Weighing Risks and Benefits: Finding the Sweet Spot for SGLT -2 …sites.utexas.edu/pharmacotherapy-rounds/files/2017/08/... · 2018-01-19 · 2 | Rumbellow I. Diabetes mellitus (DM)

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Weighing Risks and Benefits: Finding the Sweet Spot for SGLT-2 Inhibitor Use in Treatment of Type 2 Diabetes

Sarah Rumbellow, PharmD PGY1 Pharmacy Resident

South Texas Veterans Health Care System The University of Texas at Austin College of Pharmacy

UT Health San Antonio

January 19, 2018

Objectives I. Outline current guideline recommendations for the treatment of type 2 diabetes mellitus (T2DM) and the use of

sodium-glucose cotransporter 2 inhibitors (SGLT-2i) II. Analyze the results of recent research on SGLT-2i use with respect to potential cardiovascular benefits and safety

concernsIII. Select patient populations most appropriate for treatment with SGLT-2i


I. Diabetes mellitus (DM)

a. Disease burden1

i. As of 2015, 9.4% of the United States (US) population had a diagnosis of DM ii. DM was the seventh leading cause of death in the US in 2015 iii. Total direct and indirect cost of diagnosed DM was $245 billion in 2012 (including complications, iv. see Table 1)

b. T2DM2 i. Accounts for 90-95% of all cases of diabetes ii. Characterized by relative insulin deficiency and peripheral insulin resistance iii. Insulin secretion is insufficient to compensate for the level of hyperglycemia

c. Risk factors for development of T2DM1-2 i. Advancing age ii. Physical inactivity iii. Prior gestational DM iv. Cardiovascular disease (CVD) v. Hypertension (HTN) vi. Dyslipidemia

vii. African American, Hispanic/Latino, American Indian, or Asian American ethnicity

viii. First degree relative with T2DM ix. Polycystic ovary syndrome (PCOS) x. Obesity

Table 1: Complications of Uncontrolled DM2*

Macrovascular complications Microvascular complications Coronary heart disease (CHD) Cerebrovascular disease Peripheral arterial disease (PAD)

Diabetic nephropathy Diabetic retinopathy Peripheral & autonomic neuropathy

*Risk for complications exist if long-standing hyperglycemia regardless of diagnosis2

II. Treatment of T2DM (see Table 2)

Table 2: Guideline Recommendations for the Treatment of T2DM3-4 American Academy of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) 2017 Clinical Practice Guidelines

American Diabetes Association (ADA) 2018 Treatment Guidelines

• Lifestyle therapy • Medication management – first line agents

o Metformin o Glucagon-like peptide-1 receptor agonists (GLP-

1 RA) o SGLT-2i o Dipeptidyl peptidase-4 inhibitors (DPP-4i) o Alpha-glucosidase inhibitor (AGi)

• Lifestyle therapy, medical evaluation, management of comorbidities, and management of obesity for all patients

• Medication management o First line - metformin first line if tolerated and

not contraindicated o Second line or add-on: basal insulin or other

oral agent o Patients with established atherosclerotic

cardiovascular disease (ASCVD): prefer liraglutide or empagliflozin as add-on to reduce cardiovascular (CV) and all-cause mortality

• Manage CVD & CVD risk o Blood pressure (BP) management o Lipid management

*See Appendix A for more details on treatment of T2DM


III. Management of common comorbidities (see Appendix B for more information)

a. Risk factors for complications of DM include HTN, dyslipidemia, uncontrolled hyperglycemia, overweight

or obesity, and smoking 1 b. CVD1,5

i. Includes: cerebrovascular disease (stroke), coronary artery disease, and CHD i. In 2014, 7.2 million hospital discharges included DM as a diagnosis with 1.5 million of those also

including major CVD ii. CVD is the primary cause of death for most diabetic patients and at least 68% of those ≥ 65 years

old with DM die from CVD iii. Adults with DM are two to four times more likely to have a stroke than their non-diabetic peers iv. Antiplatelet therapy for CVD risk reduction (recommendations in Appendix B)

1. Primary prevention - consider in patients with T2DM with high ASCVD risk 2. Secondary prevention for patients with a history of clinical ASCVD

c. Heart failure (HF)2,4,6 i. Develops in up to 50% of patients with T2DM ii. European Society of Cardiology (ESC) 2016 Heart Failure Guideline

1. Recommends metformin first-line for patients with DM and stable HF (avoid use in unstable, hospitalized HF patients)

2. Consider empagliflozin to prevent development of HF (Table 3) d. HTN4-5,7-9,10

i. Present in approximately 66% of patients with diagnosed T2DM ii. Associated with increased risk of CVD, microvascular and macrovascular damage iii. Reduction in blood pressure (BP) decreases risk of negative outcomes - reduction by 10 mmHg in

systolic BP provides a 17% decrease in diabetes-related mortality, a 12% decrease in myocardial infarction (MI) and a 13% decrease in microvascular endpoints

iv. Management of HTN in T2DM 1. BP goal of < 130/80 mmHg is recommended 2. Pharmacotherapy recommended immediately in diabetics with BP above goal

a. First line agents: angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), calcium channel blocker (CCB), or thiazide

b. Prefer ACEI or ARB if urine albumin-to-creatinine ratio ≥ 300 mg/g e. Dyslipidemia3-4,11,14-15

i. In The National Health and Nutrition Examination Survey (NHANES) 1999-2010 analysis, 79.22% of patients with T2DM had elevated cholesterol

ii. T2DM can cause elevated triglycerides iii. Regular screening for dyslipidemia recommended iv. American College of Cardiology (ACC) and American Heart Association (AHA) 2013 guidelines

recommend lipid-lowering therapy for certain diabetic patients (see Appendix B for details) f. Obesity3-4,12-13,15

i. According to NHANES 1999-2010, 26% of patients with T2DM were overweight, and an additional 58.81% were obese

ii. Associated issues: increased CVD risk, increased insulin resistance, limited physical activity iii. AACE and ADA recommend all patients with T2DM be evaluated for obesity iv. Weight loss

1. Can increase insulin secretion and insulin sensitivity 2. Use of antihyperglycemic agents that promote weight loss can be beneficial (Table 3)


