T2DM PATIENTS ACROSS THE CARDIOVASCULAR RISK CONTINUUM - HEART A PRACTICAL GUIDE FOR THE PHARMACOLOGICAL MANAGEMENT OF

 
T2DM PATIENTS ACROSS THE CARDIOVASCULAR RISK CONTINUUM - HEART A PRACTICAL GUIDE FOR THE PHARMACOLOGICAL MANAGEMENT OF
A PRACTICAL GUIDE FOR THE PHARMACOLOGICAL MANAGEMENT OF
   T2DM PATIENTS ACROSS THE
CARDIOVASCULAR RISK CONTINUUM

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T2DM PATIENTS ACROSS THE CARDIOVASCULAR RISK CONTINUUM - HEART A PRACTICAL GUIDE FOR THE PHARMACOLOGICAL MANAGEMENT OF
FOREWORD
As 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 CHAN
Chairperson
Writing committee
TABLE OF CONTENTS
FOREWORD			                                                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                            12
      Case study 2 : Newly diagnosed T2DM presenting
      		 with acute coronary syndrome and
      		 normal renal function                            15
      Case 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                                       20
      Case study 5 : T2DM with established CVD and
      		 impaired renal function
      		 (eGFR 45-60 ml/min/1.73 m2)                      23
      Case 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                           27
       Case study 8 : T2DM with high-risk for CVD and
       		 impaired renal function                         29
TABLE OF CONTENTS

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                            33
        Case study 2 : Newly diagnosed T2DM presenting
        		 with acute coronary syndrome and
        		 normal renal function                            40
        Case 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                                      47
        Case study 5 : T2DM with established CVD and
        		 impaired renal function
        		 (eGFR 45-60 ml/min/1.73 m2)                      51
        Case 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                           58
         Case study 8 : T2DM with high-risk for CVD and
         		 impaired renal function                         67
REFERENCES			                                               74
ACKNOWLEDGMENT 		                                           79
INTRODUCTION
T2DM 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.

OBJECTIVE
To 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.

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

FORMAT
The 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 INTENT
This 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.

                                                                                                 05
INTRODUCTION

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

COPYRIGHT
A 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/

                                                                                                06
WRITING COMMITTEE
CHAIRPERSON
PROFESSOR DR CHAN SIEW PHENG
Honorary Professor
Consultant Endocrinologist
University of Malaya Medical Centre, KL/ Subang Jaya Medical Centre

COMMITTEE MEMBERS
DR SUNITA BAVANANDAN
Consultant Nephrologist
Hospital Kuala Lumpur

DR CHOO GIM HOOI
Consultant Cardiologist
Cardiac Vascular Sentral Kuala Lumpur

DR ZANARIAH HUSSEIN
Consultant Endocrinologist
Hospital Putrajaya

DR LAM KAI HUAT
Consultant Cardiologist
Assunta Hospital, Petaling Jaya

ASSOCIATE PROFESSOR DR LIM SOO KUN
Consultant Nephrologist
University Malaya Medical Centre, Kuala Lumpur

                                                                      07
REVIEWERS
ENDOCRINOLOGY
DR FLORENCE TAN HUI SENG
Consultant Endocrinologist
Hospital Umum Sarawak

DR. HEW FEN LEE
Consultant Endocrinologist
Subang Jaya Medical Centre

DATO’ DR MAFAUZY MOHAMAD
Professor of Medicine and Senior Consultant Endocrinologist
Hospital University Sains Malaysia

DR NORLAILA MUSTAFA
Associate Professor and Senior Consultant Endocrinologist
Universiti Kebangsaan Malaysia Medical Centre

NEPHROLOGY
DR CHOW YOK WAI
Consultant Nephrologist
Pantai Hospital, Air Keroh

DR WONG HIN SENG
Consultant Nephrologist and Head of Nephrology Department
Hospital Selayang

CARDIOLOGY
DR SAZZLI BIN KASSIM
Associate Professor of Medicine, Consultant Cardiologist and Head of Cardiology Department
University Technology MARA

FAMILY MEDICINE
DR. MASTURA BT ISMAIL
Consultant Family Medicine Specialist
Klink Kesihatan Seremban 2

