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Early Combination Therapy and Treatment Escalation for Sustained Glycemic Control in T2DMStefano Del PratoSection of Metabolic Diseases and Diabetes, Department of Clinical and Experimental Medicine, University of Pisa, Italy
@SDelprato
Objective of this Session
• This session is not conceived to provide guidance to treatment
• This session would like to discuss available evidence on:
• The relevance of achieving early and durable glycaemic control
• The therapeutic options for achieving such a goal
• The strategies for initial therapeutic strategy selection and escalation
Our First Patient: Please, Meet Anna
Anne is free of symptoms, and much engaged with her family and job
• 54-year-old female• Diagnosed with T2DM 3 months ago• Hypertension • Dyslipidaemia
Not a real patient
Metabolic parameters
• HbA1c: 6.7%• BP: 135/84 mmHg• LDL-C: 71 mg/dl• HDL: 56 mg/dl• Triglycerides: 119 mg/dl
• Tot-C: 158 mg/dl• BMI: 31 kg/m2
• eGFR: 88 ml/min/1.73 m2
• UACR: 15 mg/g
Our First Patient: Please, Meet Anna
Not a real patient
• Lisinopril/Hydrochlorothiazide 20/12.5 mg qd• Atorvastatin 20 mg qd• Clodronic acic 100mg im every 2 weeks
Medication
Our First Patient: Please, Meet Anna
Not a real patient
HbA1c target• <6.0%• <6.5%• <7.0%• <7.5%
Which glycaemic target for Anna?
Not a real patient
Our First Patient: Please, Meet Anna
Time to Treatment Intensification after Monotherapy Failure and Its Association With Subsequent Glycaemic Control
Attaining glycaemic control (HbA1c <7%) after intensification
Time to intensification (months) HR 95% CI P value
Parameters
<12 Reference
12 to <24 0.78 0.76-0.81 <0.0001
24 to < 36 0.76 0.70-0.75 <0.0001
0.5 0.75 1.0 1.25
Desai U et al Diabetes Care 2018 ;41:2096-2104
N= 93,515
10-yr Risk of Complication for Early HbA1c >6.5%
HRs adjusted for year of diagnosis, age at diagnosis, sex, race/ethnicity, BMI, systolic and diastolic blood pressure, total cholesterol, HDL cholesterol, smoking status, HbA1c after each early exposure period, and comorbidity.
Laiteerapong N et al Diabetes Care 2019; ;42:416-426
34,737 managed care newly diagnosed T2DM patients; 10 years of survival (average follow-up 13.0 years)
Mac
rova
scul
arev
ents
Mic
rova
scul
arev
ents
• Lifestyle modification• Metformin• Lifestyle modification + metformin• Lifestyle modification + combination therapy
Which anti-hyperglycemic treatment?
Not a real patient
Our First Patient: Please, Meet Anna
FIRST-LINE THERAPY IS METFORMIN AND COMPREHENSIVE LIFESTYLE (INCLUDING WEIGHT MANAGEMENT AND PHYSICAL ACTIVITY)
FIRST-LINE THERAPY IS METFORMIN AND COMPREHENSIVE LIFESTYLE (INCLUDING WEIGHT MANAGEMENT AND PHYSICAL ACTIVITY)
Davies MJ et al Diabetologia. 2018;61:2461-2498
Is Disease Progression Predictable? The UKPDS Lesson
Conventional treatment
Glyburide
Chlorpropamide
Metformin
Insulin
ULN=6.2%
9
8
7
6
0
Years after randomisation
2 4 6 8 10
HbA
1c (%
)
HbA1c, glycated haemoglobin; UKPDS, UK Prospective Diabetes Study; ULN, upper limit of normal
UKPDS Group. Lancet. 1998;352:854–65.
% o
f ref
eren
ce c
ateg
ory
NFG IFG Diabetes
100
75
50
25
0
<5.0
5.0-
5.4
5.5-
5.9
6.0-
6.4
6.5-
6.9
7.0-
7.4
7.5-
7.9
8.0-
8.4
8.5-
8.9
≥9.0
Fasting plasma glucose (mM)
1st phase insulin secretion
Ref.