IV. Antidiabetic agents & CVD effects (Tables 3 and 4)

Table 3: Antidiabetic agents with proven CV benefits10, 16-18 Agent

CVD Benefits

Metformin

↓ risk of MI by 39% ↓ risk of other diabetes-related endpoints ↓ overall mortality by 36% ↓ risk of diabetes-related death by 42%

Thiazolidinediones ↓ risk of MI and stroke Liraglutide LEADER trial: ↓ rate of first occurrence of death from CV causes, nonfatal MI, or nonfatal

stroke in patients with T2DM when compared to placebo Semaglutide SUSTAIN-6 trial: ↓ incidence of CV death, nonfatal MI, or nonfatal stroke when compared

to placebo in patients with high CVD risk *FDA approval anticipated soon

Empagliflozin See information on EMPA-REG OUTCOME below Canagliflozin See information on CANVAS below

CV: cardiovascular; CVD: cardiovascular disease; MI: myocardial infarction; LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; T2DM: type 2 diabetes mellitus; SUSTAIN-6: Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes trial; FDA: Food and Drug Administration; EMPA-REG OUTCOME: Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes; CANVAS: Canagliflozin Cardiovascular Assessment Study

Table 4: Antidiabetic agents with proven CV harms 16 Agent CVD harms Sulfonylureas ↑ CV risk DPP-4i Possible ↑ risk of HF Thiazolidinediones ↑ hospitalizations for heart failure (HHF)

CV: cardiovascular; DPP-4i: dipeptidyl peptidase-4 inhibitor; HF: heart failure

V. SGLT-2i

Table 5: FDA Approved SGLT-2i19 Agent Canagliflozin Dapagliflozin Empagliflozin Ertugliflozin

Date approved

March 2013 January 2014 August 2014 December 2017

FDA indication(s)

T2DM in adults T2DM in adults CV disorder prophylaxis in T2DM, T2DM in adults

T2DM in adults

Dose 100 mg – 300 mg daily 5mg – 10 mg daily 10 mg – 25 mg daily 5 mg – 15 mg daily FDA: Food and Drug Administration; SGLT-2i: Sodium-glucose cotransporter 2 inhibitor; T2DM: type 2 diabetes mellitus; CV: cardiovascular

*see Appendix C for more detailed information on available SGLT-2i

a. Mechanism of action (MOA) in T2DM2, 19-20 i. Sodium-glucose cotransporter 2 (SGLT-2) receptors in the proximal tubule are responsible for

reabsorption of about 90% of glucose in the kidney (Figure 1) ii. Expression and activity of SGLT-2 increases in hyperglycemia, leading to maintenance of elevated

blood glucose levels iii. SGLT-2i block SGLT-2 prevent glucose reabsorption increase glucose excretion net

lowering of glucose in blood 1. Inhibition of SGLT-2 decreases renal glucose reabsorption by 30-50% 2. Effect: decreased fasting and post-prandial blood glucose levels 3. MOA is independent of beta cell function, therefore low hypoglycemia risk


. Figure 1: SGLT-2i and the kidney21

b. Proposed MOA in HF & CVD22

i. Originally proposed osmotic diuretic mechanism, but cannot explain the HF-only benefit through blood glucose lowering or osmotic diuresis alone

ii. SGLT-2i differ from diuretics 1. Sustained decrease in body weight 2. Decreased plasma volume without electrolyte imbalances 3. Hemoconcentration 4. Long term improvements in renal function

iii. Novel mechanism proposed: interact with sodium-hydrogen exchanger (NHE, Figure 2) 1. Kidney proximal tubule: NHE causes majority of tubular sodium reuptake, increases sodium

retention increases blood volume cardiac stress 2. Cardiac myocytes: increased NHE activity increases intracellular calcium

cardiomyopathy 3. NHE activity is increased in HF patients 4. SGLT-2i block NHE

a. Decreases sodium reuptake in kidney decreases cardiac stress b. Decreases intracellular calcium in cardiac muscle prevents cardiomyopathy c. Favorable effect on arterial stiffness and diastolic cardiac filling d. Could benefit both heart failure with reduced ejection fraction (HFrEF) and heart

failure with preserved ejection fraction (HFpEF)


Figure 2: Mechanism of SGLT-2i in CVD22

c. Efficacy & benefits of use2-3,19,23

Figure 3: Effects of SGLT-2i24

i. Expected decrease in A1c ~0.6% 1. A1c effect blunted if eGFR < 60 mL/min/1.73 m2 2. CV benefits remain with eGFR > 30 mL/min/1.73 m2

ii. Weight loss 1. Between 0.6 – 2.19 kg loss 2. Generally due to decreased body fat

iii. Decrease in visceral adiposity when compared to glimepiride iv. Decreased systolic and diastolic BP (SBP, DBP)

1. SBP decrease 1.4 – 5.4 mmHg 2. DBP decrease 0.6 – 2.0 mmHg 3. Theorized to be partly due to osmotic diuretic effect


v. Possible CV benefit 1. Possible HF benefit with empagliflozin 2. Decreased triglycerides 3. Reduced arterial wall stiffness (not due to reduction in BP or renin-aldosterone-angiotensin

system (RAAS) effects, possibly anti-inflammatory effect) vi. Possible renal benefits: decreased albuminuria found in several studies vii. Neutral hypoglycemia risk and gastrointestinal adverse effects

d. Safety concerns2-3,19,25 i. Fracture risk - increased with canagliflozin

1. More common if lower baseline eGFR, diuretic use, older age 2. Decrease in bone mineral density documented

ii. Genitourinary infection 1. Genital mycotic infections generally only with associated risk factor 2. Rarely urinary tract infection (UTI), urosepsis, pyelonephritis

iii. Diabetic ketoacidosis (DKA) – avoid SGLT-2i use if 1. Critical illness, surgical procedures 2. Ketones present 3. Prolonged fasting

iv. Polyuria, dehydration, volume depletion, hypotension 1. Risk factors: elderly, use of diuretics or aldosterone antagonists, low baseline SBP, renal

impairment 2. Prevention: maintain hydration, effective counseling

v. Increased low density lipoprotein cholesterol (LDL-C) vi. Transient increase in creatinine vii. Acute kidney injury (AKI)

