and the dryness of the air.

“It’s really hard to know how bad a fire will be

when it starts,” said Dedy Tarsedi, a farmer in

the Riau village of Bungaraya. We were sitting in

a roadside café flanked by oil palm trees. Tarse-

di told me that oil palm is the crop of choice for

Bungaraya farmers because it is more valuable

than paddy rice. A hectare of oil palm, he said,

typically earns a farmer around 48 million Indo-

nesian rupiah (nearly US$4,000) per year. Paddy

rice, by contrast, brings in just 40 million rupiah.

But as oil palm cultivation has increased in

the village, so have fires. And they affect both

corporate plantations and smallholder farmers.

“If a fire happens and we can’t control it, we’ll

report it,” said Maman, a Bungaraya farmer. But

sometimes, even helicopters are powerless to

stop the burning, he added. “And during the re-

ally bad fires, a lot of the kids cough and end up

at the clinic with health problems.”

In 2009, Indonesia passed a law banning

fires on peat plantations. Farmers in Bunga-

raya told me that, as a result, they had started

to clear peat bogs manually, without using fire.

But Tarsedi said manual clearance is more la-

bour-intensive and requires extra fertilisers. And

that, he said, requires extra time and money that

most farmers don’t want to part with.

When the wind blows from the west, smoke

can whip east across the Straits of Malacca and

into both Singapore and Kuala Lumpur (the

capital of nearby Malaysia) – collectively home

to about 7 million people. Southeast Asia is not

the only place where the burning of vegetation

occurs over large areas; most of the world’s fires


occur in Africa and South America. But South-

east Asia’s fires are unique, says Miriam Marlier,

an atmospheric researcher at Columbia Univer-

sity, because they occur so close to dense ur-

ban centres.

There are no comprehensive studies on how

repeated exposure to peat smoke affects human

health over the long term, much less how peat

smoke’s chemical properties differ from other

kinds of biomass smoke. Yet emerging research

offers early clues.

US researchers have found that peat fires

in the southern states during the summer of

2008 caused a spike in emergency room visits

for heart failure and asthma-related respiratory

complications. In a follow-up study, published in

June 2014, they burned semi-charred peat from

the fires in the vicinity of lab mice. Subsequent

pulmonary problems in the mice were mainly

linked to coarser-grained smoke particles and

cardiac problems to finer-grained particles.

A primary concern from a health perspective

is that peat fires tend to generate larger amounts

of fine-grained particulate matter, called PM2.5,

than normal forest fires. That is worrying main-

ly because finer-grained particles are thought

to penetrate further into the bloodstream than

coarser ones do, posing a potentially higher risk

to the heart and other internal organs. Finer-

grained particles are also harder to block with

the simple surgical masks that many people in

Asian cities have traditionally worn as protection

against air pollution.

A widely cited 2012 study, published in the

journal Environmental Health Perspectives, esti-

mated that about 339,000 deaths between 1997

and 2006 were associated with landscape fires.

About four in five deaths were linked to chronic,

rather than sporadic, exposure. Sub-Saharan Af-

rica and Southeast Asia accounted for 157,000

and 110,000 deaths, respectively, and the rate

of mortality spiked during years dominated by

El Niño weather phenomenon, which typically

correlates with drier conditions in Southeast

Asia. “Reducing population level exposure to

air pollution from landscape fires is a worthwhile

endeavor that is likely to have immediate and

measurable health benefits,” the researchers

concluded.

Another 2012 study, by Miriam Marlier and

other scientists from American and British insti-

tutions, found that between 1 and 11 per cent

of Southeast Asia’s population was repeatedly

exposed to pollution above the WHO’s recom-

mended air quality levels during sporadic haze

episodes between 1997 and 2006. Elevated

exposure during El Niño years caused around

15,000 cardiovascular-linked adult deaths per

year, the researchers wrote. Roughly two-thirds

of those were linked to fine-grained PM2.5 par-

ticles, while the other third were linked to levels

of ozone. However, there was not enough evi-

dence available to determine exactly how the

toxicity of PM2.5 in peat fires differed from that

of PM2.5 emissions in American cities.

