A PRACTICAL GUIDE FOR THE PHARMACOLOGICAL MANAGEMENT … · THEME : TYPE 2 DIABETES MELLITUS WITH...

HEART

PANCREAS

KIDNEY

A PRACTICAL GUIDE FOR THE PHARMACOLOGICAL MANAGEMENT OF

T2DM PATIENTS ACROSS THECARDIOVASCULAR RISK CONTINUUM

FOREWORDAs practicing clinicians, our main objectives for management of patients with T2DM are to strive for reduction of complications associated with the disease and, prevention (either Primary or Secondary) of both macrovascular as well as microvascular complications. A well-established fact is that CVD will claim the lives of more than two-third of people with T2DM and their life expectancy also shortened as a result.

In the past, with older anti-hyperglycaemic agents, improvement of glucose (using HbA1c as the surrogate marker) were unable to reduce CV events during the intervention phase of the clinical trials. The “motto” for CVD reduction was “to be patient” as, CV benefits could only be apparent many years (> 10 years) after initial HbA1c improvement.

However, we are now entering a new era where specific glucose-lowering therapies have been proven in landmark CVOTs, with SGLT2-i and GLP-1 RAs (i.e. EMPA-REG, CANVAS, LEADER, SUSTAIN-6, DECLARE-TIMI and REWIND), to have positive beneficial effects on CV outcomes (MACE) – in individuals with T2DM and either established CVD or with risk factors for CVD. Guidelines and health authorities have recognised these exciting results and have changed their indications for use and many CPGs have modified the algorithms for clinical decision-making in the choice of medication according to risk stratification/categories.

The objective of this practical guide is to reflect the uptake of the new data in clinical decision-making for our T2DM patients across the continuum of CV risk. The CPG for management of T2DM remains relevant. It is our fervent hope that this guide will help clarify and reduce the complexity when deciding how, when and what to prescribe for our patients with T2DM.

We have enlisted the 3 main stakeholders in this endeavor: Malaysian Endocrine and Metabolic Society (MEMS), National Heart Association of Malaysia (NHAM) and Malaysian Society of Nephrology (MSN). All 3 societies have representation in our working committee.

DR SP CHANChairpersonWriting committee

TABLE OF CONTENTSFOREWORD 2

INTRODUCTION 5

WRITING COMMITTEE 7

REVIEWERS 8

ABBREVIATION LIST 9

SECTION A: CASE STUDIES 11

THEME : TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND NORMAL RENAL FUNCTION 12

Case study 1 : T2DM with established CVD and normal renal function 12Case study 2 : Newly diagnosed T2DM presenting with acute coronary syndrome and normal renal function 15Case study 3 : T2DM patient presenting with heart

failure and normal renal function 18

THEME : TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND CHRONIC KIDNEY DISEASE 20

Case study 4 : T2DM with established CVD and albuminuria 20Case study 5 : T2DM with established CVD and impaired renal function (eGFR 45-60 ml/min/1.73 m2) 23Case study 6 : T2DM with established CVD and

impaired renal function (eGFR < 45 ml/min/1.73 m2) 25

THEME : TYPE 2 DIABETES MELLITUS WITH HIGH-RISK FOR CARDIOVASCULAR DISEASE 26

Case study 7 : T2DM with high-risk for CVD and normal renal function 27Case study 8 : T2DM with high-risk for CVD and impaired renal function 29

SECTION B: CASE STUDIES ANSWERS AND DISCUSSION POINTS 31

THEME : TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND NORMAL RENAL FUNCTION 33

Case study 1 : T2DM with established CVD and normal renal function 33Case study 2 : Newly diagnosed T2DM presenting with acute coronary syndrome and normal renal function 40Case study 3 : T2DM patient presenting with heart

failure and normal renal function 42

THEME : TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND CHRONIC KIDNEY DISEASE 47

Case study 4 : T2DM with established CVD and albuminuria 47Case study 5 : T2DM with established CVD and impaired renal function (eGFR 45-60 ml/min/1.73 m2) 51Case study 6 : T2DM with established CVD and

impaired renal function (eGFR < 45 ml/min/1.73 m2) 55

THEME : TYPE 2 DIABETES MELLITUS WITH HIGH-RISK FOR CARDIOVASCULAR DISEASE 58

Case study 7 : T2DM with high-risk for CVD and normal renal function 58Case study 8 : T2DM with high-risk for CVD and impaired renal function 67

REFERENCES 74

ACKNOWLEDGMENT 79

TABLE OF CONTENTS

INTRODUCTIONT2DM patients are a heterogeneous group either presenting with or developing various risks for comorbidities. With the recent rapid advances, management of T2DM has to evolve as new evidence become available, allowing timely application of the data.

There are existing, evidence-based CPGs developed by the MEMS, NHAM and the MSN that have been endorsed by the Ministry of Health. These CPGs include pharmaceutical management algorithms that aim to encompass the heterogeneity of T2DM patients. However, it is often not possible to fit individual patients into specific categories within these algorithms, making interpretation and implementation of these algorithms difficult.

Therefore, this practical guide has been purpose built for primary healthcare providers to supplement these CPGs and to bridge their various pharmacological treatment algorithms. In addition, this practical guide includes the latest data from rapidly accumulating CVOTs so as to deliver a timely easy to follow format that will allow clinicians to choose the appropriate therapies for T2DM patients across the whole spectrum of CV risk.

OBJECTIVETo deliver a clinically relevant and practical guide to assist healthcare professionals decide the pharmacological management of T2DM patients across different CV risks whilst taking into consideration the patient’s renal function status.

TARGETThis practical guide is intended for general practitioners and primary care physicians involved in the management of T2DM patients with variable levels of CV risk.

FORMATThe contents of this book are presented as case studies with different levels of CV risk and renal functional status followed by in-depth discussions to explain the reasons for the responses.

STATEMENT OF INTENTThis practical guide and the contents within it are meant as a guide to support general practitioners and primary healthcare professionals in the pharmacological management of T2DM. The case studies and information presented aim to bridge the current available Malaysian CPGs on the subject of T2DM management in addition to adding the most current available treatments and data. It is not intended to replace the overall management paradigm set out by these CPGs. The ultimate decision on management of T2DM must be made based on clinical judgment, available resources and the individualised needs of each patient.

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SOURCE OF FUNDINGThe development of this practical guide was made possible by an educational grant from AstraZeneca (Malaysia) Sdn. Bhd.

COPYRIGHTA Practical Guide For The Pharmacological Management Of T2DM Patients Across The Cardiovascular Risk Continuum and all of its contents, belong to the following societies – MEMS, NHAM and MSN. Reproduction of its contents in any number of copies and in any format is allowed provided that the societies are acknowledged as the copyright owners. No changes in the contents of this practical guide in any form or method are allowed. This practical guide and its contents as a whole cannot be sold, used to promote or endorse any product or service and/or used in any inappropriate or misleading context.

Disclaimer: The contents of this practical guide do not guarantee the best outcomes in every patient and therefore, the responsibility in managing a T2DM patient lies with the individual healthcare provider depending on the patient’s clinical manifestations and the diagnostic and therapeutic options available locally.

© 2019. All rights reserved.

A Practical Guide For The Pharmacological Management Of T2DM Patients Across The Cardiovascular Risk Continuum is available for download at the following websites:

http://mems.my/https://www.malaysianheart.org/https://www.msn.org.my/msn/

INTRODUCTION

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WRITING COMMITTEECHAIRPERSONPROFESSOR DR CHAN SIEW PHENGHonorary ProfessorConsultant EndocrinologistUniversity of Malaya Medical Centre, KL/ Subang Jaya Medical Centre

COMMITTEE MEMBERSDR SUNITA BAVANANDANConsultant NephrologistHospital Kuala Lumpur

DR CHOO GIM HOOIConsultant CardiologistCardiac Vascular Sentral Kuala Lumpur

DR ZANARIAH HUSSEINConsultant EndocrinologistHospital Putrajaya

DR LAM KAI HUATConsultant CardiologistAssunta Hospital, Petaling Jaya

ASSOCIATE PROFESSOR DR LIM SOO KUNConsultant NephrologistUniversity Malaya Medical Centre, Kuala Lumpur

REVIEWERSENDOCRINOLOGYDR FLORENCE TAN HUI SENGConsultant EndocrinologistHospital Umum Sarawak

DR. HEW FEN LEEConsultant EndocrinologistSubang Jaya Medical Centre

DATO’ DR MAFAUZY MOHAMADProfessor of Medicine and Senior Consultant EndocrinologistHospital University Sains Malaysia

DR NORLAILA MUSTAFAAssociate Professor and Senior Consultant EndocrinologistUniversiti Kebangsaan Malaysia Medical Centre

NEPHROLOGYDR CHOW YOK WAIConsultant NephrologistPantai Hospital, Air Keroh

DR WONG HIN SENGConsultant Nephrologist and Head of Nephrology DepartmentHospital Selayang

CARDIOLOGYDR SAZZLI BIN KASSIMAssociate Professor of Medicine, Consultant Cardiologist and Head of Cardiology DepartmentUniversity Technology MARA

FAMILY MEDICINEDR. MASTURA BT ISMAILConsultant Family Medicine SpecialistKlink Kesihatan Seremban 2

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ABBREVIATION LISTACE Acarbose Cardiovascular Evaluation trialACR Albumin-creatinine ratioADVANCE Action in Diabetes and Vascular Disease: Preterax and Diamicron MR

Controlled Evaluation trialAE Adverse eventAV Atrio-ventricularb.d Twice dailyBMI Body-mass indexBP Blood pressureBU Blood ureaCAD Coronary artery diseaseCANVAS CANagliflozin cardioVascular Assessment StudyCARMELINA Cardiovascular and Renal Microvascular Outcome Study With Linagliptin

in Patients With Type 2 Diabetes Mellitus CCS Canadian Cardiovascular SocietyCI Confidence intervalCKD Chronic kidney diseaseCompoSIT Comparative Trials with Sitagliptin CompoSIT-R Safety and Efficacy of Sitagliptin Compared with Dapagliflozin in Subjects

with Type 2 Diabetes, Mild Renal Impairment and Inadequate Glycemic Control on Metformin ± a Sulfonylurea

CPG Clinical Practice GuidelinesCREDENCE Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular

Outcomes in Participants With Diabetic NephropathyCV CardiovascularCVD Cardiovascular diseaseCVD-REAL Nordic Comparative Effectiveness of Cardiovascular Outcomes in New Users of

Sodium-Glucose Cotransporter-2 InhibitorsCVOTs Cardiovascular outcomes trialsDapa-CKD Evaluate the Effect of Dapagliflozin on Renal Outcomes and

Cardiovascular Mortality in Patients With Chronic Kidney DiseaseDECLARE-TIMI58 Dapagliflozin Effect on CardiovascuLAR Events - Thrombolysis in

Myocardial Infarction Study Group trial 58DPP4-i Dipeptidyl peptidase 4 inhibitorsECHO EchocardiogrameGFR Estimated glomerular filtration rateEMPA-REG OUTCOME

Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose

ESC European Society of CardiologyEXAMINE EXamination of cArdiovascular outcoMes with alogliptIN versus standard

of carEFBS Fasting blood sugar

FIGHT Functional Impact of GLP-1 for Heart Failure TreatmentGLP-1 RA Glucagon-like peptide-1 receptors agonistsHARMONY trial Effect of Albiglutide, When Added to Standard Blood Glucose Lowering

Therapies, on Major Cardiovascular Events in Subjects With Type 2 Diabetes Mellitus.