                                                                                             08
ABBREVIATION LIST
ACE               Acarbose Cardiovascular Evaluation trial
ACR               Albumin-creatinine ratio
ADVANCE           Action in Diabetes and Vascular Disease: Preterax and Diamicron MR
                  Controlled Evaluation trial
AE                Adverse event
AV                Atrio-ventricular
b.d               Twice daily
BMI               Body-mass index
BP                Blood pressure
BU                Blood urea
CAD               Coronary artery disease
CANVAS            CANagliflozin cardioVascular Assessment Study
CARMELINA         Cardiovascular and Renal Microvascular Outcome Study With Linagliptin
                  in Patients With Type 2 Diabetes Mellitus
CCS               Canadian Cardiovascular Society
CI                Confidence interval
CKD               Chronic kidney disease
CompoSIT          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 Guidelines
CREDENCE          Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular
                  Outcomes in Participants With Diabetic Nephropathy
CV                Cardiovascular
CVD               Cardiovascular disease
CVD-REAL Nordic   Comparative Effectiveness of Cardiovascular Outcomes in New Users of
                  Sodium-Glucose Cotransporter-2 Inhibitors
CVOTs             Cardiovascular outcomes trials
Dapa-CKD          Evaluate the Effect of Dapagliflozin on Renal Outcomes and
                  Cardiovascular Mortality in Patients With Chronic Kidney Disease
DECLARE-TIMI58    Dapagliflozin Effect on CardiovascuLAR Events - Thrombolysis in
                  Myocardial Infarction Study Group trial 58
DPP4-i            Dipeptidyl peptidase 4 inhibitors
ECHO              Echocardiogram
eGFR              Estimated glomerular filtration rate
EMPA-REG          Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes
OUTCOME           Mellitus Patients–Removing Excess Glucose
ESC               European Society of Cardiology
EXAMINE           EXamination of cArdiovascular outcoMes with alogliptIN versus standard
                  of carE
FBS               Fasting blood sugar

                                                                                               09
ABBREVIATION LIST

FIGHT             Functional Impact of GLP-1 for Heart Failure Treatment
GLP-1 RA          Glucagon-like peptide-1 receptors agonists
HARMONY 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 cholesterol
HR                Hazard ratio
LDL-C             Low-density lipoprotein cholesterol
LEADER            Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes
LIVE              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 fraction
MACE              Major adverse cardiovascular events
MEMS              Malaysian Endocrine and Metabolic Society
MI                Myocardial infarction
MSN               Malaysian Society of Nephrology
NHAM              National Heart Association of Malaysia
NNT               Numbers needed to treat
o.d               Daily
o.n               On night
PROACTIVE trial   PROspective pioglitAzone Clinical Trial in macroVacsular Events.
REWIND trial      Researching Cardiovascular Events With a Weekly Incretin in Diabetes
S/C               Subcutaneous
SAVOR-TIMI53      Saxagliptin Assessment of Vascular Outcomes Recorded in Patient with
                  DM -Thrombolysis in Myocardial Infarction Study Group trial 53
SGLT2-i           Sodium-glucose co-transporter-2 inhibitors
STEMI             ST segment elevated myocardial infarction
STENO-2           Intensified Multifactorial Intervention in Patients With Type 2 Diabetes
                  and Microalbuminuria
SU                Sulfonylureas
T2DM              Type 2 diabetes mellitus
TC                Total cholesterol
TZD               Thiazolidinediones (glitazones)
TECOS             Trial Evaluating Cardiovascular Outcomes with Sitagliptin
TG                Triglycerides
UK                United Kingdom
UKPDS             United Kingdom Prospective Diabetes Study
USFDA             United States Food and Drug Administration
VADT              Veteran’s Affair Diabetes Trial

                                                                                             10
SECTION A:
CASE STUDIES

               11
THEME:
TYPE 2 DIABETES MELLITUS WITH
CARDIOVASCULAR DISEASE AND NORMAL
RENAL FUNCTION
                                    CASE STUDY 1
 T2DM with established CVD 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 years
                                   Medical history
 Presenting complaint        Mild to moderate angina (CCS II)
 Medical history             •   T2DM for 2 years         • Benign prostatic
                             •   Hypertension               hypertrophy
                             •   Dyslipidemia             • Smoker
                             •   Stable CAD
 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.    • Isosorbide dinitrate
                             •   Perindopril 5 mg o.d.      10 mg b.d.
                             •   Simvastatin 20 mg o.n.   • Tamsulosin 0.4 mg b.d.
                             •   Aspirin 100 mg o.d.