1. Studies show SGLT-2i are well tolerated in CKD up to stage 3 2. Changes in eGFR occur early after starting SGLT-2i, are not sustained 3. Recommendations: assess AKI risk before starting, discontinue SGLT-2i immediately if AKI

occurs 4. Monitoring: eGFr, SCr

viii. Recent finding of increased risk of amputation with use of canagliflozin (see CANVAS analysis below)

e. Safety analyses i. Canagliflozin & fracture risk analysis by Watts, et al. published in 201626

1. N=10,194 2. Results: incidence of fracture similar for canagliflozin vs. comparator

a. CANVAS alone: significant increase seen (4% vs. 2.6%) b. Overall pooled analysis: 2.7% vs. 1.9% (driven by CANVAS results)

3. Conclusion: fracture risk higher with canagliflozin, mainly seen in older patients with history of or risk for CVD, lower baseline eGFR, higher incidence of diuretic use

ii. Systematic review of 34 DKA case reports by Burke, et al. published in 201727 1. Common precipitating factors: diagnosis of T2DM later found to have latent autoimmune

diabetes of adults, recent major surgery, patients with recent decrease in or discontinuation of insulin use

2. Conclusion: incidences of DKA all had a causative factor, none were fatal


iii. Meta-analysis by Monami, et al. investigating the effect of SGLT-2i on DKA or severe adverse drug reaction (ADR), published in 201728

1. Results: no increase in risk of DKA with use of individual SGLT-2ior as a class 2. Conclusion: when SGLT-2i are used correctly, DKA risk is negligible

VI. Recommended use of SGLT-2i

a. T2DM only, not yet studied in type 1 diabetes (T1DM) b. Not studied in eGFR < 45 ml/min/1.73 m2 (3) c. Can combine with any oral agent or insulin19 d. From T2DM treatment guidelines2-3

i. Not yet in pre-diabetes algorithm ii. ADA: second-line, empagliflozin or liraglutide preferred if ASCVD iii. AACE: first-line agent by AACE for any baseline A1c

e. ESC 2016 Heart Failure Guideline6 i. “Empagliflozin should be considered in patients with T2DM in order to prevent or delay the

onset of HF and prolong life.” (Class IIa recommendation, level B evidence) ii. Recent evidence for HF benefit, reduced hospitalizations for heart failure (HHF) iii. Uncertain if class-wide effect

VII. Clinical Question & Evidence Review

Table 6: EMPA-REG OUTCOME Summary & Analysis29

Zinman B, Wanner C, Lachin JM, et al. NEJM. 2015;373(22):2117-2128. Objective Examine the effects of empagliflozin compared to placebo on CV morbidity and mortality in patients with T2DM at

high risk for CV events who are receiving standard care Design Randomized, double-blind, placebo-controlled trial at 590 sites in 42 countries Patient Population

Inclusion • Adults ≥ 18 years old with T2DM • At high risk for CV event • A1c 7-9% + no glucose-lowering agents for 12

weeks before randomization or A1c 7-10% + stable glucose-lowering agents for at least 12 weeks before randomization

• BMI ≤ 45 kg/m2

Exclusion (partial list) • Fasting blood glucose > 240 during placebo run-in at

least twice • Evidence of liver disease • eGFR < 30 ml/min/1.73 m2 at screening or during

run-in • ACS, TIA, or stroke in prior 2 months

Intervention • 2-week open-label, placebo run-in period with unchanged background T2DM therapy • Randomized 1:1:1 to empagliflozin 10 mg daily, empagliflozin 25 mg daily, or placebo • Stratified by A1c (< 8.5% or ≥ 8.5%), BMI (< 30 or ≥ 30 kg/m2), renal function (eGFR 30-59, 60-89, or ≥ 90

ml/min/1.73 m2) Outcomes Primary composite of death from CV causes, nonfatal

MI (including silent), or nonfatal stroke Secondary primary outcomes plus hospitalization for unstable angina

Methods • Adjustment of glucose-lowering therapy at discretion of provider after first 12 weeks to target glucose level per local guidelines

Clinical question: in what populations is use of SGLT-2i most appropriate?


• Encouraged treatment of other CV risk factors (dyslipidemia, HTN) • Follow-up conducted throughout study and 30 days after end of treatment • Continued until primary outcome occurred in at least 691 patients • Safety: adverse events during study, days after last dose; reviewed by independent committee every 90 days • Analyzed change in: A1c, weight, waist circumference, BP, pulse, LDL, HDL, uric acid • Subgroup analyses: age, HbA1c, BMI, weight, geographical region, race, gender, ethnicity, time since diagnosis

of T2DM, BP, eGFR, urine albumin:creatinine ratio, glucose-lowering medication, use of statins/ezetimibe, use of antihypertensitves, use of aspirin, CV complications and cohort, hypoglycemia

Results • 7020 patients treated from September 2010 to April 2013 for a median of 2.6 years o 97% completed study, 25.4% discontinued study drug early o Final vital status available for 99.2% of patients enrolled

• Baseline: well balanced, average age 63 years, mostly white and Asian males with DM for > 5 years o Most taking metformin, aspirin, statin, 94% on antihypertensive medications o Average A1c ~8%, 68% with A1c < 8.5% o >99% with established CVD

Outcome HR (95.02% CI) for empagliflozin

P value non-inferiority

P value superiority

NNT per 100 patient years

Primary 0.86 (0.74-0.99) <0.001 0.04 15 Key secondary 0.89 (0.78-1.01) <0.001 0.08

Outcome HR (95.02% CI) for

empagliflozin P value non-inferiority

NNT per 100 patient years

Death from CV causes 0.62 (0.49-0.77) <0.001 13 Death from any cause 0.68 (0.57-0.82) <0.001 38 (25 mg), 41 (10 mg) HHF 0.65 (0.50-0.85) 0.002 19 Fatal/non-fatal MI 0.87 (0.70-1.09) 0.23 Fatal/non-fatal stroke 1.18 (0.89-1.56) 0.26 HHF or death from CV cause excluding fatal stroke