HDL-C High-density lipoprotein cholesterolHR Hazard ratioLDL-C Low-density lipoprotein cholesterolLEADER Liraglutide and Cardiovascular Outcomes in Type 2 DiabetesLIVE Effect of liraglutide, a glucagon-like peptide-1 analogue, on left

ventricular function in stable chronic heart failure patients with and without diabetes

LVEF Left ventricular ejection fractionMACE Major adverse cardiovascular eventsMEMS Malaysian Endocrine and Metabolic SocietyMI Myocardial infarctionMSN Malaysian Society of NephrologyNHAM National Heart Association of MalaysiaNNT Numbers needed to treato.d Dailyo.n On nightPROACTIVE trial PROspective pioglitAzone Clinical Trial in macroVacsular Events.REWIND trial Researching Cardiovascular Events With a Weekly Incretin in DiabetesS/C SubcutaneousSAVOR-TIMI53 Saxagliptin Assessment of Vascular Outcomes Recorded in Patient with

DM -Thrombolysis in Myocardial Infarction Study Group trial 53SGLT2-i Sodium-glucose co-transporter-2 inhibitorsSTEMI ST segment elevated myocardial infarctionSTENO-2 Intensified Multifactorial Intervention in Patients With Type 2 Diabetes

and MicroalbuminuriaSU SulfonylureasT2DM Type 2 diabetes mellitusTC Total cholesterolTZD Thiazolidinediones (glitazones)TECOS Trial Evaluating Cardiovascular Outcomes with Sitagliptin TG TriglyceridesUK United KingdomUKPDS United Kingdom Prospective Diabetes StudyUSFDA United States Food and Drug AdministrationVADT Veteran’s Affair Diabetes Trial

ABBREVIATION LIST

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SECTION A:CASE STUDIES

CASE STUDY 1 T2DM with established CVD and normal renal function

THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND NORMAL RENAL FUNCTION

Established CVD is defined as documented atherosclerosis or CV event in the heart and/or vascular system. This includes confirmation of vascular disease i.e. stroke, heart attack or peripheral vascular disease by history or various imaging modalities.

CASE STUDY 1A

Mr AB; Age: 60 yearsMedical history

Presenting complaint Mild to moderate angina (CCS II)

Medical history • T2DM for 2 years• Hypertension• Dyslipidemia• Stable CAD

• Benign prostatic hypertrophy

• Smoker

Treatment history • Declined revascularisation therapy and managed with medical therapy for angina pectoris.

• History of poor compliance and adherence to prescribed medications.

Present treatment regimen • Metformin 850 mg b.d.• Perindopril 5 mg o.d.• Simvastatin 20 mg o.n.• Aspirin 100 mg o.d.

• Isosorbide dinitrate 10 mg b.d.

• Tamsulosin 0.4 mg b.d.

Physical examination

Height: 165.0 cm Weight: 65.4 kg BMI: 24.0 kg/m2

Fundoscopy: Non- proliferative retinopathy

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THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND NORMAL RENAL FUNCTIONCase study 1: T2DM with established CVD and normal renal function

INVESTIGATIONS

Parameters Results

FBS 8.5 mmol/L

HbA1c 8.3%

TC 5.4 mmol/L

HDL-C 0.8 mmol/L

LDL-C 3.2 mmol/L

TG 3.1 mmol/L

BU 7.8 mmol/L

Creatinine 80.0 μmol/L

eGFR > 90.0 ml/min/1.73 m2

Urine ACR 5.0 mg/mmol (Normal range: < 3.5 mg/mmol)

ECHO Basal inferior hypokinesia; LVEF 68% and normal diastolic function.

1. What would the optimal HbA1c target be for Mr. AB? a. < 6.5%b. < 7.0%c. < 7.5%

d. < 8.0% 2. How would you achieve the HbA1c target?

3. What additional anti-hyperglycaemic agent would you consider?

DISCUSSION (Refer to page 33 for case studies answers and discussion points)

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1. Would the HbA1c target be different?a. Yesb. No

2. How would you achieve this HbA1c target? (Choose all that apply)a. Improve lifestyle i.e. diet and physical activityb. Ensure adherence to medicationc. Add insulin (basal + oral agents)d. Add insulin (basal + prandial insulin)e. Add 2 additional anti-hyperglycaemic agents (combination of any of the

following: SGLT2-i, GLP1-RA/DPP4-i, SU, alpha-glucosidase inhibitor, TZD)


CASE STUDY 1BIn this case, Mr. AB presents with the same parameters as case 1A except, his HbA1c is > 10% and FBS is 11.0 mmol/L.

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CASE STUDY 2 Newly diagnosed T2DM presenting with acute coronary

syndrome and normal renal function

Mr CD; Age: 47 yearsMedical history

Presenting complaint Chest pain with diagnosis of acute inferior/posterior/lateral STEMI with 1st degree AV-block

Medical history • Smoker (1 pack/day since his teenage years)• Not previously known to be diabetic

Family history Father had history of CAD in his 70’s

ECG of Mr. CD on presentation


Height: 168 cm Weight: 75.4 kg BMI: 26.7 kg/m2

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THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND NORMAL RENAL FUNCTIONCase study 2: Newly diagnosed T2DM presenting with acute coronary syndrome and normal renal function

INVESTIGATIONS ON ADMISSION

Parameters Results

Admission glucometer 12.8 mmol/L

FBS 7.3 mmol/L

HbA1c 8.8%

TC 4.9 mmol/L

HDL-C 1.2 mmol//L

LDL-C 2.7 mmol/L

TG 2.1 mmol/L


eGFR 87.3 ml/min/1.73 m2

Urine ACR 0.4 mg/mmol (Normal range < 3.5 mg/mmol)

ECHO LVEF 57% with hypokinesia in inferior and posterior segments, and mild tricuspid regurgitation

TREATMENT DURING ADMISSION

Procedure • Primary angioplasty/stenting of the right coronary artery with 2 overlapping drug-eluting stents was performed

• Mild diffuse disease of the left anterior descending artery noted

Medication • SGLT2-i with CV protection • Metformin 850 mg b.d. • Perindopril 5 mg o.d. • Bisoprolol 2.5 mg o.d. • Rosuvastatin 20 mg o.n. • Aspirin 100 mg o.d. • Ticagrelor 90 mg b.d.

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FOLLOW-UP INVESTIGATION 2 MONTHS AFTER DISCHARGE

Parameters Results

FBS 7.6 mmol/L

HbA1c 7.0%

TC 3.3 mmol/L

HDL-C 1.1 mmol/L

LDL-C 1.4 mmol/L

TG 1.7 mmol/L

1. What would the optimal HbA1c target be for Mr. CD?a. < 6.5%b. < 7.0%c. < 7.5%

d. < 8.0% 2. Inthiscase,Mr.CDwasstartedonempagliflozin.Whataretheotheroptionsfor

initial therapy in this patient?

3. If Mr. CD has presented with HbA1c of 7.1% instead of 8.8%, what would his optimal HbA1c and initial therapy be?


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CASE 3A

Mr EF; Age: 69 yearsMedical history

Presenting complaint • Symptoms of left sided heart failure • Admitted for further evaluation

Medical history • T2DM for 10 years• Hypertension• Elevated lipid levels• History of acute myocardial infarction 5 years ago,

currently stable

Treatment regimen on presentation

• Metformin 1 g b.d. • Gliclazide80mgb.d.• Acarbose 50 mg b.d. • Metoprolol 50 mg b.d.

• Perindopril 8 mg o.d. • Simvastatin 40 mg o.d. • Frusemide 40 mg o.d. • Slow K 1 tablet o.d.

INVESTIGATIONS

Parameters Results

FBS 7.5-8.2 mmol/L

HbA1c 7.8%



ECHO There was an infarcted and scarred left anterior descending artery territory with LVEF of 30-40% and no demonstrable ischaemia seen

CASE STUDY 3 T2DM patient presenting with heart failure

and normal renal function

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THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND NORMAL RENAL FUNCTIONCase study 3: T2DM patient presenting with heart failure and normal renal function

1. What would the optimal HbA1c target be for Mr. EF?a. < 6.5%b. < 7.0%c. < 7.5%

d. < 8.0% 2. How would you optimise the glycaemic control of Mr. EF?

3. After being on an SGLT2-i for 6 months to a year, Mr. EF’s HbA1c is still not at target (i.e. > 7.0%-7.5%). Will you add another anti-hyperglycaemic agent?

4. Is Mr. EF’s HbA1c on target?

5. Would it be appropriate to add an SGLT2-i into his treatment regimen and if so, how would you proceed?



CASE 3BWhat if Mr. EF presented with:• HbA1c 6.7%,• no history of hypoglycaemia; and• is performing self-blood glucose monitoring

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THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND CHRONIC KIDNEY DISEASE

CASE 4A

Mr GH; Age: 60 yearsMedical history

Presenting complaint Albuminuria

Medical history • T2DM for 12 years• Hypertension for 10 years • CAD with stenting to the left anterior descending

artery 2 years ago


• Metformin SR 1700 mg om/850 mg pm

• GliclazideMR120mgo.d.• Bisoprolol 5 mg o.d.