MatsudalSI
InsAUC30/GluAUC30
InsAUC120/GluAUC120
2nd phase insulinsecretion
(N=6414)
Progressive Loss of Insulin Sensitivity and β-cell Function in the Natural History of Type 2 Diabetes
AUC, area under curve; HbA1c, glycated haemoglobin; IFG, impaired fasting glucose; Ins, insulin; NFG, normal fasting glucose; OGTT, oral glucose tolerance test
Stančáková A et al. Diabetes. 2009;58:1212–21.
The stepwise approach may often lead to treatment failure with prolonged periods of hyperglycaemia as a consequence of clinical inertia and delays in achieving optimal glycaemic control
OAD, oral antidiabetes drug
Adapted from: Del Prato S et al. Int J Clin Pract. 2005;59:1345–55.
7
6
9
8
10
0
OADmonotherapy
OAD monotherapyuptitration
OAD combination
+
OAD + basal insulin
OAD + multipledaily insulin injections
+
Duration of diabetes (years)
HbA
1c(%
)
+
Present Conservative Strategy to Treat Hyperglycaemia
Diet andExercise
The stepwise approach may often lead to treatment failure with prolonged periods of hyperglycaemia as a consequence of clinical inertia and delays in achieving optimal glycaemic control
7
0
9
8
10
0
OAD combination
+
OAD + basal insulin
OAD + multipledaily insulin injections
+
Duration of diabetes (years)
HbA
1c(%
)
OADmonotherapy
OAD monotherapyuptitration
+
Diet andExercise
Present Conservative Strategy to Treat Hyperglycaemia
OAD, oral antidiabetes drug
Adapted from: Del Prato S et al. Int J Clin Pract. 2005;59:1345–55.
Management of Hyperglycaemia in Type 2 Diabetes 2018 - A Consensus Report by the ADA and EASD
…While there is some support for initial combination therapy due to the greater initial reduction of A1c than can be provided by metformin alone,
there is little evidence that this approach is superior to sequential addition of medications for maintaining glycemic control, or slowing the
progression of diabetes…Davies MJ et al Diabetologia. 2018;61:2461-2498
The stepwise approach may often lead to treatment failure with prolonged periods of hyperglycaemia as a consequence of clinical inertia and delays in achieving optimal glycaemic control
7
0
9
8
10
0
OAD combination
+
OAD + basal insulin
OAD + multipledaily insulin injections
+
Duration of diabetes (years)
HbA
1c(%
)
Diet andExercise
Present Conservative Strategy to Treat Hyperglycaemia
OAD, oral antidiabetes drug
Adapted from: Del Prato S et al. Int J Clin Pract. 2005;59:1345–55.
VariableEarly combinationN=998
Initial monotherapyN=1003
Women 55% 51%
Age (years) 54.1 (9.5) 54.6 (9.2)
T2DM duration (months)* 3.3 (1.0–9.8) 3.4 (0.9–10.4)
HbA1c (%) 6.7 (0.4) 6.7 (0.5)
FPG (mmol/L)* 6.9 (6.1–7.8) 6.9 (6.2–7.9)
BMI (kg/m2) 31.2 (4.8) 31.0 (4.7)
Weight (kg)* 85.0 (72.8–97.3) 84.0 (72.0–97.0)
Normal baseline eGFR (MDRD), mL/min/1.73m2 43.3% 44.3%
Current smoker 15.4% 13.6%Data is presented as mean (SD), unless specified. *Median (IQR). The baseline demographics and clinical characteristics were similar between the treatment arms
VERIFY - Baseline Characteristics
BMI, body mass index; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; MDRD, modification of diet in renal disease; T2DM,type 2 diabetes mellitus
Matthews DR et al. Lancet. 2019; 26;394:1519-1529
Del Prato S et al. Diabet Med. 2014;31:1178–84. Matthews DR et al. Diabetes Obes Metab. 2019;21:2240–47.
RA
ND
OM
ISA
TIO
N Metformin + Vildagliptin
Metformin + Placebo
Early combination
Initial monotherapy
Time to failure
Time to failure is the Primary Outcome
It addresses the first question –Q1: Do those with type 2 diabetes
benefit from having combined therapy at the beginning of their
pharmacological treatment?
Rate of failure is calculated in each
strategy group by an assessment of those
failing as a proportion of all those in that group.