Some scientists suggest that peat smoke’s

long-term effects on humans may be broadly

similar to those of urban air pollution, which also

includes PM2.5 particles. No one is sure be-

cause so little research has been done to test

the theory.

Rajasekhar Balasubramanian, an American


environmental engineer who studies haze at the

National University of Singapore, speculates that

long-term exposure to haze episodes could po-

tentially make the population less healthy over

time, even if people continue to live long lives. In

a 2013 study, he and his colleagues found that

the air above Singapore during a smoke haze

episode contained arsenic, chromium, cadmi-

um and other carcinogenic elements. They esti-

mated that normal urban levels of PM2.5 pollu-

tion would cause about 12 out of every million

Singaporeans to develop cancer over a lifetime,

but if haze were to occur for 10 days per year

over 70 straight years, the number of likely can-

cer cases would increase by nearly half.

Yet there still is no coordinated international

effort to analyse haze in a truly interdisciplinary

fashion. That is partly due to the sporadic and

unpredictable nature of haze, Balasubramanian

said: Southeast Asia’s highly variable weather

makes it tricky to predict when haze will appear

or where it could spread. He likens a particle of

peat smoke to a grasshopper that jumps into

the air, shoots along horizontally, then quickly

zooms back to earth – only to jump again.

Another problem, Balasubramanian said, is

that the general public does not yet view haze as

a serious health threat. “People view it as, ‘Oh,

yeah, it’s a problem that occurs in Indonesia’,” he

told me one afternoon in his office at the National

University of Singapore. For governments and

funding bodies, “the priority’s more mitigation:

how to mitigate human exposure to this haze is-

sue, rather than to study the problem itself”.

The task of mitigating pollution is also cloud-

ed by politics. Countries in Southeast Asia have

little control over what blows across their bor-

ders: unlike the European Union, the Associa-

tion of Southeast Asian Nations (ASEAN) lacks

the legal authority to force its members to act

against their own interests.

A case in point is ASEAN’s 2002 trans-bound-

ary haze agreement, a non-binding document in

which the group’s 10- member states pledged

to prevent and monitor peat fires. The agree-

ment called for technology exchanges and

other measures to improve regional dialogue

and cooperation on haze. It was initially hailed

as a landmark achievement, but until Septem-

ber 2014, Indonesia’s parliament had refused to

ratify it. Laode M. Syarif, an environmental law-

yer based in the Indonesian capital of Jakarta,

said that was mainly because Indonesia has

long tried to use the haze agreement as a way

to leverage Singapore into overturning a refusal

to extradite Indonesian citizens who are wanted

for crimes in their homeland.

ASEAN tends to view economic develop-

ment, national sovereignty and mutual non-in-

terference as its highest priorities, said Helena

Varkkey, a senior lecturer in the Department of

International and Strategic Studies at the Uni-

versity of Malaya. In her view, ASEAN has taken

a mild-mannered approach to haze fighting out

of deference to powerful palm-oil companies,

many of them based in Singapore or Malaysia.

Indeed, many analysts have said that Indo-

nesia’s land concessions – areas allocated for

commercial plantations – are deeply entwined

with corruption. A popular joke has it that, if In-

donesia’s overlapping concession maps were

all counted as national territory, the country


would grow in size. But companies and offi-

cials mostly refuse to share those maps with the

public. “It’s a mess,” said Andika Putraditama,

a research analyst at the Jakarta office of the

World Resources Institute, a research organisa-

tion headquartered in Washington, DC. It’s also

another reason why Indonesia’s peatlands con-

tinue to burn.

Against this backdrop, Tan Yi Han, the Singa-

porean financial consultant and self-styled haze

activist, is hoping to influence the regional debate

on haze. In early 2014, he founded a citizens’ or-

ganisation called People’s Movement to Stop

Haze, or PM Haze, to kick-start the discussion.

“My gut feeling is, we need influence,” Tan

said at a Sunday-evening PM Haze meeting.

There was only one other participant: Putera

Zenata, an Indonesian schoolteacher who had

joined the group after finding Tan online. The

venue was Zenata’s modest apartment in a mid-

dle-class Singapore neighbourhood.