• Perindopril 8 mg o.d. • Atorvastatin 40 mg o.d. • Aspirin 100 mg o.d.

HIS MOST RECENT LABORATORY TESTS ARE AS BELOW:

Parameters Results

FBS 8.0 mmol/L

HbA1c 8.2%



Urine ACR 50.0 mg/mmol (Normal range < 3.5 mg/mmol)

CASE STUDY 4 T2DM with established CVD and albuminuria

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THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND CHRONIC KIDNEY DISEASECase study 4: T2DM with established CVD and albuminuria

1. What would the optimal HbA1c target be for Mr. GH?a. < 6.5%b. < 7.0%c. < 7.5%

d. < 8.0% 2. How would you optimise the glycaemic control of Mr. GH?


CASE 4B

Mr JK; Age: 55 yearsMedical history

Presenting complaint Albuminuria

Medical history • T2DM for 15 years• Hypertension for 10 years • CAD with triple vessel disease on optimal

medical therapy


• Metformin XR 2 g o.d. • Gliclazide80mgb.d.• Bisoprolol 10 mg o.d.

• Losartan 100 mg o.d. • Rosuvastatin 20 mg o.d. • Aspirin 100 mg o.d.

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HIS RECENT LABORATORY TESTS ARE AS BELOW:

Parameters Results

FBS 6.5 mmol/L

HbA1c 6.8%



Urine protein 2+ with no active sediments


ECHO Impaired ejection fraction at 40%

1. What would the optimal HbA1c target be for Mr. JK?a. < 6.5%b. < 7.0%c. < 7.5%

d. < 8.0% 2. Would you consider altering Mr. JKs anti-hyperglycaemic regimen?


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CASE 5A

Mr LM; Age: 54 years oldMedical history

Presenting complaint Suboptimal HbA1c of 7.8%

Medical history • Presented 6 months ago with AMI • Diagnosed with T2DM during admission

Treatment regimen forglycaemic control

• Metformin 1 g b.d.

OTHER LABORATORY INVESTIGATION RESULTS AT PRESENTATION ARE:

Parameters Results

FBS 8.3 mmol/L

HbA1c 7.8%

TC 6.0 mmol/L

HDL-C 0.8 mmol/L

LDL-C 2.54 mmol/L

TG 2.1 mmol/L

Urea 5.0 mmol/L

Na+ 135.0 mmol/L

K+ 4.0 mmol/L




CASE STUDY 5 T2DM with established CVD and impaired renal function

(eGFR 45-60 ml/min/1.73 m2)

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THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND CHRONIC KIDNEY DISEASECase study 5: T2DM with established CVD and impaired renal function (eGFR 45-60 ml/min/1.73 m2)

Based on the above, Mr. LM is started on an SGLT2-i.

1. What precautions should be taken when starting patients on an SGLT2-i?

2. Apart from glycaemic indices, how else should a patient be monitored?

3. With an eGFR of > 45 ml/min/1.73 m2, what HbA1c improvement can be expected? In this patient (Mr. LM), what would the expected improvement be?

4. If the HbA1c in this patient is still above target (> 7.0%), what would you do?


CASE 5B

Mr QRMedical history

Presenting complaint • Decreased eGFR of 53.0 ml/min/1.73 m2 • Optimal HbA1c of 6.8%

Medical history • Presented 6 months ago with AMI • Diagnosed with T2DM during admission

Treatment regimen forglycaemic control

• Metformin 500 mg b.d. • Gliclazide80mgb.d.

1. Is there a compelling reason to start SGLT2-i or GLP-1RA for Mr. QR?


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CASE 6

Mr PQ; Age: 54 yearsMedical history

Presenting complaint Declining eGFR over a one-year period from 52 ml/min/1.73 m2 to 44 ml/min/1.73 m2 (< 45 ml/min/1.73 m2)

Medical history • Presented 8 months ago with AMI• Diagnosed with T2DM and impaired renal function

(eGFR of 52.0 ml/min/1.73 m2) at presentation• Suboptimal HbA1c at 7.0%-7.5% with dual

anti-hyperglycaemic agents (metformin + SU)

Treatment regimen for glycaemic control

• Metformin 500 mg b.d. • Gliclazide80mgb.d.

• SGLT2-i with CV protection

1. How would Mr. PQ’s treatment regimen change with the current eGFR?



(eGFR < 45 ml/min/1.73 m2)

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THEME: TYPE 2 DIABETES MELLITUS WITH HIGH-RISK FOR CARDIOVASCULAR DISEASE

Definition of high-risk

CRITERIA FOR HIGH-RISK in CVOTsBased on LEADER inclusion criteria1

Age≥60yearswithatleast one of the following CV risk factors:

• microalbuminuria or proteinuria,• hypertension and left ventricular hypertrophy,• left ventricular systolic or diastolic dysfunction; or• an ankle-brachial index < 0.9 (ratio of systolic blood

pressure at ankle to systolic blood pressure in arm)

Based on CANVAS inclusion criteria2

Age≥50yearswithatleast two or more of the following CV risk factors:

• diabetes for ≥ 10 years,• systolic blood pressure > 140 mmHg or on ≥ 1

medication,• current smoker,• micro- or macroalbuminuria; or• HDL-C < 1 mmol/L

Based on DECLARE-TIMI 58 multiple risk factor criteria3,4

Age > 55 years (men) and > 60 years (women) with at least one or more of the following CV risk factors in addition to T2DM:

• hypertension (defined as systolic BP > 140 mmHg and diastolic BP > 90 mmHg or on anti-hypertensive therapy)

• dyslipidemia (defined as LDL-cholesterol > 3.36 mmol/l or on lipid lowering therapy)

• current smoker (defined as > 5 cigarettes/day for > 1 year

Table 7: Definition of criteria for high-risk for CVD based on three major CVOT trials.

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CASE STUDY 7 T2DM with high-risk for CVD and normal renal function

Mrs. RS, Age: 64 yearsMedical history

Presenting complaint T2DM with high-risk of CVD

Medical history • T2DM for 12 years• Hypertension• Dyslipidemia• No known CAD

• Claims compliant with sugar-free food choices

• Does not exercise regularly

Family history • Father developed CAD at 46 years of age • T2DM in both parents

Present treatment regimen • Metformin 1 g b.d. • GliclazideMR120mgo.d.• S/C Insugen basal 18 U o.n.

• Telmisartan 80 mg o.d. • Simvastatin 20 mg o.n.



BP: 140/90 mmHg Pulse: 70/min

Peripheral pulses: Well felt and equal

Heart: No cardiomegaly, dual rhythm, no murmur Lung: Clear

Abdomen: No organomegaly

Ankle jerk: Absent Vibration sense: Reduced both feet

Fundus: Non-proliferative retinopathy

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THEME: TYPE 2 DIABETES MELLITUS WITH HIGH-RISK FOR CARDIOVASCULAR DISEASECase study 7: T2DM with high-risk for CVD and normal renal function

INVESTIGATIONS RESULTSParameters Results

FBS 9.1 mmol/L

HbA1c 8.5%

TC 6.0 mmol/L

HDL-C 0.9 mmol/L

LDL-C 3.8 mmol/L

TG 2.8 mmol/L



Urine protein Trace

Urine glucose Negative

Urine microscopy Clear


1. What is the CV risk score for Mrs. RS, based on the Framingham scoring system?a. < 10%b. 10-20%c. > 20%

2. What is the optimal HbA1c for Mrs. RS?

a. < 6.5%b. < 7.0%

3. To reduce the HbA1c by 1.5% (8.5% to 7.0%), which of these treatment options

will you offer this patient? (more than one answer is applicable)

a. Lifestyle modificationb. SGLT2-ic. GLP-1RA


c. < 7.5%d. < 8.0%

d. DPP4-ie. Escalation of basal insulin

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CASE STUDY 8 T2DM with high-risk for CVD and impaired renal function

Mrs. RS, Age: 64 yearsMedical history

Presenting complaint T2DM with high-risk of CVD

Medical history • T2DM for 12 years• Hypertension• Dyslipidemia• No known CAD

• Claims compliant with sugar-free food choices

• Does not exercise regularly

Family history • Father developed CAD at 46 years of age • T2DM in both parents

Present treatment regimen • Metformin 500 mg b.d. • GliclazideMR120mgo.d.• S/C Insugen basal 18 U o.n.

• Telmisartan 80 mg o.d. • Simvastatin 20 mg o.n.



BP: 140/90 mmHg Pulse: 70/min

Peripheral pulses: Equivocal

Heart: No cardiomegaly, dual rhythm, no murmur Lung: Clear

Abdomen: No organomegaly

Ankle jerk: Absent Vibration sense: Reduced both feet

Fundus: Pre-proliferative retinopathy

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THEME: TYPE 2 DIABETES MELLITUS WITH HIGH-RISK FOR CARDIOVASCULAR DISEASECase study 8: T2DM with high-risk for CVD and impaired renal function

INVESTIGATIONS RESULTS

Parameters Results

FBS 6.6 mmol/L

HbA1c 7.9%

TC 6.0 mmol/L

HDL-C 0.9 mmol/L



Urine protein 2+

Urine glucose Negative

Urine microscopy Clear


1. What would the optimal HbA1c target be for Mrs. RS?a. < 6.5%b. < 7.0%

2. What is the CV risk score for Mrs. RS, based on the Framingham scoring system?

a. < 10%b. 10-20%c. > 20%

3. To reduce the HbA1c from 7.9% to < 7.0% which of these treatment options will

you offer this patient? (more than one answer is applicable)a. Lifestyle modificationb. SGLT2-ic. GLP-1RA


c. < 7.5%d. < 8.0%


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SECTION B:CASE STUDIES ANSWERS AND DISCUSSION POINTS

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SECTION B: CASE STUDIES ANSWERS AND DISCUSSION POINTS

Section B contains the answers and points of discussion for each case study. The discussion points are based on the latest publications and are aligned to the current local CPGs, which include the 5th edition CPG for the management of T2DM, 2015.