0.66 (0.55-0.79) <0.001 9

• 0.54% average A1c decrease with 10 mg, 0.6% with 25mg • Consistent benefit for CV outcomes across all subgroups • Observed more weight loss, ↓ waist circumference, ↓ SBP in empagliflozin groups • More genital infection in empagliflozin groups, other safety outcomes non-significant • Many patients did not reach glycemic targets (average A1c 7.81% - 8.1%)

Reviewer critique

Strengths • Benefits observed started early in the trial

and continued throughout • Stratification before randomization to

prevent some potential confounding • Included appropriate adverse events in

analysis (most common events for these agents)

• Continued background standard care • More realistic patient cohort with higher

A1c at end of trial (many not reaching goal)

Limitations • Selected for patients with somewhat better DM control

(max A1c 10%); however, may be appropriate given estimated 0.5% A1c reduction by empagliflozin

• Short treatment duration (3 years) analyzed compared to expected DM treatment duration

• Decreased effect of glucose control over time, longer-term effects uncertain

• Patients had well-treated CV disease, effect uncertain if other disease states untreated or poorly controlled

• Extrapolate only to patients with established CVD Conclusions • Empagliflozin use leads to significantly lower rates of composite death from CV causes, nonfatal MI, or nonfatal

stroke in patients with T2DM and established CVD • Difference driven by reduction in death from CV causes, no difference in MI or stroke • Generally well tolerated with expected A1c lowering with empagliflozin is about 0.5% • Other potential benefits include modest weight loss, BP reduction, reduced HHF

BMI: body mass index; CV: cardiovascular; eGFR: estimated glomerular filtration rate; ACS: acute coronary syndromes; TIA: transient ischemic attack; MI: myocardial infarction; HTN: hypertension; LDL-C: low-density lipoprotein cholesterol; HDL: high-density lipoprotein; HbA1c: hemoglobin A1c; T2DM: type 2 diabetes mellitus; BP: blood pressure; HR hazard ratio; CI: confidence interval; NNT: number needed to treat; HHF: hospitalization for heart failure; CVD: cardiovascular disease


a. EMPA-REG EXTEND MET30 – empagliflozin added to metformin i. Exploratory endpoint analysis: change in A1c from baseline, weight, BP at week 72 ii. Results & conclusions: significant reductions in A1c and BP seen at week 24 were sustained at

week 76; agent is well-tolerated over a longer-term treatment with increased genital infections b. EMPA-REG31

i. Time-to-benefit post-hoc analysis of EMPA-REG OUTCOME with groups split by 5-year HF risk into low (< 10%), high (10-20%), or very high risk (≥ 20%)

ii. Results: decreased risk of HF outcomes in all three risk groups for empagliflozin arm iii. Conclusions:

1. Authors: most patients with T2DM and CVD have very high HF risk at baseline, and empagliflozin improves HF outcomes in all HF risk groups

2. Presenter: use of empagliflozin in patients with T2DM and CVD but WITHOUT HF may reduce HF incidence/outcomes, need further studies to prove benefit

Table 7: CANVAS Summary & Analysis25 Neal B, Perkovic V, Mahaffey KW, et al. NEJM. 2017. Doi: 10.1056/NEJMoa1611925 Objective Show CV safety of canagliflozin, evaluate the balance between potential benefits and risks, and assess effects on

albuminuria Design Two sister randomized, double-blind, placebo-controlled trials in 667 centers in 30 countries Patient Population

Inclusion (identical for both trials) • T2DM with A1c ≥ 7% and ≤ 10.5% • eGFR > 30 mL/min/1.73 m2 • One of the following

o ≥ 30 years old with history of symptomatic ASCVD

o ≥ 50 years old with ≥ 2 risk factors for CVD

Exclusion (partial list) • History of DKA, T1DM • Changed hypoglycemics in past 8 weeks • Fasting glucose > 270 mg/dL at baseline • Glucose < 110 mg/dL if on insulin or sulfonylurea or severe

hypoglycemia in last 6 months • MI, unstable angina, CVA within last 3 months or planned

coronary intervention Intervention CANVAS: 1:1:1 to canagliflozin 100 mg, canagliflozin 300 mg, or placebo

CANVAS-R: 1:1 to canagliflozin 100 mg (optional increase to 300 mg after week 13) or placebo Outcomes Primary composite of death from CV causes,

nonfatal MI, nonfatal stroke Secondary • Death from any cause • Death from CV cause • Progression of albuminuria • Composite death from CV causes and HHF

Exploratory • Nonfatal MI • Nonfatal stroke • HHF • Regression of albuminuria • Total hospitalizations • Renal composite: 40% decrease in eGFR sustained for at least

2 measures, need for RRT, or death from renal causes Methods • 2-week single-blind, placebo run-in period

• Allowed other treatment for glycemic control and CV risk factors • Follow-up visits 3 times during first year, then at 6-month intervals • Complete when at least 688 CV events observed and all participants with 78 weeks of follow-up (ended Feb 2017)

Results • Total 10,142 participants enrolled, 9734 (96%) completed the trial, ~29% discontinued drug early in both arms • Mean follow-up of 188 weeks (3.3 years) • Baseline characteristics well balanced & similar for both CANVAS and CANVAS-R

o Mean age 63 years old, mostly white, 35.8% female, average duration of DM 13.5 years, average baseline A1c 8.2%, about 65% with history of CVD

o Most patients on appropriate CV-risk reduction therapy (statin, ACEI, beta-blocker) o Use of other hypoglycemic agents 9.3% lower in canagliflozin group

• CV risk markers canagliflozin v. placebo (p<0.001 for all): o Difference in A1c: -0.58% (95% CI -0.61 to -0.56) o Difference in body weight: -1.60 kg (95% CI -1.70 to -1.51)


T2DM: type 2 diabetes mellitus; eGFR: estimated glomerular filtration rate; CVD: cardiovascular disease; DKA: diabetic ketoacidosis; T1DM: type 1 diabetes mellitus; MI: myocardial infarction; CVA: cerebrovascular accident; CV: cardiovascular; RRT: renal replacement therapy; HR: hazard ratio; CI: confidence interval; RAAS: renin-aldosterone-angiotensin system; HHF: hospitalization for heart failure

c. Canagliflozin effect on CV biomarkers in older adults32

i. Use of canagliflozin delayed increase of NT-pro-BNP and troponin I for over 2 years in adults with T2DM aged 55-80 years old

ii. Supports potential for CV benefit of canagliflozin in older adults with T2DM

o Difference in SBP: -3.93 mmHg (95% CI -4.30 to -3.56) o Difference in DBP: -1.39 mmHg (95% CI -1.61 to -1.17)