VERIFY Study Design
Patie
nts
with
an
even
t (%
)
Initial monotherapyEarly combination 983 960 862 815 752 671 597 551 509 478 187Patients at risk
989 937 733 661 576 503 434 377 337 299 108
Early combination
Initial monotherapy
Hazard ratio (95% CI): 0·51 (0·45,0·58);p<0·0001
VERIFY - Time to Initial Treatment Failure
CI, confidence interval
Matthews DR et al. Lancet. 2019; 26;394:1519-1529
Insulin
Insulin
Not failed
Not failed
Failed – move to combination
Failed – stay on combination
Period 3Period 2
RA
ND
OM
ISA
TIO
N Metformin + Vildagliptin
Metformin + Placebo
Combination strategy
Sequential strategy
Period 1
Time to second failure is the Secondary Outcome
It addresses the question –Q2: Do those with type 2
diabetes benefit more from having combined therapy at
the beginning of their pharmacological treatment compared to a sequential
additive strategy?
Rate of failure is calculated in each
strategy group by an assessment of those failing as a proportion
of all those in that group.
No insulin
No insulin
VERIFY Study Design
Del Prato S et al. Diabet Med. 2014;31:1178–84. Matthews DR et al. Diabetes Obes Metab. 2019;21:2240–47.
Hazard ratio (95% CI): 0·74 (0·63, 0·86);{p<0·0001}
983 966 918 870 830 768 715 644 602 565 221
Patie
nts
with
an
even
t (%
)
Initial monotherapy
Early combination
Patients at risk
989 968 897 821 761 698 643 575 531 490 179
Initial monotherapy
Early combination
VERIFY - Time To Second Failure
CI, confidence interval
Matthews DR et al. Lancet. 2019; 26;394:1519-1529
Safety EventsEarly combinationN=998, n (%)
Initial monotherapyN=1001, n (%)
Patients with at least one AE 833 (83.5) 833 (83.2)SAE 166 (16.6) 183 (18.3)Drug-related AE 159 (15.9) 143 (14.3)Severe AE 105 (10.5) 106 (10.6)AEs leading to permanent discontinuation of treatment
41 (4.1) 53 (5.3)
Death 13 (1.3) 9 (0.9)Hypoglycaemic events 13 (1.3) 9 (0.9)
AE, adverse event; SAE, serious adverse event
Matthews DR et al. Lancet. 2019; 26;394:1519-1529
VERIFY - Overall Safety Events
Hazard ratio (95% CI): 0·71 (0·42,1·19);{p=0·19}
Early combination
Initial monotherapy
Matthews DR et al. Lancet. 2019; 26;394:1519-1529
VERIFY - Time to First Adjudicated Macrovascular Event
Although this is an indicative signal, more dedicated studies are required
10-yr Mortality Risk for Early HbA1c >6.5%34,737 managed care newly diagnosed T2DM patients; 10 years of survival (average follow-up 13.0 years)
HRs adjusted for year of diagnosis, age at diagnosis, sex, race/ethnicity, BMI, systolic and diastolic blood pressure, total cholesterol, HDL cholesterol, smoking status, HbA1c after each early exposure period, and comorbidity.
Laiteerapong N et al Diabetes Care 2019; ;42:416-426
Management of Hyperglycaemia in Type 2 Diabetes ADA-EASD Consensus Report 2018
…While there is some support for initial combination therapy due to the greater initial reduction of A1c than can be provided by metformin alone,
there is little evidence that this approach is superior to sequential addition of medications for maintaining glycemic control, or slowing the
progression of diabetes…
now
2020
Adapted from Davies MJ et al Diabetologia. 2018;61:2461-2498
John attends a follow-up appointment after his stent procedure
• 63-year-old male• Diagnosed with T2D 15 years ago• Dyslipidaemia• Diffuse moderate multi-vessel CAD• NYHA class III
Not a real patient
LAD, left anterior descending
Our Second Patient: Please, Meet Giulio
Meet John
• HbA1c: 8.3%• BP: 143/83 mmHg• Tot-C: 181 mg/dl• LDL-C 97 mg/dl• TG 195 mg/dl
• BMI: 31.3 kg/m2
• eGFR: 52 ml/min/1.73 m2
• UACR: 597 mg/g
Metabolic parameters
Not a real patient
Our Second Patient: Please, Meet Giulio
Meet John
• Metformin 1000 mg bid• Sitagliptin 100 mg qd• Atorvastatin 40 mg qd• Telmisartan 20 mg qd• Nifedipine 5 mg qd• ASA 100 mg qd
Medications
Not a real patientNot a real patient
Our Second Patient: Please, Meet Giulio
Meet John
Not a real patient
• Poorly Controlled DM?• CKD?• ASCVD?• HF?