Management strategy for all T2DM must include the following general recommendations.

GENERAL NON-PHARMACOLOGICAL RECOMMENDATIONS FOR T2DM PATIENTS

• Emphasise lifestyle modifications focusing on diet and physical activity.• Achievement of optimal weight.• Moderate alcohol consumption.• Address the other co-existing CV risk factors based on standard of care.• Ensure adherence to medications.

Target HbA1c• Individualise according to standard guidelines.

• < 6.5% (based on the Malaysian T2DM CPG 2015), if it can be achieved without hypoglycaemia.

• < 7.0% or higher in presence of co-morbidities, advanced age and limited life expectancy.

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CASE STUDY 1 T2DM with established CVD and normal renal function


CASE STUDY 1A

1. What would the optimal HbA1c target be for Mr. AB?a. < 6.5%b. < 7.0%c. < 7.5%

d. < 8.0%

2. How would you achieve the HbA1c target?

DISCUSSION

b (Answer < 6.5% [a] is also acceptable with caveats. (see discussion points below)

• Assess and improve the patient’s lifestyle and diet.• Follow by increasing his metformin dose.• An additional anti-hyperglycaemic agent should be added as well.

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ANTI-HYPERGLYCAEMIC AGENTS TO CONSIDER:

AgentswithpositiveCVbenefits AgentswithoutCVbenefits(neutral)

SGLT2-i*• empagliflozin**(EMPA-REG) 5 • canagliflozin¶ (CANVAS)6 • dapagliflozin [for CV death and

hospitalisation for heart failure] (DECLARE-TIMI 58)3,4

GLP-1RA• liraglutide* (LEADER)1 • semaglutide (SUSTAIN-6)7 • albiglutide (HARMONY)8 • dulaglutide (REWIND)9

Metformin10

TZD• pioglitazone (PROACTIVE)11¶§

GLP-1RA• lixisenatine (EXAMINE)12

• exenatide (EXSCEL)13

SU• gliclazide (ADVANCE)14

DPP-4i• sitagliptin (TECOS)15

• linagliptin (CARMELINA)16-18

• saxagliptin (SAVOR-TIMI 58)19

• alogliptin (EXAMINE)12

Table 1: Anti-hyperglycaemic agents and associated CV outcomes; *Positive CV benefits of SGLT2-i: includes findings from the meta-analysis by Zelnicker;20 ** empagliflozin has registered indication to reduce the risk of CV death in adult T2DM patients with established CVD; ¶ canagliflozin is indicated to reduce the risk of MACE in adults with T2DM and established CVD; § pioglitazone demonstrated positive secondary endpoints for MACE

3. What additional anti-hyperglycaemic agent would you consider?

DISCUSSION

CASE STUDY 1A (CONT’D)

The decision for an additional agent should be made based on its approved indications for CV protection.

35


If the aim is to achieve HbA1c < 7%, there is a reduction of 1.3% in HbA1c needed to optimise Mr. AB’s glycaemic control.• The main consideration is the presence of existing angina.

• Therefore, the addition of SGLT2-i or GLP-1RA is ideal as either one is indicated to provide CV protection.

• The decision between the two agents, however, would depend on the patient’s preference and the knowledge that GLP-1RA additionally has more potent HbA1c and weight loss reduction.

If the aim is to try to achieve HbA1c < 6.5%, the required HbA1c reduction is 1.8%.• Addition of 2 therapies may be required (on top of metformin + lifestyle). - The ideal would be to add both GLP1-RA + SGLT2-i (both with evidence of

CV protection). - An alternative would be: � SGLT2-i + DPP4-i (SGLT2-i for glycaemic effect + CV protection, DPP4-i

for additional HbA1c lowering). Both these therapeutic agents have minimal hypoglycaemic risk.

� If cost is a barrier to initiation of the SGLT2-i + DPP4-i combination, then SGLT2-i + other oral anti-hyperglycaemic agents may be required (SGLT2-i for CV protection + other anti-hyperglycaemic agent to assist in achieving HbA1c target).

Note on adverse effects with GLP-1RA and SGLT2-i: • If Mr. AB is started on GLP-1RA and is unable to tolerate it due to

gastrointestinal adverse events then SGLT2-i would serve as an alternate option.

• On the other hand, if SGLT2-iisstartedfirstandheexperiencesrecurrentgenitourinary infections, then GLP-1RA can be considered.

• However, if the patient is unable to tolerate or afford either one of these agents, then the aim of treatment is for glycaemic control only.

Note on use of TZD: Although TZD, specificallypioglitazone was shown to reduce composite

of all-cause mortality, non-fatal myocardial infarction, and stroke (pre-specified secondary endpoint) in patients with T2DM who have a high risk of macrovascular events, it is not recommended as a routine addition owing to concerns of possible increased heart failure.

36


1. Would the HbA1c target be different?

2. How would you achieve this HbA1c target? (Choose all that apply)

DISCUSSION

CASE STUDY 1B

• Both answers are acceptable i.e. yes and no.• If the answer is yes, the rationale is that Mr. AB’s HbA1c is too far off the

intensive target of 6.5%.

• As discussed above (case 1A), a combination of a SGLT2-i + GLP1-RA would be the 1st choice (for glycaemic efficacy and CV protection).

• If the patient is already following an appropriate lifestyle modification (i.e. diet and physical activity), and is symptomatic for hyperglycaemia, initiation of insulin may be the optimal choice.

- Once glucose control has improved, then addition of an SGLT2-i can be considered (for CV protection).

- Reason to delay initiating SGLT2-i is that the patient may have polyuria and polydipsia that may be exacerbated by SGLT2-i.

Note: There are very limited trial data assessing the HbA1c-lowering efficacy of

GLP1-RA combination with SGLT2-i.

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EfficacyofdapagliflozinwhenHbA1cbaselineishigh21

• Figure 1 shows the HbA1c lowering efficacy of SGLT2-i (in this case, dapagliflozin), when baseline HbA1c is high (> 10.0%). Therefore, in patient case 1B, his HbA1c will be reduced from ~10% to ~7.9%. This will still meet the >7.0% target.

• There is still a possibility this patient will achieve an HbA1c < 7.0%, with SGLT2-i addition + metformin, if he engages in lifestyle and dietary modification, as well as improving adherence to his treatment.

Figure 1: Adjusted mean change from baseline in HbA1c with dapagliflozin 5 mg, 10 mg and placebo. * p < 0.0001; + p < 0.05 Adapted from Skolnik N, 2016.

EfficacyofempagliflozinathighbaselineHbA1c22,23

Figures 2 and 3 show the HbA1c-lowering efficacy of empagliflozin when baseline HbA1c is high.

-0.77(-1.18, -0.36)

0

-1

-2

-3Adju

sted

mea

n ch

ange

(SE)

from

bas

elin

e in

A1c

, %

Placebo DAPA 5 mg/d DAPA 10 mg/dn 94 42 95Baseline A1c (%) 10.5 10.3 10.6

-0.82

-2.13

-1.59

-1.32

(-1.93, -0.70)*

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CASE STUDY 1B (CONT’D)

Placebo(n=51)

10 mg QD(n=54)

25 mg QD(n=45)

Sitagliptin(n=51)

Mean baseline9.06 9.16 9.18 8.99

Figure 2: Adjusted mean HbA1c change from baseline vs. empagliflozin vs. placebo. CI: confidence interval. Adapted from Roden M, 2013.

Figure 3: Empagliflozin as add-on to metformin in T2DM showing change in HbA1c over time in an uncontrolled open-label arm over 24 weeks. Adapted from Häring HU, 2014.

Efficacyofdapagliflozin+saxagliptincombinationvs.dapagliflozinalone vs. saxagliptin alone24

Figures 4 and 5 show the HbA1c-lowering efficacy of addition of SGLT2-i + DPP4-i combination as compared to addition of SGLT2-i alone or DPP4-i alone – highlighting the better HbA1c reduction of 2 agent combination, with the higher likelihood of achieving the target HbA1c.

Adju

sted

mea

n (9

5% C

l) ch

ange

from

bas

elin

e in

HbA

1C, %

0.5

0.0

-0.5

-1.0

-1.5

-2.0

Comparison with placebo

0.01

-1.44 -1.43

-1.04

-1.44(95% Cl:

-1.73, 1.15)p < 0.0001

-1.44(95% Cl:

-1.74, -1.13)p < 0.0001

-1.04(95% Cl:

-1.34, -0.75)p < 0.0001

Empagliflozin

0 6 12 18 24 30

11.5

11.0

10.5

10.0

9.5

9.0

8.5

8.0

7.5

Week

Mea

n (S

E) H

bA1c

(%)

Empagliflozin 25 mg OL (n = 101)

-3.23(0.16)

N/Week BL 6 12 18 24OL EMPA 25 mg QD 67 94 89 77 70

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Figure 4: Adjusted mean change from baseline in HbA1c at 24 weeks. b: number of randomised patients with non-missing baseline values and week 24 values; baseline %: baseline HbA1c level. Saxa: saxagliptin, Met: metformin, Dapa: dapagliflozin. Adapted from Rosentock, J, 2014.

Figure 5: Mean HbA1c over time. a: observed values. Saxa: saxagliptin, Met: metformin, Dapa: dapagliflozin. Rosenstock J, 2014.

Note: As this patient’s baseline HbA1c is > 10%, avoid rapid normalisation of HbA1c with GLP1-RA especially in presence of proliferative diabetic retinopathy.7

0.0

-0.5

-1.0

-1.5

-2.0Adju

sted

mea

n (9

5% C

I) ch

ange

fr

om b

asel

ine

in H

bA1 c (

%)

SAXA+DAPA+MET SAXA+MET DAPA+METBaseline (%) 8.93 9.03 8.87nb 158 143 151

-0.59% (-0.81%, -0.37%)P < 0.0001

-0.27% (-0.48%, -0.05%)P = 0.0166

9.5

9.0

8.5

8.0

7.5

7.0-6 0 6 12 18 24

Weeks

Mea

n (S

E) H

bA1 c,

%

SAXA + DAPA + METSAXA + METDAPA + MET

Number of patients with measurementsa

SAXA + DAPA + MET 174 176 174 169 165 158SAXA + MET 173 175 174 165 155 143DAPA + MET 171 172 171 163 159 151

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CASE STUDY 2 Newly diagnosed T2DM presenting with acute coronary

syndrome and normal renal function

1. What would the optimal HbA1c target be for Mr. CD?a. < 6.5%b. < 7.0%c. < 7.5%

d. < 8.0%

2. In this case, Mr. CD was started on an SGLT2-i with CV indication. What are the other options for initial therapy in this patient?