                                 Physical examination

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

      Fundoscopy: Non- proliferative retinopathy

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

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

                                                                                        13
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION
Case study 1: T2DM with established CVD and normal renal function

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

DISCUSSION (Refer to page 36 for case studies answers and discussion points)
1. Would the HbA1c target be different?
     a. Yes
     b. No

2. How would you achieve this HbA1c target? (Choose all that apply)
   a. Improve lifestyle i.e. diet and physical activity
     b. Ensure adherence to medication
     c. 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)

                                                                                         14
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION

                             CASE STUDY 2
 Newly diagnosed T2DM presenting with acute coronary
          syndrome and normal renal function

Mr CD; Age: 47 years
                            Medical 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

                         Physical examination

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

                                                                                15
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION
Case 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

 Creatinine                      90.0 μmol/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.

                                                                                                       16
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION
Case study 2: Newly diagnosed T2DM presenting with acute coronary syndrome and normal renal function

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

  DISCUSSION (Refer to page 40 for case studies answers and discussion points)
  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 empagliflozin. What are the other options for
     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?

                                                                                                       17
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION

                                CASE STUDY 3
          T2DM patient presenting with heart failure
                 and normal renal function

CASE 3A

Mr EF; Age: 69 years
                               Medical 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      •   Metformin 1 g b.d.        •   Perindopril 8 mg o.d.
 on presentation        •   Gliclazide 80 mg b.d.     •   Simvastatin 40 mg o.d.
                        •   Acarbose 50 mg b.d.       •   Frusemide 40 mg o.d.
                        •   Metoprolol 50 mg b.d.     •   Slow K 1 tablet o.d.

INVESTIGATIONS
 Parameters             Results
 FBS                    7.5-8.2 mmol/L

 HbA1c                  7.8%

 Creatinine             105.0 μmol/L

 eGFR                   62.0 ml/min/1.73 m2

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

                                                                                   18
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION
Case study 3: T2DM patient presenting with heart failure and normal renal function

  DISCUSSION (Refer to page 42 for case studies answers and discussion points)
  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?

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

  DISCUSSION (Refer to page 43 for case studies answers and discussion points)
  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?

                                                                                        19
THEME:
TYPE 2 DIABETES MELLITUS WITH
CARDIOVASCULAR DISEASE AND CHRONIC
KIDNEY DISEASE
                               CASE STUDY 4
          T2DM with established CVD and albuminuria

CASE 4A

Mr GH; Age: 60 years
                               Medical 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

 Treatment regimen      • Metformin SR 1700 mg        • Perindopril 8 mg o.d.
 on presentation          om/850 mg pm                • Atorvastatin 40 mg o.d.
                        • Gliclazide MR 120 mg o.d.   • Aspirin 100 mg o.d.
                        • Bisoprolol 5 mg o.d.

HIS MOST RECENT LABORATORY TESTS ARE AS BELOW:
 Parameters             Results
 FBS                    8.0 mmol/L

 HbA1c                  8.2%

 Creatinine             98.0 μmol/L

 eGFR                   72.0 ml/min/1.73 m2

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

                                                                                  20
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
CHRONIC KIDNEY DISEASE
Case study 4: T2DM with established CVD and albuminuria

  DISCUSSION (Refer to page 47 for case studies answers and discussion points)
  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 years
                                               Medical history
 Presenting complaint                    Albuminuria

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

 Treatment regimen                       • Metformin XR 2 g o.d.                 • Losartan 100 mg o.d.
 on presentation                         • Gliclazide 80 mg b.d.                 • Rosuvastatin 20 mg o.d.
                                         • Bisoprolol 10 mg o.d.                 • Aspirin 100 mg o.d.

                                                                                                             21
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
CHRONIC KIDNEY DISEASE
Case study 4: T2DM with established CVD and albuminuria

HIS RECENT LABORATORY TESTS ARE AS BELOW:
 Parameters                            Results
 FBS                                   6.5 mmol/L

 HbA1c                                 6.8%

 Creatinine                            102.0 μmol/L

 eGFR                                  71.0 ml/min/1.73 m2

 Urine protein                         2+ with no active sediments

 Urine ACR                             100.0 mg/mmol (Normal range: < 3.5 mg/mmol)

 ECHO                                  Impaired ejection fraction at 40%

 DISCUSSION (Refer to page 49 for case studies answers and discussion points)
 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?