In June 2014, one of Tan’s hometown news-

papers, the Independent, dubbed him “Singa-

pore’s intrepid haze fighter”. But PM Haze, with

10 active members and no outside funding, is

well behind many established advocacy and re-

search groups that fight air pollution elsewhere

in Asia. In New Delhi, the Centre for Science and

the Environment has proposed specific ways

that the government could tackle air pollution –

for example, by cracking down on open fires.

And in Beijing, the Institute of Public and Envi-

ronmental Affairs is promoting a pollution-moni-

toring mobile phone app as a way of ramping up

pressure on polluting companies.

By his own admission, Tan has very little ex-

perience in the non-profit sector. He told me that

he has no plans to pressure the government or

companies into action – at least not yet. For the

moment, he said, PM Haze is simply trying to

learn about the problem, in all its complexity,

and then communicate its findings to the Sin-

gaporean public. In early November 2014, the

group developed the content for an information-

al “haze exhibition” in Singapore that drew an

estimated 800 visitors. And in the longer term,

Tan said, they would like to film a documentary

in Indonesia.

“My personal goal is to stop haze by 2023,” he added casually.

That could be a pipe dream. But according to

Wilson Ang, Assistant Director for Sustainability

at the Singapore Institute of International Affairs,

the haze of June 2013 made the Singaporean

public “much more involved” in the issue. Along

with PM Haze, the episode spawned the creation

of the Haze Elimination Action Team, another

grassroots community group. Both groups have

since gone on site visits to Indonesia, opened

dialogues with palm-oil companies, and offered

feedback or recommendations to Singaporean

officials. “Such a ground-up approach is very

much welcomed by the government,” said Ang.


Haze, however, is still a growing public health

concern for many countries, especially lower-in-

come ones. “We put a lot of legislation in place

to control point sources, and still, when you add

it up, ambient conditions don’t get better,” said

Jacqueline McGlade, Chief Scientist at the United

Nations Environment Programme. Other chal-

lenges, she told me, are linking air pollution data

with research on impacts and holding govern-

ments accountable for enforcing pollution laws.

More than ever, air pollution is a prominent tar-

get of policy reforms and public health interven-

tions. Many lower-income countries, grappling

with the environmental and health consequences

of their booming populations, are tightening air

pollution standards. International aid and devel-

opment agencies are also rolling out projects to

monitor or regulate particulate emissions.

In Southeast Asia, haze has recently resur-

faced on ASEAN’s political radar. In early July

2014, officials from Riau province announced

that they would conduct a large-scale “compli-

ance audit” of local officials and agroforestry

companies linked to peatlands. On 5 August,

Singapore’s parliament passed a law that al-

lows the government to fine both domestic

and international companies up to two million

Singapore dollars (US$1.5 million) for causing

or contributing to haze. And on 16 September,

Indonesia’s parliament finally ratified ASEAN’s

2002 trans-boundary haze agreement after 12

years of resistance.

Also that summer, a senior adviser to Joko

“Jokowi” Widodo, then Indonesia’s President-

Elect, said the new administration planned to re-

new the 2009 Indonesian law that banned peat

burning when it expires in 2015. Widodo himself

said he planned to streamline land governance

by creating a “one-map” forestry policy. “The

haze is caused both by the people and also the

companies,” he told the Straits Times, a Singa-

pore newspaper, in late August. “If we have good,

tough law enforcement, then it can be resolved.”

How significant are these developments?

In conversations with several haze-watching

analysts across Southeast Asia, I heard a wide

range of opinions. Some, like Helena Varkkey,

aren’t especially optimistic, mainly because In-

donesia and ASEAN have so far made so little

progress on the haze problem. Neither the Sin-

gaporean law nor the regional haze agreement,

they pointed out, would be enforceable in Indo-

nesian courts. And if climate change increases

the number of droughts and wildfires around the

world, as many scientists predict it will, the inci-

dence of peatland fires may also rise – and pose

additional enforcement challenges.

But others said it is positive that the Indone-

sian and Singaporean governments are at least

taking action – the sort that could breathe new

life into existing Indonesian laws designed to

tackle haze. The recent political activity gives

them hope that annual peat fires will not be-

come South-east Asia’s status quo for future

generations.

“Jokowi did say that he aims to take action

against the haze,” said Tan Yi Han, the haze

fighter. “That’s just words, but it’s better than

nothing.”