DISCUSSION

a Mr. CD’s HbA1c should be at 6.5% (consistent with the T2DM CPG 2015) and is likely to be able to hit the target without added medications that could cause hypoglycaemia

Two types of treatment regimen can be used for a patient presenting as Mr. CD, i.e. monotherapy or dual combination therapy.• Anti-hyperglycaemic agents to consider for monotherapy are metformin,

SGLT2-i or GLP-1RA.• However, as Mr. CD’s baseline HbA1c is > 1.5% above target, it is more

appropriate to start with an initial dual combination therapy.• Dual combinations that could be used are metformin with SGLT2-i or GLP-1RA.

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3. If Mr. CD had presented with HbA1c of 7.1% instead of 8.8%, what would his optimal HbA1c and initial therapy be?

• His optimal HbA1c target should be the same as when he presented with a higher HbA1c level.

• The options for initial therapy for glycaemic control would also remain the same.

Note: • Note that for purely glycaemic control in these patients, metformin

alone may be adequate to bring the HbA1c to target.

• However if CV protection is deemed an important target, which it should be, add an agent that has been documented to offer this.

• Bear in mind that clinical trials on these agents were done on patients with a longer duration of diabetes and who were mostly already on metformin.

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CASE STUDY 3 T2DM patient presenting with heart failure and

normal renal function

1. What would the optimal HbA1c target be for Mr. EF?a. < 6.5%b. < 7.0%c. < 7.5%d. < 8.0%

2. How would you optimise the glycaemic control of Mr. EF?

DISCUSSION

b Note: Ideally 7.0% if it can be reached safely.

Adjusting current medications:• Increasing acarbose won’t get the patient to target HbA1c.• However, if on assessment of hypoglycaemia there has been none or no

severe hypoglycaemic episodes, gliclazide may be increased.• It is also important to bear in mind that both these agents do not offer any CV

benefits to the patient.

OfferingCVbenefit• To offer CV benefit, add SGLT2-i or GLP-1RA.• Note that DPP4-i agents are considered neutral in terms of providing benefits

in MACE (TECOS, CARMELINA, SAVOR-TIMI-53).15,18,19 In the exploratory secondary endpoint of the SAVOR TIMI-53, there was an increase in the risk of hospitalisation for heart failure.19

CASE 3A

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3. After being on an SGLT2-i for 6 months to a year, Mr. EF’s HbA1c is still not at target (i.e. > 7.0%-7.5%). Will you add another anti-hyperglycaemic agent?

Yes• In patients with heart failure, a GLP-1RA may be added to help optimise

the HbA1c levels.• A DPP4-i (except saxagliptin) can also be used instead of a GLP-1RA.• However, avoid a TZD. - TZD has been shown to increase the risk of heart failure and is

contraindicated in patients with heart failure.25

Yes

4. Is Mr. EF’s HbA1c on target?

DISCUSSION

CASE 3BWhat if Mr. EF presented with:• HbA1c 6.7%,• no history of hypoglycaemia; and• is performing self-blood glucose monitoring

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5. Would it be appropriate to add an SGLT2-i into his treatment regimen and if so, how would you proceed?

DISCUSSION

CASE 3B (CONT’D)

Yes

• Hospitalisation for heart failure was consistently reduced in all 3 CVOT with SGLT2-i irrespective of baseline heart failure status.

• Though these findings were secondary endpoints, the data is sufficiently robust to support its use in this patient. Dedicated heart failure studies are on-going in this group of patients to clarify its role.

• In a sub-analysis of DECLARE-TIMI 58, heart failure patients with documented impaired LVEF treated with dapagliflozin were associated with significant reduction of CV death and rehospitalisation for heart failure.26

NoteonadditionofSGLT2-iintreatmentregimencontaininggliclazide • The dose of gliclazide should be reduced or discontinued to avoid

hypoglycaemia.

• If the patient’s HbA1c on follow-up is not on target, he may need to adjust SU (gliclazide) or initiate another anti hyperglycaemic agent.

Note on acarbose On the other hand, maintaining acarbose may help with the glycaemic

control but does not offer any CV benefits (ACE trial).27

RECOMMENDATION

Management of T2DM in heart failure patients:• Use metformin as first line treatment• Consider addition of SGLT2-i• Alternative options: - GLP-1RA - DPP4-i – avoid saxagliptin • Avoid TZD as it is contraindicated• Avoid hypoglycaemia and consider reduction of SU dose/

discontinuation, as appropriate

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Additional notes on: Metformin • Amid concerns of metformin use in heart failure patients, the USFDA in

2006 removed heart failure as a contraindication for its use.28

• This was further cemented in the 2016 ESC guidelines which considers its use safe and the treatment of choice in heart failure patients.29

• However, during the same year, USFDA recommended that metformin can be used in CKD patients with heart failure, with eGFR > 30ml/min/1.73m2.28,30

SGLT2-i • SGLT2-i has shown significant reduction in hospitalisation for heart

failure and should be included in the treatment regime when appropriate.

• A sub-analysis from the DECLARE-TIMI 58 study, evaluated T2DM heart failure patients stratified by LVEF. This is the first SGLT2-i CVOT for this sub-group of patients.

- Results showed that dapagliflozin reduced:

� hospitalisation for heart failure in all patients with or without heart failure signs and symptoms

� CV death and all-cause mortality in those with heart failure with reduced ejection fraction26

Study HR (95% CI)

EMPA-REG OUTCOME31 0.65 (0.50,0.85)

CANVAS32 0.67 (0.52, 0.87)

DECLARE TIMI 584 0.73 (0.61,0.88)

Table 2: SGLT2-i clinical trials and heart failure hospitalisation outcomes.

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CASE 3B (CONT’D)

GLP-1RA • Four CVOTs investigating the effect of GLP-1RA showed a non-significant

trend towards reducing heart failure hospitalisation. SUSTAIN-67 using semaglutide demonstrated a non-significant increase in risk of heart failure hospitalisation.

• With regards to use of liraglutide, further evaluation in the FIGHT36 and LIVE37 trials showed associations with increased heart rate and more serious cardiac events, which can be of concern in patients with chronic heart failure and reduced left ventricular function.

SU • There is controversy surrounding SU and a potential for increased

mortality as well as heart failure, with cohort studies suggesting there is an increased mortality as well as heart failure,38,39 while all the prospectively run trials using SU (e.g. UKPDS, ADVANCE, VADT40 as well as STENO-241) have not shown any signal for increased CV risk, mortality or heart failure in the SU treated cohorts.

• If SU is chosen for glycaemic control, the newer generation SU e.g. glimepiride and gliclazide may be preferred.

• In addition, note that if an SGLT2-i or GLP1-RA is added for purpose of CV protection, based on the patient’s baseline glycaemic status, the SU dose may need to be reduced or stopped.

Study HR (95% CI)

LEADER1 0.87 (0.73,1.05; p = 0.14)

ELIXA34 0.96 (0.75,1.23; p = 0.63)

EXSCEL35 0.94 (0.78, 1.13; p = NS)

SUSTAIN-67 1.11 (0.77, 1.60; p = 0.57)

Table 3: GLP1-RA clinical trials and heart failure hospitalisation outcomes.

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CASE STUDY 4 T2DM with established CVD and albuminuria


CASE 4A

1. What would the optimal HbA1c target be for Mr. GH?a. < 6.5%b. < 7.0%c. < 7.5%

d. < 8.0%

2. How would you optimise the glycaemic control of Mr. GH?

DISCUSSION

b(Answer < 6.5% [a] is also acceptable with caveats. (See discussion in case 1A, Mr. AB)

To optimise the glycaemic control, an SGLT2-i or GLP-1 RA can be added to the treatment regimen.

SGLT2-i• This patient has similar baseline characteristics as subjects in EMPA-REG5 ,

CANVAS2 and DECLARE-TIMI 583 trials.

• At this moderate baseline HbA1c, DPP4-i has been shown to have slightly superior blood sugar lowering efficacy (CompoSIT–R).42 However, SGLT2-i is chosen over DPP4-i due to its additional CV benefits.

48

CASE 4A (CONT’D)

• SGLT2-i may also provide some renoprotection.

- Based on EMPA-REG pre-specified secondary outcome analysis, empagliflozin reduced the composite renal endpoints by 39%.43

- In the sub-analysis, the main renal effect was driven by a reduction in new onset macroalbuminuria (HR 0.62, p < 0.001).

- These were duplicated in CANVAS study, with an almost similar reduction rate (40%) in composite renal outcomes, with less subjects having progression in albuminuria (HR 0.73).2,20

- In DECLARE-TIMI 58,4 dapagliflozin has consistently demonstrated positive renal outcome of SGLT-2i (40% reduction in composite renal endpoints).

Note that the EMPA-REG, CANVAS snd DECLARE-TIMI 58 studies are CVOTs. Even though renal endpoint results are consistent, these data remain as secondary outcomes. The results of SGLT2-i renal outcomes studies, Dapa-CKD (2020) and EMPA-KIDNEY (recruitment on-going) are awaited.

The recently published CREDENCE trial44 is the first SGLT2-i (canagliflozin) renal outcome study that showed significant reduction in renal endpoints (doubling of serum creatinine, end stage kidney disease, renal/CV death) by 30% in T2DM patients with diabetic kidney disease.

GLP-1RA• An alternate agent for optimising glycaemic control in this patient is a GLP-1RA, which

has also been shown to have cardioprotective effects.

• In the LEADER1 trial, liraglutide resulted in lower rates of development and progression of diabetic kidney disease (HR 0.78, p < 0.001), mainly driven by reduction in new onset of proteinuria.

• To date, there is no renal outcome trial for GLP-1RAs.