Outcome Canagliflozin, per 1000 patient-years (N=5795)

Placebo, per 1000 patient-years (N=4347)

HR (95% CI)

Primary composite 26.9 31.5 0.86 (0.75-0.97) p<0.0001

Death from CV causes 11.6 12.8 0.87 (0.72-1.06) Nonfatal MI 9.7 11.6 0.85 (0.69-1.05) Nonfatal stroke 7.1 8.4 0.90 (0.71-1.15) Fatal or nonfatal MI 11.2 12.6 0.89 (0.73-1.09) Fatal or nonfatal stroke 7.9 9.6 0.87 (0.69-1.09) Hospitalization any cause 118.7 131.1 0.94 (0.88-1.00) Hospitalization for heart failure

5.5 8.7 0.67 (0.52-0.87)

Death from CV cause or HHF

16.3 20.8 0.78 (0.67-0.91)

Death from any cause 17.3 19.5 0.87 (0.74-1.01) Progression of albuminuria

89.4 128.7 0.73 (0.67-0.79)

40% reduction in eGFR, RRT, or renal death

5.5 9.0 0.60 (0.47-0.77)

Amputation 6.3 3.37 1.97 (1.41-12.75) Low-trauma Fracture 11.58 9.17 1.23 (0.99-1.52)

p=0.003

Reviewer critique

Strengths • Large size, randomized • Broad group of participants

including with and without established CVD

• Allowed all other treatments to continue

• Analyzed CV endpoint • Comprehensive safety analyses

Limitations • Possible false positives due to small or moderate number of events for

certain outcomes (e.g. kidney disease) • Small proportion with kidney disease, excluded severe renal dysfunction • Possible underestimation of canagliflozin effect due to high use of other

agents in placebo arm • No individual part of composite outcome significant • Secondary outcome analysis makes it difficult to tell if results are

significant • Followed for about 3 years, long-term effects unknown

Conclusions • Use of canagliflozin significantly reduced composite endpoint of risk of death from CV causes, nonfatal MI or stroke and increased risk of amputation in patients with and without preexisting CVD

• Canagliflozin led to modest A1c lowering, about 0.5% • Trend toward lower risk of HHF, progression of albuminuria, loss of kidney function with canagliflozin • Similar benefit to empagliflozin (HR same for both agents for primary outcome) • Need long-term data, further studies on safety outcomes


Table 8: CVD-REAL Summary & Analysis33

Kosiborod M, Cavender MA, Fu AZ, et al. Circulation. 2017;136:249-259. Objective Compare risk of HHF, death, and combined endpoint of HHF & death in patients with T2DM who were new

users of SGLT-2i compared to other glucose lowering drugs (oGLD) in real-world practice Design Retrospective analysis of de-identified heath records from 6 countries Patient Population Inclusion

• Age ≥ 18 years old on index date • T2DM diagnosis code • New start of SGLT-2i or oGLD between

November 2012 and July 2013 • > 1 year history of information in database

Exclusion • T1DM • Gestational diabetes

Intervention Analyzed various health claims databases across the US, Germany, Sweden, Norway, Denmark, United Kingdom (UK) from index date to date of treatment end, leaving database, last date of data collection, outcome date, or censoring date

Outcomes Primary HHF – definitions by country: • HF as primary discharge diagnosis in US, UK • Documented in health record in Germany • Hospital or outpatient visit with primary

diagnosis of HF for Nordic countries

Secondary • All cause death • Composite HF and all-cause death (time-to-first-

event)

Methods • Propensity score used for matching 1:1 SGLT-2i to oGLDs • Included first incidence of HHF or death • Analyzed primary outcomes by on-treatment approach (start of treatment to end of treatment plus

grace period for days supply of medication) Results • Baseline before matching: patients on SGLT-2i younger, less CKD or CV complications, more

microvascular disease, receiving more statins, antihypertensive drugs, fewer loop diuretics • Baseline after matching: well matched

o Mean age 57 years, 44% female, 79% on metformin o 13% established CVD o < 7% drug exposure time was with empagliflozin

Outcome Patients Person-years of follow-up (mean duration)

Events HR SGLT-2i vs. oGLD (95% CI)

P value

HHF 309,056 190,164 (239 days) 961 0.61 (0.51 - 0.73)

<0.001

All-cause death 215,622 153,990 (251 days) 1334 0.49 (0.41 - 0.57) <0.001 HHF & death 215,622 143,342 (253 days) 1983 0.54 (0.48 - 0.60) <0.001

• Sensitivity analyses - similar results for all adjustments

Reviewer Analysis Strengths • First large trial to look at real-world practice

using SGLT-2i • First to look for a class effect of SGLT-2i • First to include a majority of patients without

established CVD • First to look at HHF and all-cause death

Limitations • Observational study (possible confounding) • Focused on HHF and all-cause death, not MI or

stroke • No analysis of safety outcomes • Differences in definition of HHF across countries

(however, results consistent) • Distribution of use of specific SGLT2i variable

Conclusions • Suggests results from EMPA-REG OUTCOME may be true in real-world setting • CV benefit of SGLT-2i likely a class effect • CV benefit of SGLT-2i use likely includes patients without diagnosed CVD • Treatment with SGLT-2i associated with lower HHF, all-cause death in patients with T2DM with and

without pre-existing CVD (mainly without) • Should test in randomized trial with broader patient population to confirm results

HHF: hospitalization for heart failure; SGLT-2i: sodium-glucose cotransporter 2 inhibitor; oGLD: other glucose-lowering drug (not SGLT-2i); US: United States; UK: United Kingdom; HF: heart failure; IR: incidence ratio; HR: hazard ratio; CI: confidence interval; GLP-1 RA: glucagon-like peptide-1 receptor antagonist; CKD: chronic kidney disease; CV: cardiovascular disease; MI: myocardial infarction; CVD: cardiovascular disease