                                                                                     22
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
CHRONIC KIDNEY DISEASE

                                   CASE STUDY 5
T2DM with established CVD and impaired renal function
                         (eGFR 45-60 ml/min/1.73 m2)

CASE 5A

Mr LM; Age: 54 years old
                                   Medical history
 Presenting complaint       Suboptimal HbA1c of 7.8%

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

 Treatment regimen for      • Metformin 1 g b.d.
 glycaemic control

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
 Creatinine                 130.0 μmol/L
 eGFR                       53.3 ml/min/1.73 m2
 Urine ACR                  21.0 mg/mmol (Normal range: < 3.5 mg/mmol)

                                                                         23
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
CHRONIC KIDNEY DISEASE
Case 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.

 DISCUSSION (Refer to page 51 for case studies answers and discussion points)
 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 QR
                                                Medical 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 for                    • Metformin 500 mg b.d.
 glycaemic control                        • Gliclazide 80 mg b.d.

 DISCUSSION (Refer to page 54 for case studies answers and discussion points)
 1. Is there a compelling reason to start SGLT2-i or GLP-1RA for Mr. QR?

                                                                                                  24
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
CHRONIC KIDNEY DISEASE

                                                CASE STUDY 6
T2DM with established CVD and impaired renal function
                                   (eGFR < 45 ml/min/1.73 m2)
CASE 6

Mr PQ; Age: 54 years
                                               Medical 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                   • Metformin 500 mg b.d.                 • SGLT2-i with CV
 glycaemic control                       • Gliclazide 80 mg b.d.                   protection

  DISCUSSION (Refer to page 55 for case studies answers and discussion points)
  1. How would Mr. PQ’s treatment regimen change with the current eGFR?

                                                                                                     25
THEME:
TYPE 2 DIABETES MELLITUS WITH HIGH-RISK
FOR CARDIOVASCULAR DISEASE

Definition of high-risk

CRITERIA FOR HIGH-RISK in CVOTs
                               Based on LEADER inclusion criteria1
 Age ≥ 60 years with at                  •   microalbuminuria or proteinuria,
 least one of the following              •   hypertension and left ventricular hypertrophy,
 CV risk factors:                        •   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 ≥ 50 years with at                  • diabetes for ≥ 10 years,
 least two or more of the                • systolic blood pressure > 140 mmHg or on ≥ 1
 following CV risk factors:                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                • hypertension (defined as systolic BP > 140 mmHg
 > 60 years (women) with                   and diastolic BP > 90 mmHg or on anti-hypertensive
 at least one or more of the               therapy)
 following CV risk factors in            • dyslipidemia (defined as LDL-cholesterol
 addition to T2DM:                         > 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.

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

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

Mrs. RS, Age: 64 years
                                   Medical history
Presenting complaint         T2DM with high-risk of CVD

Medical history              •   T2DM for 12 years         • Claims compliant with
                             •   Hypertension                sugar-free food choices
                             •   Dyslipidemia              • Does not exercise
                             •   No known CAD                regularly

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

Present treatment regimen    • Metformin 1 g b.d.          • Telmisartan 80 mg o.d.
                             • Gliclazide MR 120 mg o.d. • Simvastatin 20 mg o.n.
                             • S/C Insugen basal 18 U o.n.

                                 Physical examination

     Height: 165.0 cm               Weight: 80.0 kg             BMI: 29.4 kg/m2

     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

                                                                                       27
THEME: TYPE 2 DIABETES MELLITUS WITH HIGH-RISK FOR
CARDIOVASCULAR DISEASE
Case study 7: T2DM with high-risk for CVD and normal renal function

INVESTIGATIONS RESULTS
 Parameters                            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
 Creatinine                            70.0 μmol/L
 eGFR                                  79.0 ml/min/1.73 m2
 Urine protein                         Trace
 Urine glucose                         Negative
 Urine microscopy                      Clear
 Urine ACR                             7.6 mg/mmol (Normal range: < 3.5 mg/mmol)