49


CASE 4B

1. What would the optimal HbA1c target be for Mr. JK?a. < 6.5%b. < 7.0%c. < 7.5%

d. < 8.0%

2. Would you consider altering Mr. JKs anti-hyperglycaemic regimen?

DISCUSSION

b

Yes

• Reduce gliclazide to 80 mg o.d; and• Add an SGLT2-i.

Rationale of adding SGLT2-iThis patient has severe CAD with impaired cardiac function. The glycaemic control is optimal with HbA1c of < 7%.

• In most circumstances, physicians would tend to maintain the same oral anti-hyperglycaemic agents.

• However, with the emerging evidence of CV benefits of SGLT2-i as shown

in EMPA-REG,5 CANVAS2 and DECLARE-TIMI 584 trials, one may need to consider adding a SGLT2-i to

- reduce hospitalisation for heart failure and MACE; and - reduce CV death.

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CASE 4B (CONT’D)

Proteinuria in diabetic kidney disease confers higher risk of CV morbidity and mortality as well as more rapid CKD progression.

• SGLT2-i has been shown to have anti-proteinuric effect, which is more significant in patients with macroalbuminuria.

• In the CANVAS trial,2 a reduction of 36% from baseline was observed in subjects with macroalbuminuria. This anti-proteinuric effect may explain the slower CKD progression observed in the SGLT2-i arm.

• The recently published DECLARE-TIMI 58 study,4 which recruited mostly T2DM patients with preserved renal function (93%), also consistently showed favorable renal outcome (HR 0.76, p < 0.05).

• The meta-analysis by Zelnicker,20 which included 3 landmark SGLT-2i CVOT trials, concluded positive effects of SGLT-2i in primary and secondary prevention of renal events (p < 0.001).

• The recently published CREDENCE44 study has confirmed that canagliflozin can reduce proteinuria, leading to slower progression of kidney disease (-1.85ml/min/1.73m2 per year vs. -4.59ml/min/1.73m2 per year).

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CASE 5AMr. LM is started on an SGLT2-i.


(eGFR 45-60 ml/min/1.73 m2)

1. What precautions should be taken when starting patients on an SGLT2-i?

DISCUSSION

• In frail, older patients, SGLT2-i may not be appropriate.

• Review concomitant medications

Patient Precautions45

On anti-hypertensive treatment;> 65 years old; ORhaemodynamically unstable (atrial fibrillation, orthostatic hypotension, labile BP, history of syncope)

• Monitor BP at weekly intervals until it stabilises

• Consider reducing dose of anti-hypertensive or withdraw anti-hypertensive when BP < 120/60 mmHg or patient becomes symptomatic

On metformin or GLP-1RA

Develops diarrhoea or vomiting

Monitor for adverse gastrointestinal adverse events

Consider reducing dose of metformin/GLP-1RA and ensure adequate fluid intake to avoid renal injury

On medications that predispose to acute renal injury (Non-steroidal anti-inflammatory drugs [NSAIDs], angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARB], diuretics)

On diuretics

Use SGLT2-i with caution46

Consider reducing dose or withdrawing the agent depending on clinical situation e.g. presence of clinical heart failure or peripheral oedema

Table 4: Monitoring and reviewing concomitant medications when on SGLT2-i treatment. Adapted from Gomez-Peralta 2017.

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• Review co-morbidities

Co-morbidities Precautions

Co-morbidities that may predispose to acute renal injury (hypovolaemia or decompensated chronic liver disease)

Use SGLT2-i with caution46

Predisposition to bacterial urinary tract or genitourinary yeast infections

Be aware of increased risk of infections while using SGLT2-i46-48

Development of acute diarrhoeal illness

Withhold SGLT2-i during an acute illness49

Table 5: Reviewing co-morbidities when on SGLT2-i treatment.

2. Apart from glycaemic indices, how else should a patient be monitored?

When on SGLT2-i treatment, monitor:• the usual glycaemic indices such as HbA1c and FBS,• renal function (serum creatinine and eGFR); and• volume status (BP and weight).

Recommended frequencies of renal function monitoring are:

Estimated glomerular filtrationrate(eGFR)

Renal function monitoring

> 60 ml/min/1.73 m2 Serum creatinine- after 3 months. If stable monitor annually or as clinically indicated46

45-60 ml/min/1.73 m2 Serum creatinine – within 2-4 weeks of initiation and subsequently every 3 months if stable or as clinically indicated

Table 6: Monitoring renal function when on SGLT2-i. Adapted from De Santis. 2018.

CASE 5A (CONT’D)

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3. With an eGFR of > 45 ml/min/1.73 m2, what HbA1c improvement can be expected? In this patient (Mr. LM), what would the expected improvement be?

• Depending on the baseline level of hyperglycaemia, SGLT2-i is associated with mean reductions of HbA1c ranging between 0.4-1.1% compared to placebo.46

• In this particular patient you would expect a reduction of HbA1c of 0.4-0.5%.50

4. If the HbA1c in this patient were still above target (> 7.0%), what would you do?

• First check on adherence to medications and diet restrictions.

• Continue SGLT2-i as it is still relevant for providing CV protection for the patient.

• Consider the addition of another agent to achieve target such as (in order of preference):

- GLP-1RA or - DPP4-i or - SU.

Notes on GLP-1RAs • Effective in improving glycaemic control when added to dual oral

combination therapy.

• In the short term, can be an alternative to starting insulin.

• Low incidence of hypoglycaemia because of glucose dependent action.

• Also cause weight reduction, in contrast to the weight gain seen with SU, the glitazones and insulin, and the weight neutral effects of the gliptins.51

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Note that addition of SGLT2-i or GLP-1RA, would require a reduction of the existing SU treatment dose, with an option to resume the original dose, depending on his response.

CASE 5A (CONT’D)

Notes on GLP-1RAs vs. SGLT2-i • GLP-1RAs are high-efficacy anti-hyperglycaemic agents as opposed to

SGLT2-i, which have an intermediate efficacy.

• Compared with SGLT2-i, GLP-1RAs are effective even at an eGFR < 45 ml/min/1.73 m2.

• Caution is advised with exanetide and lixisenatide use when eGFR < 30 ml/min/1.73 m2 as there is no data to support its use in this situation.51

In practice however, GLP-1RAs tend to be under-utilised because of substantially higher gastrointestinal side effects and cost.

1. Is there a compelling reason to start SGLT2-i or GLP-1RA for Mr. QR?

DISCUSSION

CASE 5B

Yes

• Although this patient is at target, addition of SGLT2-i should be considered for cardiac protection.2,3,20,50

• There is an option to use a GLP-1RA as it has shown cardiac protection.1

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CASE 6


(eGFR < 45 ml/min/1.73 m2)

Suggested treatment regimen in this case: • continue with the SGLT2-i even with eGFR < 45 ml/min/1.73 m2

because its benefits in CV protection52 and possible renoprotection are not affected by the level of renal function

• in this specific case, Mr. PQ may need to have another anti-hyperglycaemic agent added for glycaemic control

Note that at eGFR < 30 ml/min/1.73 m2, there is no data to support the continuation of SGLT2-i.

1. How would Mr. PQ’s treatment regimen change with the current eGFR?

DISCUSSION

• A rapid loss of eGFR of 8 ml/min/1.73 m2 over 1 year should be assessed for possible reversible causes for this deterioration (refer to CKD CPG 2018 – Chapter 7).

• With the deterioration in eGFR (CKD Stage 3A), the reduction in HbA1c with SGLT2-i is attenuated (approximately 0.3% reduction of HbA1c) due to the reduced glomerular filtration and therefore reduced filtered glucose load.

• With deteriorating renal function (eGFR < 60 ml/min/1.73 m2), doses of some SGLT2-imayneedadjustment-e.g.reducecanagliflozinto100mgod;withempagliflozinanddapagliflozinnodoseadjustmentisnecessary.

• Treatment is usually discontinued when recommended eGFR limits are reached.

56

THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND CHRONIC KIDNEY DISEASECase study 6: T2DM with established CVD and impaired renal function (eGFR < 45 ml/min/1.73 m2)

CASE 6 (CONT’D)

Additional notes: Currentlybothcanagliflozinanddapagliflozinarenotapprovedforpatients

with an eGFR between 30 and 45 ml/min/1.73 m2, a limitation imposed because of loss of their glycaemia-lowering effect.

However, there is evidence from the CANVAS6 and EMPA-REG5 studies of continued CV protection for both canagliflozin and empagliflozin respectively at GFR levels between 30-45 ml/min/1.73 m2.

Canagliflozin(CANVAStrial)• Post-hoc analysis has shown improved CV and renal outcomes in patients

with and without CKD, including those with eGFR down to 30 ml/min/1.73 m2.6

• The primary CV outcome was a composite of CV death, MI or stroke.

• The reduction of the primary CV outcome seen in the overall trial population (HR 0.86; 95% CI 0.75,0.97) did not differ across eGFR levels or by CKD status (p for heterogeneity = not significant for both).

• In terms of secondary outcomes, the effect on CV death, MI and hospitalisation for heart failure individually did not vary by renal function.

- The exception was stroke, with possibly greater benefits in patients with lower levels of kidney function (p for heterogeneity = 0.01).

- Safety outcomes were consistent across eGFR subgroups, including for serious renal safety outcomes.

- The exception was a borderline significant interaction test observed for hypoglycaemia, although patients were more likely to be on insulin with worsening levels of renal function.

Empagliflozin(EMPA-REGtrial)• Reductions in primary outcome and CV death were also consistent across

different levels of renal function.5

• In the EMPA-REG RENAL50 trial, there were 292 patients in CKD stage 2, 375 patients in stage 3 and 74 patients in stage 4 CKD.

• The proportions of patients with AE, including those leading to study discontinuation and serious AEs were similar across treatment groups in patients with CKD stage 2 or 3 but higher in patients with CKD stage 4.

57

THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND CHRONIC KIDNEY DISEASECase study 6: T2DM with established CVD and impaired renal function (eGFR < 45 ml/min/1.73 m2)

• In a patient with a history of CVD or at high risk who is on SGLT2-i, the SGLT2-i could conceivably still be continued for the CV benefits, at least down to an eGFR of 30 ml/min/1.73 m2.