Table 9: Summary of meta-analyses of SGLT-2i

Authors (year published)

Included studies

Efficacy outcome(s) Safety outcome(s)

Vasilakou, et al.34

(2013)

Randomized, comparing SGLT-2i to placebo or other T2DM treatment

• A1c ↓ 0.66% • ↓ weight with SGLT-2i • ↓ SBP with SGLT-2i • ↓ CV outcomes: OR 0.73 (dapagliflozin), OR

0.95 (canagliflozin) • No significant difference in all-cause

mortality

• ↑ renal-related adverse events with SGLT-2i

• ↑ UTI: OR 1.34 • ↑ genital tract infection: OR 3.50 vs.

placebo, OR 5.06 vs. active • ↑ hypotension with SGLT-2i: OR 2.68 • Non-significant ↑ in fracture with

canagliflozin Wu, et al.35 (2016)

Prospective randomized controlled trials of SGLT-2i vs. control

• ↓MACE* with SGLT-2i: RR = 0.84, p=0.006 • ↓MACE plus hospital admission for unstable

angina: RR=0.85, p=0.008 • ↓ CV death: RR 0.63, p<0.0001 • ↓ HF: RR 0.65, p=0.002 • ↓ all-cause death: RR 0.71, p<0.0001 • No benefit: nonfatal MI, unstable angina • Benefits driven by empagliflozin

• ↑ nonfatal stroke with SGLT-2i: RR 1.3, p=0.049

• ↑ UTI risk • ↑ genital infection • ↑ volume depletion • No difference in cancer,

hypoglycemia, acidosis, bone fracture, kidney disease

Tang, et al36

(2016) Randomized controlled trials of SGLT-2i use for at least 24 weeks

• ↓ risk of MACE, all-cause mortality, incidence of HF with empagliflozin

• Non-significant difference in MACE, all-cause mortality, HF for dapagliflozin & canagliflozin

• No difference in unstable angina, atrial fibrillation, TIA

• Results driven by EMPA-REG OUTCOME

No prespecified safety outcomes, but no harm seen from any SGLT-2i noted

Monami, et al37 (2017)

Randomized trials

• ↓in MI with SGLT-2i: MH-OR 0.77 [0.63–0.94], p < 0.01

• No change in stroke risk • ↓ all-cause mortality: MH-OR 0.70 [0.59–

0.83], p < 0.001 • ↓ CV mortality: MH-OR 0.43 [0.36–

0.53], p < 0.001

No safety outcomes assessed

*MACE: major adverse cardiovascular events (includes CV death, nonfatal MI, nonfatal stroke) SGLT-2i: sodium glucose cotransporter-2 inhibitor; SBP: systolic blood pressure; CV: cardiovascular; OR: odds ratio; UTI: urinary tract infection; RR: relative risk; MI: myocardial infarction; MH-OR: Mantel Haenszel odds ratio; TIA: transient ischemic attack

VIII. Summary

a. SGLT-2i currently recommended for treatment of T2DM by ADA (preferred second line in ASCVD) and

AACE (first-line option) b. ESC HF guidelines recommend use of empagliflozin in T2DM for prevention of HHF


Table 10: Summary of evidence reviewed

Study Key Outcomes & Takeaway EMPA-REG OUTCOME In patients with existing CVD, empagliflozin lowered risk for composite outcome (death

from CV causes, nonfatal MI, or nonfatal stroke), lowered risk of HHF, lowered risk of death from CV causes and death from any cause

CANVAS In patients with and without existing CVD, canagliflozin lowered risk of death from CV causes, nonfatal MI or nonfatal stroke, trended toward a decrease in HHF, and increased risk of amputation and fracture in certain patient groups

CVD-REAL In patients mainly without existing CVD, SGLT-2i use was associated with lower HHF and all-cause death which appear to be class effects

Safety data UTI, urosepsis risk very low; DKA, amputation, volume depletion risk possibly increased in specific populations; possible increase in fracture risk with use; increased risk of genital mycotic infections with SGLT-2i

IX. Ongoing Trials

a. DECLARE-TIMI 58

i. Dapagliflozin effect on CV events ii. Estimated completion April 2019

b. VERTIS CV Study i. CV outcomes following ertugliflozin treatment in T2DM participants with vascular disease ii. Expected completion October 2019

X. Recommendations

c. Established ASCVD (see Appendix B) or high risk for HF: recommend use of empagliflozin or canagliflozin

preferentially over other hypoglycemic agents to prevent negative CV outcomes i. In addition to metformin in patients who can tolerate metformin ii. Use first-line in patients with established ASCVD or high risk for HF if unable to tolerate

metformin iii. Unlikely to decrease risk of MI or stroke iv. High risk of HF: 5-year risk of HF ≥ 10% using Health ABC Heart Failure Risk Score, CHD, elevated

SBP, current smoker, left ventricular hypertrophy38 d. T2DM regardless of pre-existing CVD or HF: consider use of empagliflozin or canagliflozin to prevent

development of HF, HHF, all-cause death e. CV benefit may be a class effect though only conclusive evidence with canagliflozin and empagliflozin so

currently recommend these agents over dapagliflozin f. Consider in patients who could benefit from modest weight loss and/or BP lowering g. Expected average A1c lowering is 0.5%, recommend combination therapy if need larger effect h. Avoid use of canagliflozin (likely all SGLT-2i) in patients with a history of PVD or amputation i. Caution SGLT-2i use (not contraindication) for the following populations

i. History of frequent genital mycotic infections or at high risk for UTI ii. Elderly patients on diuretics, with reduced eGFR, baseline high risk for falls or fracture iii. Possible not true T2DM (e.g. underlying latent autoimmune diabetes of adults) iv. Unable to maintain adequate hydration


XI. References

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2. American Diabetes Association. Standards of medical care in diabetes – 2017. Dia Care. 2017; 40: S57-S63, S75-S87. 3. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American association of clinical endocrinologists and American college

of endocrinology on the comprehensive type 2 diabetes management algorithm – 2017 executive summary. Endocrine Practice. 2017;23(2):207-238.