Adapted and reprinted with permission from Mosaic (http://mosaic-science.com/story/where-theres-smoke-Asia-air-pollution-haze).

FEBRUARY 2015 CALENDAR 31

F E B R U A R Y

14th World Congress on Public Health 11/2/2015 to 15/2/2015 Kolkata, India Phone: (91) 124 463 6713Email: [email protected] Website: www.14wcph.org

M A R C H

24th Conference of the Asian Pacific Association for the Study of the Liver (APASL)12/3/2015 to 15/3/2015Istanbul, TurkeyInfo: APASL SecretariatTel: (90) 312 440 50 11Fax: (90) 312 441 45 63Email: [email protected]: www.apasl2015.org

World Congress of Nephrology (WCN) 201513/3/2015 to 17/3/2015Cape Town, South AfricaInfo: International Society of NephrologyTel: (32) 2 808 71 81Fax: (32) 2 808 4454Email: [email protected]: www.wcn2015.org

64th Annual Scientific Session of the American College of Cardiology (ACC)14/3/2015 to 16/3/2015San Diego, California, USInfo: ACC Registration and Housing CenterTel: (1) 703 449 6418Email: [email protected]: http://accscientificsession.cardiosource.org/ACC.aspx

6th Association of Southeast Asian Pain Societies (ASEAPS) Congress15/3/2015 to 17/3/2015Manila, PhilippinesInfo: ASEAPS SecretariatTel: (65) 6292 0732Fax: (65) 6292 4721Email: [email protected] Website: www.aseaps2015.org

16th World Congress on Human Reproduction 18/3/2015 to 21/3/2015Berlin, GermanyInfo: Biomedical Technologies srlTel: (39) 070340293Fax: (39) 070307727Email: [email protected]: www.humanrep2015.com

4th Global Congress for Consensus in Pediatrics and Child Health (CIP)19/3/2015 to 22/3/2015Marrakech, MoroccoInfo: Paragon GroupTel: (41) 22 5330948Fax: (41) 22 5802953Email: [email protected]: http://2015.cipediatrics.org/marrakesh/

4th Global Congress for Consensus in Pediatrics and Child Health (CIP)19/3/2015 to 22/3/2015Budapest, HungaryInfo: CIP 2015 SecretariatTel: (41) 22 5330948Fax: (41) 22 5802953Email: [email protected]: http://2015.cipediatrics.org

9th World Congress on Controversies in Neurology (CONy)26/3/2015 to 28/3/2015Budapest, HungaryInfo: CONy SecretariatTel: (49) 15202950431Email: [email protected] Website: comtecmed.com/cony

World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (WCO-IOF)26/3/2015 to 29/3/2015Milan, ItalyInfo: Yolande Piette CommunicationTel: (32) 0 4 254 1225 Fax: (32) 0 4 254 1290 Email: [email protected]: www.wco-iof-esceo.or

U P C O M I N G

7th Asian Oncology Summit10/4/2015 to 12/4/2015Shanghai, ChinaInfo: Elsevier ConferencesEmail: [email protected]: http://asianoncologysummit.com

Royal College of Obstetricians & Gynaecologists (RCOG) World Congress12/4/2015 to 15/4/2015Brisbane, AustraliaInfo: RCOG World Congress 2015, Joint RCOG / RANZCOG Event OfficeTel: (61) 3 9645 6311Fax: (61) 3 9645 6322Email: [email protected]: www.rcog2015.com

FEBRUARY 2015 CALENDAR 32

30th International Conference of Alzheimer’s Disease International (ADI)15/4/2015 to 18/4/2015Perth, AustraliaInfo: ADITel: (44) 845 1800 169Fax: (44) 1730 715 291Email: [email protected]: www.alzint.org/2015

25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)25/4/2015 to 28/4/2015Copenhagen, DenmarkInfo: Kenes International – RegistrationTel: (41) 22 908 0488Fax: (41) 22 906 9140Email: [email protected] Website: www.eccmid.org

20th Asian Pacific Society of

Cardiology (APSC) Congress29/4/2015 to 2/5/2015Abu Dhabi, UAE Info: APSC 2015 Organizing CommitteeEmail: [email protected]: www.apsc2015.com