• However it would be considered off-label use, and would require discussion with the patient regarding the risks and benefits, and special written consent.

Also note that in the case of Mr. PQ, the SU may or may not need to be continued for glycaemic control depending on the type of SU and its dose. However, bear in mind that there is an increased risk of hypoglycaemia with worsening level of renal function.

58

CASE STUDY 7 T2DM with high-risk for CVD and normal renal function


Figure 6: CVD risk calculator available at http://cvrisk.mvm.ed.ac.uk/calculator/framingham.htm

TC:HDL46810

10% 20% 30%

1. What is the CV risk score for Mrs. RS, based on the Framingham scoring system?

a. < 10%b. 10- 20%c. > 20%

DISCUSSION

c The score is 36.9% 10-year risk of CV event.

SBP

180

160

140

120

• Time period: 10 years• Age: 64 years• Diabetes• Blood pressure:

140/90 mmHg• Cholesterol:

Total – 6.0; HDL –0.9 mmol/L• Probability of developing

cardiovascular disease in next 10 years is 36.9%

• Calculated using Framingham equation

Calculate risk of CVD (Framingham)

59


2. What would the optimal HbA1c target be for Mr. RS?a. < 6.5%b. < 7.0%

b

3. To reduce the HbA1c by 1.5% (8.5% to 7.0%), which of these treatment options will you offer this patient? (more than one answer is applicable)


• The patient in this case can be prescribed further lifestyle improvements with dietary caloric restriction for weight loss and addition of anti-hyperglycaemic agents.

• The patient is already on maximal oral metformin + SU, and on basal insulin.

• SGLT2-i5 and GLP-1RA are acceptable choices. - GLP-1RA is the preferred1 choice as it is more potent at glucose-

lowering (see below) and the patient is at high CV risk.53

Note: • In the case of Mrs. RS, it is unlikely that just lifestyle modification will

help her achieve the target HbA1c.

• Although escalation of basal insulin is possible (fasting glucose is not optimally controlled), as the patient is obese, increasing insulin is likely to increase her body weight.

• In addition, self-blood glucose monitoring has been mandated in patients on insulin therapy. If patients do not perform glucose monitoring, insulin dose escalation cannot be done safely.

c. < 7.5%

d. < 8.0%


60


Add GLP-1RA vs. SGLT2-i – potency of glucose-lowering In a network meta-analysis by Lorenzi et al.,54 liraglutide at 1.2 and 1.8 mg dose were found to be more effective at lowering HbA1c, fasting glucose and achieving HbA1c < 7.0% compared to SGLT2-i.

Liraglutide vs. sitagliptin for patients with T2DM who did not have adequate glycaemic control with metformin: a 26-week randomised, parallel group, open-label trial.55

• Greater lowering of mean HbA1c (8.5% at baseline) was achieved with 1.8 mg liraglutide (−1.50%, 95% CI −1.63, −1.37, n=218) and 1.2 mg liraglutide (−1.24%, 95% CI −1.37, −1.11, n=221) than with sitagliptin (−0.90%, 95% CI −1.03, −0.77, n=219).

• Estimated mean treatment differences for liraglutide vs. sitagliptin were −0.60% (95% CI −0.77, −0.43, p < 0.0001) for 1.8 mg and −0.34% (95% CI −0.51, −0.16, p < 0.0001) for 1.2 mg liraglutide.

Efficacy and safety of dulaglutide vs. sitagliptin after 52 weeks in T2DM patients in a randomised controlled trial (AWARD-5).56

• Effect on HbA1c over time

Place

bo

Lira 1

.2

Lira 1

.8

Cana

100

Cana

300

Dapa 1

0

Dapa 5

Empa

10

Empa

25

Sita 1

00

0.0

-0.5

-1.0

-1.5

Mea

n CF

B H

bA1c

(%)

Treatment

Figure 7: Modeled outcomes in change from baseline in HbA1c (%) in metformin-experienced T2DM. Bars represent the estimated mean response and whiskers represent the 95% CI. The estimate for placebo is a pooled response estimate based on the available data. CFB: change from baseline; Lira: liraglutide; Cana: canagliflozin; Dapa: dapagliflozin; Empa: empagliflozin; Sita: sitagliptin. Adapted from Lorenzi et al. 2017, used under Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/).

61


• Change in body weight over time

Figure 8: Change in HbA1c over 52 weeks. Data presented are LS mean ± SE. ##: p < 0.001 vs. sitagliptin; **: p < 0.001 vs. placebo. Adapted from Nauck, et al. 2014.

Figure 9: Change in body weight over 52 weeks. Data presented are LS mean ± SE. #: p < 0.05 vs. sitagliptin; ##: p < 0.001 vs. sitagliptin; *: p < 0.05 vs. placebo; **: p < 0.001 vs. placebo. Adapted from Nauck, et al. 2014.

HbA1c,overtim

e(mmol/m

ol,LSMean+SE)

8.4

8.2

8.0

7.8

7.6

7.4

7.2

7.0

6.8

6.6

6.4

68

66

64

62

60

58

56

54

52

50

48

460 4 8 12 26 39 52

Time (weeks)

HbA

1c,overtim

e(%

,LSMean+S

E)

Dulaglutide 1.5 mgDulaglutide 0.75 mgSitagliptinPlacebo

**

**** **

##**

##**

##**

##**

##**

##** ##**##**

##

##

##**

##**

0

-1

-2

-3

0 2 4 8 12 26 39 52Time (weeks)

Weigh

t,changeovertim

e(kg,LSMean+S

E) Dulaglutide 1.5 mgDulaglutide 0.75 mgSitagliptinPlacebo

##**

#

##**

##**

##**

##**

##*

##**

##**

##** ## ##

#

##

62


However, if cost and injections are barriers to its uptake, then the alternative choice can be SGLT2-i, of which any of the available agents, e.g. dapagliflozin, empagliflozin or canagliflozin are acceptable choices.

Dapagliflozin Canagliflozin Empagliflozin

• DECLARE-TIMI 58 had the largest number of high CV risk patients recruited and studied for a longer duration

• The study has shown dapagliflozin to be CV neutral (2° prevention and 1° prevention for MACE) but with promise of reduction in hospitalisation for heart failure and onset of nephropathy

• CANVAS had 35% of patients without established CVD and was found to have positive reduction of MACE events

• The positive MACE outcomes were noted mainly in patients with established CVD

• EMPA-REG comprised of 99% patients with established CVD

• There was a significant 38% reduction in CV death

Table 8: Comparison between dapagliflozin, canagliflozin and empagliflozin.

An escalation of basal insulin is also appropriate to help fix the FBS but the patient will be required to perform self-blood glucose monitoring.

Remember! Lifestyle modification should be the basic management for all T2DM patients and is required at every step of management.

63

THEM

E: TY

PE 2

DIAB

ETES

MEL

LITUS

WITH

HIG

H-RI

SK FO

R CAR

DIOV

ASCU

LAR D

ISEA

SECa

se st

udy 7

: T2D

M wi

th hi

gh-ri

sk fo

r CVD

and n

orma

l ren

al fu

nctio

n

Subg

roup

: Ri

sk o

f CVD

No

of

patie

nts

Lira

glut

ide

Plac

ebo

HR

(95%

CI)

P va

lue

no o

f eve

nts/

no o

f pat

ient

s (%

)

≥50

yearsofa

geand

es

tabl

ishe

d CV

D75

9853

6/38

31

(14.

0)62

9/37

67

(16.

7)0.

83(0

.74-

0.93

)0.

04≥60

yearsofa

geand

ris

k fa

ctor

s fo

r CVD

1742

72/8

37(8

.6)

65/9

05

(7.2

)1.

20

(0.8

6-1.

67)

0.2

1.0

2.0

Lira

lglu

tide

bett

erPl

aceb

o be

tter

Addi

tiona

l not

es:

LEAD

ERstudy(L

iraglutideCV

outcome)*

Hazardratio

(95%

CI)

Pvalue

for i

nter

actio

n

Figu

re 1

0: P

rimar

y co

mpo

site

CV

outc

omes

bas

ed o

n gl

ycat

ed h

aem

oglo

bin,

dur

atio

n of

dia

bete

s an

d ris

k of

CVD

. Ada

pted

from

Mar

so e

t al.

2016

.*L

iragl

utid

e ha

s re

gist

ered

indi

catio

n to

redu

ce ri

sk o

f MAC

E (C

V de

ath,

non

-fat

al M

I and

non

-fat

al s

trok

e) in

adu

lts w

ith T

2DM

and

est

ablis

hed

CV d

isea

se o

r at h

igh

risk

of C

V di

seas

e.

• Th

e pa

tient

pop

ulat

ion

in th

e LE

ADER

1 tria

l com

pris

ed o

f 81%

pat

ient

s w

ith e

stab

lishe

d CV

D, 1

9% w

ith C

V ris

k fa

ctor

s th

at in

clud

ed

risk

fact

ors

and

pres

ence

of a

lbum

inur

ia, s

tage

3 C

KD o

r hig

her.

• Si

mila

r to

the

CAN

VAS

stud

y, th

e CV

ben

efit

appe

ars

to b

e de

rived

in th

e co

hort

of p

atie

nts

with

est

ablis

hed

CVD

(Fig

ure

5). T

he c

ohor

t w

ith C

V ris

k fa

ctor

s di

d no

t sho

w s

igni

fican

t CV

bene

fit.

• In

this

tria

l,1 the

cal

cula

ted

NN

T57 fo

r 3 y

ears

to p

reve

nt 1

MAC

E w

as 6

6 an

d to

pre

vent

dea

th fr

om a

ny c

ause

was

98.

• Th

e CV

ben

efit

from

the

LEAD

ER tr

ial o

ccur

red

at a

late

r sta

ge c

ompa

red

to th

e EM

PA-R

EG tr

ial5 a

nd is

mor

e lik

ely

to b

e re

late

d to

m

odifi

ed p

rogr

essi

on o

f ath

eros

cler

otic

vas

cula

r dis

ease

.58

THEM

E: TY

PE 2

DIAB

ETES

MEL

LITUS

WITH

HIG

H-RI

SK FO

R CAR

DIOV

ASCU

LAR D

ISEA

SECa

se st

udy 7

: T2D

M wi

th hi

gh-ri

sk fo

r CVD

and n

orma

l ren

al fu

nctio

n

Subg

roup

: H

isto

ry o

f CVD

Canagliflozin

Plac

ebo

HR

(95%

CI)

P va

lue

no. o

f par

ticip

ants

/100

0 pa

tient

-yea

r

Yes

34.1

41.3

0.82

(0

.72-

0.95

)0.