 DISCUSSION (Refer to page 58 for case studies answers and discussion points)
 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%                                                      c. < 7.5%
      b. < 7.0%                                                      d. < 8.0%

 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 modification                                      d. DPP4-i
      b. SGLT2-i                                                     e. Escalation of basal insulin
      c. GLP-1RA

                                                                                                      28
THEME: TYPE 2 DIABETES MELLITUS WITH HIGH-RISK FOR
CARDIOVASCULAR DISEASE

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

Mrs. RS, Age: 64 years
                                    Medical history
Presenting complaint         T2DM with high-risk of CVD

Medical history              •   T2DM for 12 years         • Claims compliant with
                             •   Hypertension                sugar-free food choices
                             •   Dyslipidemia              • Does not exercise
                             •   No known CAD                regularly

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

Present treatment regimen    • Metformin 500 mg b.d.       • Telmisartan 80 mg o.d.
                             • Gliclazide MR 120 mg o.d. • Simvastatin 20 mg o.n.
                             • S/C Insugen basal 18 U o.n.

                                 Physical examination

     Height: 165.0 cm               Weight: 80.0 kg             BMI: 29.4 kg/m2

     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

                                                                                       29
THEME: TYPE 2 DIABETES MELLITUS WITH HIGH-RISK FOR
CARDIOVASCULAR DISEASE
Case 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

 Creatinine                           96.0 μmol/L

 eGFR                                 54.0 ml/min/1.73 m2

 Urine protein                        2+

 Urine glucose                        Negative

 Urine microscopy                     Clear

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

DISCUSSION (Refer to page 67 for case studies answers and discussion points)
1. What would the optimal HbA1c target be for Mrs. RS?
      a. < 6.5%                                                     c. < 7.5%
      b. < 7.0%                                                     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. > 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 modification                                     d. DPP4-i
      b. SGLT2-i                                                    e. Escalation of basal insulin
      c. GLP-1RA

                                                                                                     30
SECTION B:
CASE STUDIES ANSWERS
AND DISCUSSION POINTS

                        31
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.

                                                                                        32
THEME:
TYPE 2 DIABETES MELLITUS WITH
CARDIOVASCULAR DISEASE AND NORMAL
RENAL FUNCTION
                                     CASE STUDY 1
 T2DM with established CVD and normal renal function

CASE STUDY 1A

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

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

  2. How would you achieve the HbA1c target?

          • 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.

                                                                                              33
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION
Case study 1: T2DM with established CVD and normal renal function

CASE STUDY 1A (CONT’D)

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

          ANTI-HYPERGLYCAEMIC AGENTS TO CONSIDER:
            Agents with positive CV benefits                       Agents without CV benefits
                                                                           (neutral)
            SGLT2-i*                                             GLP-1RA
            • empagliflozin**(EMPA-REG) 5                        • lixisenatine (EXAMINE)12
            • canagliflozin¶ (CANVAS)6                           • exenatide (EXSCEL)13
            • dapagliflozin [for CV death and
              hospitalisation for heart failure]                 SU
              (DECLARE-TIMI 58)3,4                               • gliclazide (ADVANCE)14

            GLP-1RA                                              DPP-4i
            • liraglutide* (LEADER)1                             • sitagliptin (TECOS)15
            • semaglutide (SUSTAIN-6)7                           • linagliptin (CARMELINA)16-18
            • albiglutide (HARMONY)8                             • saxagliptin (SAVOR-TIMI 58)19
            • dulaglutide (REWIND)9                              • alogliptin (EXAMINE)12

            Metformin10

            TZD
            • pioglitazone (PROACTIVE)11¶§

          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

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

                                                                                                                   34
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION
Case study 1: T2DM with established CVD and normal renal function

          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-i is started first and he experiences recurrent
               genitourinary 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, specifically pioglitazone 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.

                                                                                              35
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION
Case study 1: T2DM with established CVD and normal renal function

CASE STUDY 1B

 DISCUSSION
 1. Would the HbA1c target be different?

          • 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%.

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

          • A
             s 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.

                                                                                               36
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION
Case study 1: T2DM with established CVD and normal renal function

          Efficacy of dapagliflozin when HbA1c baseline is high21
          • 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.