48th Annual Meeting of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)6/5/2015 to 9/5/2015Amsterdam, NetherlandsInfo: ESPGHAN SecretariatTel: (44) 845 1800 360Email: [email protected]: www.espghan2015.org

21st World Congress on Controversies in Obstetrics, Gynaecology & Infertility (COGI)7/5/2015 to 10/5/2015Guilin, ChinaInfo: COGI SecretariatTel: (972) 73 706 695Fax: (972) 3 725 6266Email: [email protected]: www.congressmed.com/cogichina/index.php/en

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20 • NEWS • SEPTEMBER 2014

RADHA CHITALE

A review of tree nut consump-tion showed that including about two servings of these

nutrient-rich foods in a person’s diet could decrease plasma glucose levels and fasting glucose.

While tree nuts such as al-

monds, walnuts, coconuts and pe-cans (though not peanuts, which are legumes) are frequently in-cluded in heart-healthy diets such as those from the Mediterranean region or Dietary Approaches to Stop Hypertension (DASH), data linking nut consumption to a lower incidence or risk of type 2 diabetes

is spotty. The review included 12 trials of

450 middle-aged adults with diabe-tes that included key glycemic end-points. [PLoS ONE 9(7):e103376. doi:10.1371/journal.pone.0103376]

Adults who consumed a me-dian 56 g/day of tree nuts showed a 0.07 percent decrease in HbA1c levels and 0.15 mmol/L lower fast-ing glucose, both of which were significant, according to a pooled analysis over a median 8 weeks.

Improvements were not as clear for other glycemic endpoints.

“Although significant advantag-es for fasting insulin and homeo-stasis model assessment of insulin resistance were not seen, the direc-tion of effect favored the tree nut intervention,” the researchers said.

Lead researcher Dr. John Siev-enpiper of the Clinical Nutrition and Risk Factor Modification Centre of St. Michael’s Hospital in Toronto, Canada, said that nuts probably tended to take the place of some carbohydrates in the diet, thereby lowering the dietary glycemic load.

The nuts’ micronutrient profile may also play a role in decreasing diabetes risk and improving gly-cemic control. Magnesium, found in high concentrations in many tree nuts, might be important for insulin-mediated glucose uptake or proper tyrosine-kinase activity in insulin receptors.

And while tree nuts may be low in sugar, they are high in fat, but it is monounsaturated fat, which in some studies have been shown to reduce HbA1c levels in higher quantities.

High quantities of tree nut con-sumption over time may also be important in diabetes control. Stud-ies shorter than 12 weeks were less likely to include patients who had lower HbA1c levels compared to those of 12 weeks or more. Stud-ies with a crossover design had a washout period of up to 8 weeks and demonstrated a corresponding smaller effect of tree nut consump-tion on blood sugar compared to trials with a parallel design.

Limits of the meta-analysis included whether the follow-up period in many of the trials was long enough to significantly affect glycemic control, as well as be-tween-study heterogeneity in out-come monitoring. Still, most of the data pointed towards including tree nuts in the diet for diabetes benefits.

Tree nuts help lower blood sugar in diabetics

Tree nuts appeared to take the place of carbohydrates in the diet and reduce dietary glycemic level.

“ The direction of

effect favored

the tree nut

intervention”

MT(SG)Sep14_FINAL.indd 20 8/29/14 10:44 AM

For A 5-minute UpdateGo to www.mims.asia/video

MIMS Video Series features interviews with leading experts

Find out what these experts have to say about how to improve patient care for osteoporosis and sarcopenia in Asia through awareness building and the use of new therapies

_seriesBrought to you by MIMS

SCAN TO WATCH VIDEO

Professor Peter Ebeling

Widespread vitamin D deficiency and low calcium levels in Asians

How low levels of awareness in the public and in healthcare professionals affect osteoporosis care in Asia

Benefits of fracture registries and fracture liaison registries (FLS) in Asia

Professor Serge Ferrari

Selective estrogen receptor modulators (SERMs), a new class of therapy for post-menopausal woman with osteoporosis

Dr Edith Lau

Treatment plans for post-menopausal women with osteoporosis

Professor Bess Dawson-Hughes

How aging contributes to sarcopenia and impaired muscle function in the elderly

FEBRUARY 2015 CONFERENCE COVERAGE 34

Early initiation of estrogen therapy may slow onset of Alzheimer’s in women

20th World Congress on Controversies in Obstetrics, Gynecology & Infertility (COGI), December 4-7, Paris, France

ELVIRA MANZANO

Levels of circulating sex steroid hormones

decline with normal aging, leaving the brain

unprotected against neurotoxic factors. This

makes hormone therapy early after menopause

a logical approach, says an expert.