Not a real patient
Our Second Patient: Please, Meet GiulioWhat the main clinical problem
Renal Insufficiency And Cardiovascular Events (RIACE)Phenotypic Characteristics Associated with Hypertension in T2DM Patients
Solini A et al Diabetes Care 2012; 35: 143–49.
DKD, diabetic kidney disease; T1D, type 1 diabetes; T2D, type 2 diabetes; IDNT, Irbesartan Type 2 Diabetic Nephropathy Trial; RAAS, renin–angiotensin-aldosterone system; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan.
1Mogensen CE et al. Br Med J (Clin Res Ed) 1982;285:685; 2Parving HH et al. Lancet 1983;1:1175; 3Lewis EJ et al. N Engl J Med 1993;329:1456; 4Lewis EJ et al. N Engl J Med 2001;345:851;6Brenner BM et al. N Engl J Med 2001;345:861
1980 1990 2000
No new DKD-specific treatment after the start of the RAAS blokade
High blood pressure
identified as DKD risk factor
ß-blockers1
Hydralazine2
Captopril3T1D
IDNT4, IRMA 25
Irbesartan T2D
RENAAL6
LosartanT2D
RAAS blockade
No New DKD-specific Treatment in the last 15 Years
2015
Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
Wanner C et al N Engl J Med. 2016 375:323-34
Proposed Renal Protective Pathways with SGLT2-inhibitors
CREDENCE (Canagliflozin and Renal Events in Diabetes with Established NephropathyClinical Evaluation)
Percovic V et al. N Engl J Med. 2019;380:2295-2306
Hazard ratio (95% CI) P value
Primary composite outcome 0.70 (0.59–0.82) 0.00001
Doubling of serum creatinine 0.60 (0.48–0.76) <0.001
ESKD 0.68 (0.54–0.86) 0.002
eGFR <15 mL/min/1.73 m2 0.60 (0.45–0.80) –
Dialysis initiated or kidney transplantation 0.74 (0.55–1.00) –
Renal death 0.39 (0.08–2.03) –
CV death 0.78 (0.61–1.00) 0.0502
CV death or hospitalization for heart failure 0.69 (0.57–0.83) <0.001
CV death, MI, or stroke 0.80 (0.67–0.95) 0.01
Hospitalization for heart failure 0.61 (0.47–0.80) <0.001
ESKD, doubling of serum creatinine, or renal death 0.66 (0.53–0.81) <0.001
CREDENCE - Summary of Key Renal and CV Outcomes
Favors Canagliflozin Favors Placebo
0.25 0.5 1.0 2.0 4.0
Percovic V et al. N Engl J Med. 2019;380:2295-2306
Declining Renal Function Is Associated with Incident HF
CKD= chronic kidney disease; HF= heart failure; HFpEF= heart failure with preserved ejection fraction; HFrEF= heart failure with reduced ejection fraction.