                                            Placebo                     DAPA 5 mg/d      DAPA 10 mg/d
          n                                    94                           42                95
          Baseline A1c (%)                    10.5                         10.3              10.6
                                       0
                                            -0.82
           Adjusted mean change (SE)
            from baseline in A1c, %

                                                                                            -1.59
                                       -1                                -2.13

                                       -2
                                                         -1.32
                                                      (-1.93, -0.70)*

                                       -3                                   -0.77
                                                                        (-1.18, -0.36)

          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.

          Efficacy of empagliflozin at high baseline HbA1c22,23

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

                                                                                                              37
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION
Case study 1: T2DM with established CVD and normal renal function

CASE STUDY 1B (CONT’D)

                                                                 Empagliflozin
                                                   Placebo   10 mg QD 25 mg QD       Sitagliptin
                                         0.5                                                                 Comparison with placebo
                                                    (n=51)    (n=54)      (n=45)       (n=51)
         Adjusted mean (95% Cl) change
           from baseline in HbA1C, %

                                         0.0
                                                   0.01                                               -1.44           -1.44           -1.04
                                                                                                    (95% Cl:        (95% Cl:        (95% Cl:
                                     -0.5                                                          -1.73, 1.15)   -1.74, -1.13)   -1.34, -0.75)
                                                                                                   p < 0.0001     p < 0.0001      p < 0.0001

                                     -1.0
                                                                                      -1.04
                                     -1.5
                                                              -1.44     -1.43
                                     -2.0                       Mean baseline
                                                    9.06       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.
                                                                                                                  Empagliflozin 25 mg OL
                                  11.5
                                                                                                                  (n = 101)
                                  11.0
         Mean (SE) HbA1c (%)

                                  10.5
                                  10.0
                                         9.5                                                                                      -3.23
                                         9.0                                                                                      (0.16)

                                         8.5
                                         8.0
                                         7.5
                                               0                6               12                 18                  24                   30
                                                                                      Week
            N/Week   BL                                         6               12                 18                  24
            OL EMPA
            25 mg QD 67                                         94              89                 77                   70
         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.

         Efficacy of dapagliflozin + saxagliptin combination vs. dapagliflozin
         alone 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.
                                                                                                                                                  38
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION
Case study 1: T2DM with established CVD and normal renal function

                                                            SAXA + DAPA + MET           SAXA + MET               DAPA + MET
        Baseline (%)                                               8.93                    9.03                     8.87
        nb                                                         158                     143                      151
                                                    0.0
           Adjusted mean (95% CI) change
             from baseline in HbA1c (%)

                                              -0.5

                                              -1.0

                                              -1.5                    -0.59% (-0.81%, -0.37%)
                                                                            P < 0.0001
                                                                                    -0.27% (-0.48%, -0.05%)
                                              -2.0                                        P = 0.0166

        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.

                                                      9.5                                                     SAXA + DAPA + MET
                                                                                                              SAXA + MET
                                                      9.0                                                     DAPA + MET
                               Mean (SE) HbA1c, %

                                                      8.5

                                                      8.0

                                                      7.5

                                                      7.0
                                                              -6         0             6            12         18           24
                                                                                            Weeks
        Number of patients with measurementsa
        SAXA + DAPA + MET 174                                           176           174           169        165          158
        SAXA + MET        173                                           175           174           165        155          143
        DAPA + MET        171                                           172           171           163        159          151
        Figure 5: Mean HbA1c over time. a: observed values. Saxa: saxagliptin, Met: metformin, Dapa:
        dapagliflozin. Rosenstock J, 2014.

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

                                                                                                                                  39
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION

                                   CASE STUDY 2
Newly diagnosed T2DM presenting with acute coronary
         syndrome and normal renal function

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

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

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?

        Two types of treatment regimen can be used for a patient presenting as
        Mr. CD, i.e. monotherapy or dual combination therapy.
           nti-hyperglycaemic agents to consider for monotherapy are metformin,
        • A
          SGLT2-i or GLP-1RA.
        • H
           owever, 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.

                                                                                         40
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION
Case study 2: Newly diagnosed T2DM presenting with acute coronary syndrome and normal renal function

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

           • H
              is optimal HbA1c target should be the same as when he presented with a
             higher HbA1c level.
           • T
              he options for initial therapy for glycaemic control would also remain the
             same.