“Estrogen deficiency, for example, contrib-

utes to Alzheimer’s disease,” said Professor An-

drea Riccardo Genazzani from the University of

Pisa, Pisa, Italy. “Early initiation [of estrogen] at

the time of menopausal transition may prevent

neurocognitive deterioration and activate sec-

ondary prevention and intervention to reduce

the risk of dementia.”

Many observational and preclinical studies

have shown that treatment with estrogens has

beneficial effects on the central nervous system

and cognitive function. Estrogen increased syn-

apse density and enhanced memory in young

animal models, but not in older ones. [Proc Natl Acad Sci 2001;98:8071-8076; J Neuroscience

2002;22:10985-10995]

“These findings suggest that aging substan-

tially modulates the mechanism of estrogen ac-

tion on the hippocampus and memory, and that

estrogen may be more effective in younger ani-

mals,” said Genazzani.

A meta-analysis of studies involving wom-

en with menopausal symptoms also found an

association between hormone therapy and

a decreased risk of dementia. [JAMA 2001;

285:1489-1499] Another study suggested

that post-menopausal estrogen replacement

therapy (ERT) reduced the risk of Alzheimer’s

disease among long-term users of ERT. [JAMA 2002;288:2123-2129]

However, the Women’s Health Initiative (WHI)

studies had contradictory findings – estrogen

therapy initiated alone, or in combination with

progestin, during the late menopausal stage in-

creased the risk of dementia or mild cognitive im-

pairment, regardless of the type of menopause

(natural or surgical). [JAMA 2003;289:2651-

2662; JAMA 2004;291:2947-2958]

“The difference with other studies is that

women in the WHI studies were generally older

[≥65 years] when treatment was started,” said

Genazzani. “This suggests a critical period for

ERT timing.”

“Alzheimer’s in women is a terrible disease

with no possibility of defense. Early, individual-

ized estrogen therapy regimens may be a good

choice for certain women, depending on their


risk profile. We also have to maintain therapy

in younger women in the early postmenopausal

stage and in those who underwent bilateral oo-

phorectomy before the onset of natural meno-

pause to improve their mental well-being,”

Genazzani concluded.

Hormone therapy a viable option to prevent postmenopausal osteoporosisCHUAH SU PING

Hormone replacement therapy (HRT) can

help reduce the incidence of all osteoporo-

sis-related fractures, even in women not at high

risk of fracture, according to an expert.

“In their 2012 Hormone Therapy Position

Statement, the North American Menopause

Society (NAMS) noted that there is clinical evi-

dence that standard-dose hormone therapy

(HT) reduces postmenopausal osteoporotic

fractures, including hip, spine and all non-spine

fractures, even in women without osteoporosis,”

said Professor Robert D. Langer, Associate Dean

for Clinical and Translational Research and Pro-

fessor of Medicine at the University of Nevada

School of Medicine in Reno, Nevada, US.

“Low doses, according to the NAMS, are ef-

fective in maintaining or improving bone mineral

density,” added Langer. He noted that when al-

ternate osteoporosis therapies are not appropri-

ate or cause adverse effects, the extended use

of HT is an option for women at high risk of os-

teoporotic fracture. [Menopause 2012;19:257-

271] This stand is echoed by the International

Menopause Society’s (IMS) recommendations

on menopausal HT, which noted that HT “can

be considered as one of the first-line therapies

for the prevention and treatment of osteoporo-

sis-related fractures.” [Climacteric 2013;16:316-

337]