Nayor M et al. Eur J Heart Fail. 2017;19:615-623
Incidence rates of HF are higher in those with CKD compared to those without
Incidence rates of HF are higher in those with microalbuminuria compared to those without
Cum
ulat
ive
inci
denc
e of
HF
Years
CKD HFrEFCKD HFpEFNo CKD HFrEFNo CKD HFpEF
0 2 4 6 8 10 12
8%
6%
4%
2%
0%
Cum
ulat
ive
inci
denc
eof
HF
Years
Microalbuminuria HFrEFMicroalbuminuria HFpEFNo microalbuminuria HFrEFNo microalbuminuria HFpEF
0 2 4 6 8 10 12
8%
6%
4%
2%
0%
John attends a follow-up appointment after his stent procedure
• 63-year-old male• Diagnosed with T2D 15 years ago• Dyslipidaemia• Diffuse moderate multi-vessel CAD• Recent percutaneous coronary intervention
(stent) due to obstruction at medial LAD• NYHIA class III
Not a real patient
LAD, left anterior descending
Our Second Patient: Please, Meet Giulio
CREDENCE - Primary Outcome by Screening eGFR and AlbuminuriaHazard ratio
(95% CI)Interaction
P value
Screening eGFR 0.11
30 to <45 mL/min/1.73 m2 0.75 (0.59–0.95)
45 to <60 mL/min/1.73 m2 0.52 (0.38–0.72)
60 to <90 mL/min/1.73 m2 0.82 (0.60–1.12)
Baseline UACR 0.49
≤1000 mg/g 0.76 (0.55–1.04)
>1000 mg/g 0.67 (0.55–0.81)
Favors Canagliflozin Favors Placebo
0.25 0.5 1.0 2.0 4.0
Percovic V et al. N Engl J Med. 2019;380:2295-2306
EMPA-REG CANVAS DECLARE CREDENCE
Drug Empagliflozin Canagliflozin Dapaglifozin Canagliflozin
Doses analysed 10, 25 mg QD 100, 300mg QD 10 mg QD 100 mg QD
Median follow-up, time 3.1 2.4 4.2 2.6
Trial participants 7020 10142 17160 4401
Age, mean 63 63 64 63
Pts with established ASCVD 100% 66% 41% 50%
Women 29% 36% 37% 34%
Pts with history of HF 10% 14% 10% 15%
Pts with eGFR<60ml/min 26% 20% 7% 60%
Primary EP 3P-MACE 3P-MACE 3P-MACE Renal worsening
Secondary EP Renal worsening Renal worsening Renal worsening CV outcomes
Randomized Controlled Phase 3/4 CVOTs of SGLT2Is
Adapted from Zelniker TA et al Lancet. 2019;393:31-39
38373
Meta-Analysis of SGLT2 Inhibitor CVOTs:Renal Worsening, ESRD or Renal Death Composite
Zelniker TA et al Lancet. 2019;393:31-39
By Presence of Baseline eGFR
Meta-Analysis of SGLT2 Inhibitor CVOTs
Hospitalization for Heart Failure and CV DeathBy Presence of Atherosclerotic Cardiovascular Disease
Zelniker TA et al Lancet. 2019;393:31-39
DAPA-HF: CV Death or hHF or an Urgent HF Visit
2105931096147819172075216322582371Placebo2106121146156020022147222123052373DAPA
32
28
24
20
16
12
8
4
0242115 18129630
No. at Risk Months from Randomization
Cum
ulat
ive
Perc
enta
ge (%
)
36
HR 0.74 (0.65, 0.85)p=0.00001
NNT = 21
DAPA
Placebo26% RRRT2DM at baseline
Yes 0.75 (0.63, 0.90)
No 0.73 (0.60, 0.88)
0.800.50 1.00 1.25 2.00
Placebo BetterDAPA Better
McMurray JJV et al. N Engl J Med. 2019 Sep 19. doi: 10.1056/NEJMoa1911303. [Epub ahead of print]
• SGLT2-inhibitor?
• GLP1 Receptor Agonist?
Not a real patient
Our Second Patient: Please, Meet Giulio
Meta-analysis of GLP1-RAs and SGLT2 Inhibitors Trials on Renal End Points
Zelniker TA et al Circulation 2019;139:2022-2031
Meta-analysis of GLP1-RAs and SGLT2 Inhibitors Trials on Renal End PointsExcluding Macroalbuminuria
Zelniker TA et al Circulation 2019;139:2022-2031
Management of Hyperglycaemia in Type 2 Diabetes 2018 - A Consensus Report by the ADA and EASD
Davies MJ et al Diabetologia. 2018;61:2461-2498
Choosing Glucose-lowering Medication in Those With Established ASCVD or CKD
HF CKD
Davies MJ et al Diabetologia. 2018;61:2461-2498
• Age: 62• Diagnosed with type 2 diabetes 14 yrs
ago • Good glycemic control maintained for
many years but recently hitting >7.5%• AMI and coronary angioplasty with
stenting 5 years ago• TIAs in the past 4 yrs• Takes multiple medications for
cardiovascular disease• Hypertension• Lives alone, arthritis in both hips
Current medications• Metformin 1000 mg bid• Glibenclamide 10 mg bid • Ramipril 5 mg b.i.d.• Furosemide 25 mg• Atorvastatin 80 mg daily• Glyceryl trinitrate spray 400 µg x 2 as
needed• Propranolol 80 mg b.i.d.• ASA 75 mg daily
Not a real patient
Our Third Patient: Please, Meet Sandra
Clinical chemistry†
FPG: 10.0 mmol/l (180 mg/dl)HbA1c: 7.8% (62 mmol/mol)LDL-cholesterol: 1.1 mmol/l (43 mg/dl)HDL-cholesterol: 1.5 mmol/l (58 mg/dl)Triglycerides: 1.2 mmol/l (106 mg/dl)Creatinine 1.08 mg/mleGFR (CKD-EPI) 55 ml/minBP: 138/77 mmHgBMI: 31 kg/m2
Additional examinations• Foot exam: no abnormalities• Eye exam: initial signs of non-
proliferative retinopathy
Not a real patient
Our Third Patient: Please, Meet Sandra
How happy are you with Sandra’s therapy?