              Note:
              • N
                 ote that for purely glycaemic control in these patients, metformin
                alone may be adequate to bring the HbA1c to target.
              • H
                 owever if CV protection is deemed an important target, which it
                should be, add an agent that has been documented to offer this.
              • B
                 ear 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.

                                                                                                       41
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION

                                      CASE STUDY 3
    T2DM patient presenting with heart failure and
               normal renal function

CASE 3A

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

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

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

          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.

          Offering CV benefit
          • 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

                                                                                              42
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION
Case study 3: T2DM patient presenting with heart failure and normal renal function

  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.
            • H
               owever, avoid a TZD.
              -	TZD has been shown to increase the risk of heart failure and is
                 contraindicated in patients with heart failure.25

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

  DISCUSSION
  4. Is Mr. EF’s HbA1c on target?

            Yes

                                                                                         43
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION
Case study 3: T2DM patient presenting with heart failure and normal renal function

CASE 3B (CONT’D)

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

          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

              Note on addition of SGLT2-i in treatment regimen containing gliclazide
             • T
                he 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

                                                                                             44
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION
Case study 3: T2DM patient presenting with heart failure and normal renal function

            Additional notes on:
             Metformin
             • A
                mid concerns of metformin use in heart failure patients, the USFDA in
               2006 removed heart failure as a contraindication for its use.28
             • T
                his was further cemented in the 2016 ESC guidelines which considers
               its use safe and the treatment of choice in heart failure patients.29
                owever, during the same year, USFDA recommended that
             • H
               metformin can be used in CKD patients with heart failure, with
               eGFR > 30ml/min/1.73m2.28,30

             SGLT2-i
             • S
                GLT2-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 OUTCOME            31
                                                   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.

                                                                                              45
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
NORMAL RENAL FUNCTION
Case study 3: T2DM patient presenting with heart failure and normal renal function

CASE 3B (CONT’D)

             GLP-1RA
             • F
                our 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.

              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.

                ith regards to use of liraglutide, further evaluation in the FIGHT36 and
             • W
               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
             • T
                here 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.

                                                                                            46
THEME:
TYPE 2 DIABETES MELLITUS WITH
CARDIOVASCULAR DISEASE AND CHRONIC
KIDNEY DISEASE
                                       CASE STUDY 4
          T2DM with established CVD and albuminuria

CASE 4A

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

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

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

          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.

                                                                                                    47
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
CHRONIC KIDNEY DISEASE
Case study 4: T2DM with established CVD and albuminuria

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.

                                                                                                48
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
CHRONIC KIDNEY DISEASE
Case study 4: T2DM with established CVD and albuminuria

CASE 4B

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

           b

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

           Yes

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

           Rationale of adding SGLT2-i
           This 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.

                                                                                       49
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
CHRONIC KIDNEY DISEASE
Case study 4: T2DM with established CVD and albuminuria

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).

                                                                                           50
THEME: TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE AND
CHRONIC KIDNEY DISEASE

                                          CASE STUDY 5
 T2DM with established CVD and impaired renal function
                             (eGFR 45-60 ml/min/1.73 m2)

CASE 5A
Mr. LM is started on an SGLT2-i.

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

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

           Patient                                    Precautions45
           On anti-hypertensive treatment;            • M onitor BP at weekly intervals until
           > 65 years old; OR                            it stabilises
           haemodynamically unstable                  • Consider reducing dose of anti-
           (atrial fibrillation, orthostatic             hypertensive or withdraw anti-
           hypotension, labile BP, history               hypertensive when BP < 120/60 mmHg
           of syncope)                                   or patient becomes symptomatic
           On metformin or GLP-1RA                    Monitor for adverse gastrointestinal
                                                      adverse events
           Develops diarrhoea or vomiting             Consider reducing dose of metformin/
                                                      GLP-1RA and ensure adequate fluid
                                                      intake to avoid renal injury
           On medications that predispose to Use SGLT2-i with caution46
           acute renal injury (Non-steroidal
           anti-inflammatory drugs [NSAIDs],
           angiotensin-converting enzyme
           [ACE] inhibitors, angiotensin
           receptor blockers [ARB], diuretics)
           On diuretics                               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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