“While there is still a lack of evidence that

HT stops working with long-term use, the avail-

able evidence indicate that the benefits of HT

on bone mass and fracture reduction dissipate

quickly upon discontinuation of treatment,” said

Langer. To illustrate this, Langer described a

study of 80,955 postmenopausal women us-

ing HT who were followed up from July 2002

to December 2008. After 6.5 years of follow-up,

age- and race-adjusted Cox proportional hazard

models showed that women who discontinued

HT were at 55 percent greater risk of hip frac-

ture compared with those who continued using

HT (HR, 1.55 95% CI, 1.36-1.77). “Hip fracture

risk increased as early as 2 years after cessa-

tion of HT, and this risk incrementally increased

with longer duration of cessation.” [Menopause


2011;18:1172-1177]

Langer noted that at present, while no HT

product is approved for the treatment of os-

teoporosis, many systemic HT products have

government approval for the prevention of post-

menopausal osteoporosis. The IMS however

cautioned in their 2011 Position Statement that

the initiation of HRT for the sole purpose of the

prevention of fractures after the age of 60 years

is not recommended, and should take into ac-

count the possible long-term effects of the spe-

cific dose and method of administration of HRT,

compared with other proven non-hormonal ther-

apies. [Climacteric 2011;14:302-320]

In his conclusion, Langer noted that the updat-

ed 2013 IMS recommendations for menopausal

HT state that it is an effective treatment for the

prevention of fracture in at-risk women before age

60 years or within 10 years after menopause. [Cli-macteric 2013;16:316-337]

Researchers search for ways to preserve fertility during chemotherapyRADHA CHITALE

Chemotherapy can damage ovarian func-

tion enough to significantly reduce fertil-

ity, but pre-treatment with certain drugs may be

able to prevent this, researchers said.

“It would be very good to block the toxic-

ity of chemotherapy or radiotherapy but there

is no drug for this,” said presenter Dr. Philippe

Bouchard, of the Hospital Saint Antoine at Uni-

versite Paris in France.

In addition to follicular damage, ovarian dam-

age can deprive women of estrogen, which is

associated with osteoporosis and neurocogni-

tive impairment and Bouchard noted it should

be preserved, along with ovarian function.

Current methods to preserve fertility include

oocyte and embryo cryopreservation. However,

these are expensive procedures that can delay

cancer therapy and they do not preserve estro-

gen function.

Some fetoprotective agents that shield ovar-

ian function from the effects of chemotherapy or

radiotherapy have shown promising results in

mouse models, Bouchard said.

The chemotherapy adjuvant bortezomib, for

example, has proven an effective shield against

doxorubicin, an anthracycline that is used in

about half of patients treated for cancer, includ-

ing those that are at high risk for reduced fertility

such as breast, bladder and thyroid cancer, as

well as many pediatric cancers such as leuke-

mia and neuroblastoma.

However, doxorubicin can cause follicular

apoptosis in mouse ovaries within 12 hours of

drug administration. Treated mice only recover

about 50 percent of their pre-treatment ovulation


rate and have long-term follicle depletion.

Bortezomib competes with doxorubicin bind-

ing sites in key areas to prevent doxorubicin ac-

cumulation in the follicles. Female mice treated

with bortezomin 1 hour prior to treatment with

DXR reduced DNA damage in ovarian cells and

follicular apoptosis. [PLoS One 2014;9:e108174]

“Bortezomib pre-treatment extended the

number of litters per mouse, improved litter size

and increased pup weight following doxorubi-

cin treatment, thus increasing the duration of

post-chemotherapy fertility and improving pup

health,” the study authors said.

In addition, bortezomib did not interfere with

doxorubicin efficacy as a chemotherapy.

Stem cells use is also on the rise among re-

searchers seeking ways to restore ovarian func-

tion and female fertility following chemotherapy

or radiotherapy, Bouchard said, primarily by acti-

vating dormant ovarian follicles. However, further

translational and clinical research is needed in

this area.

FEBRUARY 2015 HUMOR 38

“I think it’s your heart, but on the other hand it could be your

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“I can understand a moose’s head, even a fish, but your appendix?”

“I won’t be able to get home in time for supper dear.

I’m having a kidney transplant!”

“It’s a boy. We thought you would never show up!”

“The guy who painted that was probably a medical cartoonist!”

“Does doctor Granfleet know what this is in reference to?”

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Medical Tribune February 2015 RG

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