• Poorly Controlled DM?• Hypoglycemia?• ASCVD?• Stroke?
Not a real patient
Our Third Patient: Please, Meet Sandra
What’s your clinical concern about her?
Antidiabetic Agents and Risk of Hypoglycaemia
1. Henderson JN, et al. Diabet Med. 2003;20:1016; 2. Bolen S, et al. Ann Intern Med. 2007;147:386; 3. Kahn SE, et al. N Engl J Med. 2006;355:2427; 4. Krentz AJ, Bailey CJ. Drugs. 2005;65:385; 5. Prandin® (repaglinide) package insert. Novo Nordisk; June 2006; 6. Kahn SE, et al. N Engl J Med. 2006;355:2427; 7. Cefalu WT. Nature. 2007;81:636; 8. Bolen S, et al. Ann Intern Med. 2007;147:386; 9. DeFronzo RA, et al. Diabetes Care. 2005;28:1092;
10. Stonehouse A. Curr Diabetes Rev 2008;4:101; 11. Aschner P et al. Diabetes Care. 2006; 29:2632; 12. Rosenstock J et al. Diabetes Obes Metab 2008;10:376.
q Metformin6
q a-glucosidase inhibitors7
q Pioglitazone6,8
q GLP-1 agonists9
q DPP-4 inhibitors10-12
q SGLT2-inhibitors13
q Insulin therapy1
q Sulfonylureas2
q Glinides (less than SUs)1,3
q Drug-drug interaction can potentiate hypo-glycemia4,5
High risk Low risk✓
✓
✓
✓
Potential Interactions Between Pioglitazone and Alogliptin
Potential advantages• Synergistic effect• Beta-cell protection• Efficacy on FPG and PPG• Durability• Tolerability in CKD• CV protection
Potential concerns• Fluid retention• Heart failure• Body weight gain• Bone fractures
Meta-Analysis of GLP1-RA and SGLT2i Trials on the Composite of Myocardial Infarction, Stroke, and CV Death (MACE)
Zelniker TA et al Circulation 2019;139:2022-2031
Meta-Analysis of GLP1-RA and SGLT2i Trials on Hospitalization for Heart Failure (HHF)
Zelniker TA et al Circulation 2019;139:2022-2031
Study Glucose-loweringdrug HR 95% CI
EMPA-REG Empagliflozin 1.24 0.92 – 1.67
CANVAS Canagliflozin 0.90 0.71 – 1.15
DECLARE Dapagliflozin 1.01 0.84 – 1.21
0.6 1 1.4
Favors placeboFavors study drug
Effect of SGLT2 Inhibitors on Nonfatal Stroke
1.60.8 1.2 1.8
Zinman B et al. NEJM 2015;373:2117; Pfeffer MA et al. NEJM 2015;373:2247; Neal B et al. NEJM 2017;377:644; Wiviott SD et al NEJM 2019;380:347
Fatal and Nonfatal Outcomes with GLP1RAs in T2DM: a Systematic Review and Meta-analysis of CVOTs
Kristensen SL et al Lancet Diabetes Endocrinol. 2019 Aug 14. [Epub ahead of print]
SGLT2 Inhibitors and GLP1-RAs: Adverse Effects
SGLT2-Inhibitors GLP1-RAsDehydration Nausea, vomiting
Genitourinary tract infections Pancreatitis (not confirmed)
Euglycemic DKA
Bone fractures (canagliflozin)
Lower limb amputation (canagliflozin?)