18

No

15.8

15.5

0.98

(0.7

4-1.

30)

0.25

1.00

0.50

2.00

4.00

Canagliflozinbetter

Plac

ebo

bett

er

Hazardratio

(95%

CI)

Figu

re 1

1: E

ffec

ts o

f can

aglifl

ozin

on

the

prim

ary

CV o

utco

me

in p

atie

nts

with

his

tory

of C

VD.2 A

dapt

ed fr

om N

eal,

et a

l. 20

17.

In C

ANVA

S, th

e te

st fo

r het

erog

enei

ty w

as n

ot s

tatis

tical

ly s

igni

fican

t, w

hich

mea

ns th

at b

oth

grou

ps, i

.e. t

hose

with

est

ablis

hed

CVD

an

d th

ose

at h

igh

CV ri

sk b

enef

itted

from

can

aglif

lozi

n (F

igur

e 11

).

64

65


Patient and clinician preferences and priorities for considering SGLT2-i with demonstratedCVbenefitvs.GLP-1RAswithdemonstratedCVbenefit.59

SGLT2-iasfirstchoiceif: GLP-1RAasfirstchoiceif:

• reduction of MACE and CV death• prevention of heart failure

hospitalisation• reduction of BP• reduction of body weight• preference for oral therapies• cost

• reduction of MACE and CV death

• reduction of body weight• willing to give injections (once

daily or weekly S/C)• eGFR is consistently

< 45 ml/min/1.73 m2

Choose alternative therapies if, Choose alternative therapies if,

• significant CKD• history of one or more of the

following: - previous amputation - severe peripheral arterial

disease - peripheral neuropathy - diabetic foot ulcers (avoid

canagliflozin) - recurrent genital candidiasis - diabetic ketoacidosis - osteoporosis (avoid

canagliflozin)

• persistent nausea. gastrointestinal disturbance

• history of one or more of the following:

- pancreatitis - gastroparesis - multiple endocrine

neoplasia type 2 (MEN2) or medullary thyroid cancer

- proliferative retinopathy (avoid semaglutide)

Table 9: Guidance on choice of either SGLT2-i or GLP-1RA for treatment based on patient and clinicians’ preference. Adapted from Das et al. 2018.

66


Some points to consider: • Mrs. RS’s profile accounts for about 60% of T2DM patients. - Consider costs when advocating the suggested anti-

hyperglycaemic agents. - Bear in mind that the inclusion criteria for CANVAS and LEADER

trials did not include patients < 60 years of age.• Remember other therapeutic options are available e.g. insulin - Keep in mind that the existing clinical practice guidelines for

management of T2DM within the CV risk continuum are still relevant.

- Achieving HbA1c is still an important target. - The aim of this practical guide is to assist clinical decision making,

using the evidence from the latest CVOTs.• If the newer, more expensive therapies are unavailable, every attempt

to reduce HbA1c to target safely with the available resources should remain a priority.

67


CASE STUDY 8 T2DM with high-risk for CVD and impaired renal function

DISCUSSION1. What would the optimal HbA1c target be for Mrs. RS?

a. < 6.5%b. < 7.0%

b

c. < 7.5%

d. < 8.0%

2. What is the CV risk score for Mrs. RS, based on the Framingham scoring system?a. < 10%b. 10- 20%

c

The score is 36.9% 10-year risk of CV event.

SBP

TC:HDL

180

160

140

120

4 6 8 10

10% 20% 30%

• Time period: 10 years• Age: 64 years• Diabetes• Blood pressure:

140/90 mmHg• Cholesterol: Total – 6.0; HDL –0.9 mmol/L• Probability of developing

cardiovascular disease in next 10 years is 36.9%

• Calculated using Framingham equation

Calculate risk of CVD (Framingham)

c. > 20%

Figure 12: CVD risk calculator available at http://cvrisk.mvm.ed.ac.uk/calculator/framingham.htm

68

THEME: TYPE 2 DIABETES MELLITUS WITH HIGH-RISK FOR CARDIOVASCULAR DISEASECase study 8: T2DM with high-risk for CVD and impaired renal function

DISCUSSION

Similar to Case 7, the patient in this case would be considered to have high CV risk and can be prescribed further lifestyle improvements with dietary caloric restriction for weight loss.

In T2DM patients with multiple risk factors, SGLT2-i would be the preferred choice

• Expected HbA1c reduction is approximately 0.3% in most trials with SGLT2-i in T2DM with CKD stage 3A.

• In addition, SGLT-2i appears to have renoprotective effects.

- Data for multiple risk factor patients subgroup: � CANVAS program: HR = 0.63 (0.39, 1.02)60

� DECLARE: HR = 0.51 (0.37,0.69)*61

� CREDENCE: HR = 0.69 (0.54, 0.88)44

*composite of 40% decrease in eGFR to below 60mL/min, ESRD or renal death

• Therefore, if the clinical decision is nephroprotection, in addition to HbA1c lowering, then there is probably a clinical reason to initiate SGLT2-i.52

• However, as addition of SGLT2-i in this patient may not achieve the desired HbA1c <7.0%, there may be a need to add another anti-hyperglycaemic agent; which can be GLP1-RA, or DPP4-i.

Escalation of insulin may not be the right choice as the patient’s fasting blood glucose level is acceptable.

Addition of GLP-1RA can also be considered because of its HbA1c lowering efficacy and additional beneficial effects of weight reduction.

• In addition, sub-group analysis of liraglutide in the LEADER trial showed that the CV benefit in the liraglutide arm was seen even in subjects with severe as well as moderate CKD, eGFR < 60 ml/min/1.73 m2.

3. To reduce the HbA1c by 1.5% (8.5% to 7.0%), which of these treatment options will you offer this patient? (more than one answer is applicable)



69

THEM

E: TY

PE 2

DIAB

ETES

MEL

LITUS

WITH

HIG

H-RI

SK FO

R CAR

DIOV

ASCU

LAR D

ISEA

SECa

se st

udy 8

: T2D

M wi

th hi

gh-ri

sk fo

r CVD

and i

mpair

ed re

nal f

uncti

on

Subg

roup

: Re

nal f

unct

ion

No

of

patie

nts

Lira

glut

ide

Plac

ebo

HR

(95%

CI)

P va

lue

no o

f eve

nts/

no o

f pat

ient

s (%

)

Seve

re o

r mod

erat

e di

seas

e

< 60

ml/

min

/1.7

3 m

221

5817

2/11

16

(15.

4)22

3/10

42

(21.

4)0.

69

(0.5

7-0.

85)

0.01

≥60

ml/min/1.73m

271

8243

6/35

52

(12.

3)47

1/36

30

(13.

0)0.

94(0

.83-

1.07

)

Seve

re d

isea

se

< 30

ml/

min

/1.7

3 m

222

425

/117

(2

1.4)

26/1

07

(24.

3)0.

89(0

.51-

1.54

)0.

93

≥30

ml/min/1.73m

291

1658

83/4

551

(12.

8)66

8/45

65

(14.

6)0.

87

(0.7

7-0.

97)

0.2

1.0

2.0

Lira

lglu

tide

bett

erPl

aceb

o be

tter

Figu

re 1

3: R

esul

ts fr

om L

EAD

ER w

ith li

ragl

utid

e an

d CV

(MAC

E) o

utco

mes

.1 Ada

pted

from

Mar

so e

t al.

2016

.

THEM

E: TY

PE 2

DIAB

ETES

MEL

LITUS

WITH

HIG

H-RI

SK FO

R CAR

DIOV

ASCU

LAR D

ISEA

SECa

se st

udy 8

: T2D

M wi

th hi

gh-ri

sk fo

r CVD

and i

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ed re

nal f

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on

The

met

a-an

alys

is b

y Ze

lnic

ker o

f all

3 SG

TL2-

i CVO

Ts s

how

that

the

MAC

E CV

ben

efits

are

see

n ev

en w

hen

eGFR

is

< 60

ml/

min

/1.7

3 m

2 as

wel

l as

betw

een

60-9

0 m

l/m

in/1

.73

m2 .20

Patie

nts

Even

ts

Even

ts p

er 1

000

patie

nt-y

ears

Wei

ght

(%)

HR

(95%

CI)

Trea

tmen

t (n

/N)

Plac

ebo

(n/N

)Tr

eatm

ent

Plac

ebo

eGFR

< 6

0 m

l/m

in/m

2

EMPA

-REG

O

UTCO

ME

1212

/181

960

7/18

1927

552

.760

.536

.20.

88

(0.6

9-1.

13)

CAN

VAS

prog

ram

NA/

2039

NA/

2039

261

36.3

49.5

36.6

0.69

(0

.54-

0.89

)D

ECLA

RE-

TIM

I 58

606/

1265

659/

1265

189

37.3

43.1

27.2

0.92

(0

.69-

1.23

)

Fixe

d ef

fect

s m

odel

for e

GFR

< 60

(p =

0.0

077)

0.82

(0

.70-

0.95

)eG

FR 6

0 to

< 9

0 m

l/m

in/m

2

EMPA

-REG

O

UTCO

ME

2423

/366

112

38/3

661

351

30.8

40.6

22.5

0.76

(0

.61-

0.94

)CA

NVA

S pr

ogra

mN

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A/56

2556

326

.829

.032

.80.

95

(0.8

0-1.

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DEC

LARE

-TI

MI 5

838

38/7

732

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/773

275

724

.525

.844

.70.

95

(0.8

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Fixe

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ACKNOWLEDGMENTThe members of A Practical Guide For The Pharmacological Management Of T2DM Patients Across The Cardiovascular Risk Continuum writing committee would like to express their gratitude and appreciation to the following for their contribution:

• Panel of reviewers who reviewed and contributed their expert feedback on the draft copy.

• All those who have contributed directly or indirectly to the development of this practical guidebook.

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