Fournier’s gangrene
Presence of cardiovascular disease is compelling indication
Step 1: Assess Cardiovascular Disease
Management of Hyperglycaemia in Type 2 Diabetes 2018 - A Consensus Report by the ADA/EASD
Davies MJ et al Diabetologia. 2018;61:2461-2498
Choosing Glucose-lowering Medication in Those With Established ASCVD or CKD
Davies MJ et al Diabetologia. 2018;61:2461-2498
Integrating Metabolic Control and Organ Damage Prevention
YoungShort DM duration
No micro-macrovascular complications
LongtermGlycemic control
Reduced risk of microvascularcomplications
Improved adherenceReduced clinical inertia
Prefer glucose-lowering agents with low risk of hypoglycaemia
Reduced risk of CV
Epicardial Coronary Arteries and the Full Coronary Circulation
Taqueti, V.R. et al. J Am Coll Cardiol. 2018;72:2625–41
Microvascular Disease and CV Risk in T2DM IndividualsUK Clinical Practice Research Datalink; n=49,027; median follow-up 5.5 yrs
Brownrigg JRW et al Lancet Diabetes Endocrinol 2016;4:588-97
0
10
20
30
HbA1c <7.0%BP <140/90 mmHgLDL <2.5 mmol/L
HbA1c �7.0%BP <140/90 mmHgLDL <2.5 mmol/L
HbA1c �7.0%BP �140/90 mmHgLDL <2.5 mmol/L
HbA1c �7.0%BP �140/90 mmHgLDL �2.5 mmol/L
Risk Factors
Prim
ary O
utcom
e (pe
r 100
0 pers
on-ye
ars)
Numb
er of
Micro
vasc
ular R
isk Fa
ctors
0
1
2
3
YoungShort DM duration
No micro-macrovascular complications
LongtermGlycemic control
Reduced risk of microvascularcomplications
Improved adherenceReduced clinical inertia
Prefer glucose-lowering agents with low risk of hypoglycaemia
Reduced risk of CV
Integrating Metabolic Control and Organ Damage Prevention
Prefer glucose-lowering agents with low risk of hypoglycaemia
(and ancillary properties?)
CONSIDER COMBINATION
Reduced risk of CKDReduced risk of CV and
Heart Failure
CONSIDER SGLT2-i
YoungShort DM duration
No micro-macrovascular complications
Prefer glucose-lowering agents with low risk of hypoglycaemia
and ancillary properties?
Improved adherenceReduced clinical inertia
LongtermGlycemic control
Reduced risk of microvascularcomplications
Reduced risk of CV and all-cause mortality
SGLT2i(CANVAS, DECLARE, EMPA-REG)
CREDENCE
Impaired kidney function
Integrating Metabolic Control and Organ Damage Prevention
CONSIDERSGLT2i
Reduced risk of CKDReduced risk of CV and
Heart Failure
YoungShort DM duration
No micro-macrovascular complications
Prefer glucose-lowering agents with low risk of hypoglycaemia
and ancillary properties?
Improved adherenceReduced clinical inertia
LongtermGlycemic control
Reduced risk of microvascularcomplications
Reduced risk of CV and all-cause mortality
SGLT2i(CANVAS, DECLARE, EMPA-REG)
CREDENCE
Impaired kidney function
Integrating Metabolic Control and Organ Damage Prevention
CONSIDERSGLT2i
Reduced risk of CKDReduced risk of CV and
Heart Failure
YoungShort DM duration
No micro-macrovascular complications
Prefer glucose-lowering agents with low risk of hypoglycaemia
and ancillary properties?
Improved adherenceReduced clinical inertia
LongtermGlycemic control
Reduced risk of microvascularcomplications
Reduced risk of CV and all-cause mortality
SGLT2i(CANVAS, DECLARE, EMPA-REG)
CREDENCE
History of CV disease
ASCVD HF
Metformin(UKPDS34)
Pioglitazone(PROACTIVE, IRIS)SGLT2-I
(CANVAS, EMPA-REG)GLP1RAs
(EXSCEL, HARMONY, LEADER, SUSTAIN 6)
SGLT2i(CANVAS, CVD-REAL,
EMPA-REG, DECLARE)
Impaired kidney function
Integrating Metabolic Control and Organ Damage Prevention
CONSIDERSGLT2i
Reduced risk of CKDReduced risk of CV and
Heart Failure