4. American Diabetes Association. Standards of medical care in diabetes – 2018. Dia Care. 2018;41:S73-S85. 5. Cardiovascular Disease & Diabetes. American Heart Association website. 2017. Updated August 2015. Available at:

http://www.heart.org/HEARTORG/Conditions/More/Diabetes/WhyDiabetesMatters/Cardiovascular-Disease-Diabetes_UCM_313865_Article.jsp/#.We5q-DYUkdU Accessed October 23, 2017.

6. Ponikowski P, Voors AA, Anker SD, et al. The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2016;37:2129-2200. doi:10.1093/eurheartj/ehw128

7. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321:412-419.

8. Whelton PK, Carey RM, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: executive summary. J Am Coll Cardiol. 2017. Doi: 10.1016/j.jacc.2017.11.005

9. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure. JAMA. 2003;289(19):2560-2572.

10. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703-713.

11. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. Circulation. 2013;00:000-000. Doi: 10.1161/01.cir.0000437738.63853.7a

12. Management of Common Comorbidities of Diabetes. American Association of Clinical Endocrinologists: Diabetes Resource Center website http://outpatient.aace.com/type-2-diabetes/management-of-common-comorbidities-of-diabetes. Accessed October 24, 2017.

13. Garvey WT, Mechanick JI, Brett EM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract. 2016;22(Suppl 3):1-203.

14. Jallinger PS, Handelsman Y, Rosenbilt PD, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract. 2017;23(Suppl 2):1-87.

15. Zhang N, Yang X, Zhu X, et al. Type 2 diabetes mellitus unawareness, prevalence, trends, and risk factors: National Health and Nutrition Examination Survey (NHANES) 1999-2010. J Int Med Res. 2017;45(2):594-609.

16. Paneni F and Luscher TF. Cardiovascular protection in the treatment of type 2 diabetes: a review of clinical trial results across drug classes. Am J Med. 2017;130(6S):S18-S29.

17. Marso SP, Daniels SH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. NEJM. 2016;375(4):311-322. Doi: 10.1056/NEJMoa1603827

18. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. NEJM. 2016;375:1834-1844. Doi: 10.1056/NEJMoa1607141

19. DRUGDEX® System [database online]. Ann Arbor, MI: Truven Health Analytics, Inc. Available at: http://www.micromedexsolutions.com. Accessed October 15, 2017.

20. Trujillo JM, Nuffer WA. Impact of sodium-glucose cotransporter 2 inhibitors on nonglycemic outcomes in patients with type 2 diabetes. Pharmacotherapy. 2017;37(4):481-491. Doi: 10.1002/phar.1903

21. Chao EC, Henry RR. Nat Rev Drug Discov. 2010 Jul;9(7):551-9. 22. Packer M, Anker SD, Filipatos G, et al. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure:

proposal of a novel mechanism of action. JAMA Cardiology. 2017;2(9):1025-1029. 23. Liakos A, Karagiannis T, Athanasiadou E, et al: Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis.

Diabetes Obes Metab. 2014; 16(10):984-993. 24. DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Neph. 2017;13:11-26. 25. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. NEJM. 2017. Doi:

10.1056/NEJMoa1611925 26. Watts NB, Bilezikian JP, Usiskin K, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Endocrinol Metab.

2016;101(1):157-161. Doi:0.1210/jc.2015-3167 27. Burke KR, Schumacher CA, Harpe SE, et al. SGLT2 inhibitors: a systematic review of diabetic ketoacidosis and related risk factors in the primary

literature. Pharmacotherapy. 2017;37(2):187-194. Doi: 10.1002/phar.1881

https://www.cdc.gov/media/releases/2017/p0718-diabetes-report.html

http://www.heart.org/HEARTORG/Conditions/More/Diabetes/WhyDiabetesMatters/Cardiovascular-Disease-Diabetes_UCM_313865_Article.jsp/#.We5q-DYUkdU

http://www.heart.org/HEARTORG/Conditions/More/Diabetes/WhyDiabetesMatters/Cardiovascular-Disease-Diabetes_UCM_313865_Article.jsp/#.We5q-DYUkdU

http://outpatient.aace.com/type-2-diabetes/management-of-common-comorbidities-of-diabetes

http://www.micromedexsolutions.com/


28. Monami M, Nreu B, Zannoni S, et al. Effects of SGLT-2 inhibitors on diabetic ketoacidosis: a meta-analysis of randomized controlled trials. Diab Research and Clin Prac. 2017;130:53-60.

29. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. NEJM. 2015;373(22):2117-2128.

30. Merker L, Haring HU, Christiansen AV, et al. Empagliflozin as add-on to metformin in people with type 2 diabetes. Diabet Med. 2015;32:1555-1567.

31. Fitchett D, Butler J, van de Borne P, et al. Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME trial. Eur Heart J. 2017;0:1-8. Doi: 10.1093/eurheartj/ehx511

32. Januzzi JL, Butler J, Jarolim P, et al. Effects of canagliflozin on cardiovascular biomarkers in older adults with type 2 diabets. JACC. 2017;70(6):704-712.

33. Kosiborod M, Cavender MA, Fu AZ, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs. Circulation. 2017;136:249-259. Doi:10.1161/circulationaha.117.029190

34. Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes. Ann Intern Med. 2013;159:262-274.

35. Wu JHY, Foote C, Blomster J, et al. Effets of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabet Endocrinol. 2016;4:411-419.

36. Tang H, Fang Z, et al. Meta-analysis of effects of sodium-glucose cotransporter 2 inhibitors on cardiovascular outcomes and all-cause mortality among patients with type 2 diabetes mellitus. Am J Cardiol. 2016;118:1774-1780.

37. Monami M, Dicembrini I, Mannucci E. Effects of SGLT-2 inhibitors on mortality and cardiovascular events: a comprehensive meta-analysis of randomized controlled trials. Acta Diabetol. 2017;54:19-36. Doi: 10.1007/s00592-016-0892-7

38. Butler J, Kalogeropoulos A, Georgiopoulou V, et al. Incident heart failure prediction in the elderly: the health ABC heart failure score. Circ Heart Failure. 2008;1(2):125-133.

39. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17(suppl 2):1-53.

40. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: (JNC8). JAMA. 2014;311(5):507-520.

41. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused update of the 2013 ACCF/AHA guideline for the management of heart failure. Circulation. 2017;000:e000-e000. Doi: 10.1161/CIR.000000000000050


APPENDIX A: TREATMENT OF T2DM 3-4

APPENDIX B: TREATMENT OF COMORBIDITIES Table 1B: Management goals for CV risk factors10, 39-40

Risk Factor Recommended Goal Anticoagulant therapy Use aspirin for primary prevention and secondary prevention of CVD events Weight Reduce by 5-10%; avoid weight gain Lipids Total cholesterol < 200 mg/dL LDL < 100 mg/dL; < 70 mg/dL for very high risk patients Triglycerides < 150 mg/dL Blood pressure <140/90 mmHg

CV: cardiovascular; CVD: cardiovascular disease; LDL: low-density lipoprotein

1. Management of dyslipidemia in T2DM3-4, 14

a. Dietary and lifestyle changes, patient education 14 b. Pharmacologic therapy if goals are not met with lifestyle changes alone c. Statins remain the drug of choice11,14


d. ACC/AHA 2013 guidelines and ADA 2018 guidelines recommend treatment for patients4,14

i. With established ASCVD (defined as history of acute coronary syndromes including MI, stable or unstable angina, or arterial revascularization, history of stroke or TIA, history of coronary artery disease, PAD, CHD)11,25,29,41

ii. With familial hyperlipidemias (LDL-C ≥ 190 mg/dL at baseline) iii. With T2DM and age 40-75 years (see Table 2B for ASCVD risk factors)

1. 10-year ASCVD risk < 7.5% moderate-intensity statin 2. 10-year ASCVD risk ≥ 7.5% high-intensity statin 3. ADA 2018 guideline recommends moderate intensity statin in all diabetic patients

iv. Less evidence for patients with T2DM < 40 or > 75 years old – consider moderate-intensity statin 1. T2DM age < 40 years with ASCVD risk factors (see Table 2B) 2. T2DM age > 75 years

Table 2B: Major ASCVD Risk Factors14

Major Additional Nontraditional • Advancing age • Elevated total serum cholesterol • Elevated non-HDL-C • Elevated LDL-C • Low HDL-C • DM • HTN • CKD stage 3 or 4 • Cigarette smoking • Family history of ASCVD

• Obesity or abdominal obesity • Family history of dyslipidemia • Elevated small, dense LDL-C • Increased Apo B • Increased LDL particle number • Fasting/postprandial

hypertriglyceridemia • PCOS • Dyslipidemic triad*

• Elevated lipoprotein (a) • Elevated clotting factors • Inflammation markers (hsCRP) • Elevated homocysteine • Apo E4 isoform • Elevated uric acid • Elevated TG-rich remnants

ASCVD: atherosclerotic cardiovascular disease; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; DM: diabetes mellitus; HTN: hypertension; CKD: chronic kidney disease; Apo B: apoprotein B; PCOS: polycystic ovarian syndrome; hsCRP: high-sensitivity c-reactive protein; Apo E4: apoprotein E4; TG: triglyceride *Hypertriglyceridemia; low high-density lipoprotein cholesterol; and small, dense low-density lipoprotein cholesterol.

e. Combination therapy or alternatives available if goals not met or contraindications to statin therapy

i. Bile acid sequestrants ii. Ezetimibe in combination with statin iii. PCSK-9 inhibitors combined with statin in familial hyperchloesterolemias or inadequate control

with statin monotherapy f. Fibrates or omega-3 fatty acids recommended for treatment of hypertriglyceridemia

i. Goal tiglycerides (TG) < 150 mg/dL for all patients, always treat if TG ≥ 500 mg/dL4, 14 ii. Consider addition to lower ASCVD risk in patients with TG ≥ 200 mg/dL

2. Treatment of heart failure4, 41

a. Use ACEI or ARB (if intolerant to ACEI) to decrease mortality in HFrEF; valsartan/sacubitril if New York Heart Association class II or III symptomatic HF and able to tolerate ACEI or ARB

b. Beta blockers in patients with HFrEF or ivabradine if beta blocker does not acheive HR < 70 beats/min c. Diuretics for symptom management as needed d. Add on: aldosterone antagonist, BiDil, ICD, CRT, ivabradine e. HFpEF: can use aldosterone antagonist, ACEI, ARB, BB to manage atrial fibrillation and HTN f. Avoid TZD therapy in patients with symptomatic HF


3. CVD – antiplatelet therapy a. Primary prevention - consider in T2DM with high ASCVD risk

i. Age ≥ 50 years with one additional risk factor ii. Risk factors: HTN, dyslipidemia, family history of premature ASCVD, smoking, albuminuria (Table

2B for additional risk factors)4 iii. Clinical judgment for patients < 50 years iv. Do not use for primary prevention in low risk patients

b. Secondary prevention for patients with a history of clinical ASCVD c. Choice of agent

i. Aspirin 75-162 mg daily4 ii. Clopidogrel 75 mg daily if aspirin allergy/intolerance

APPENDIX C: SGLT-2I DRUG INFORMATION4,20

Table 1C: SGLT-2i Drug Information

Agent Canagliflozin Dapagliflozin Empagliflozin Ertugliflozin Date approved

March 2013 January 2014 August 2014 December 2017

FDA indication(s)

T2DM in adults T2DM in adults CV disorder prophylaxis in T2DM, T2DM in

adults

T2DM in adults

Dose 100 mg – 300 mg daily 5mg – 10 mg daily 10 mg – 25 mg daily 5 mg – 15 mg daily Adverse effects

Hypoglycemia, polyuria, UTI, genital mycotic infections, hypovolemia, pancreatitis,

hypotension, hypersensitivity reaction, bone fracture, DKA,

AKI, pyelonephritis, leg/foot limb loss, angioedema

Hypoglycemia, UTI, genital mycotic

infections, hypotension, hypersensitivity

reaction, bone fracture, bladder cancer, DKA, AKI, pyelonephritis,

urosepsis

Hypoglycemia, UTI (higher in age ≥75

years), mycotic infections, DKA, AKI,

pyelonephritis, urosepsis

UTI, hypovolemia, increased thirst, genital

mycotic infections, hypoglycemia (if used

with insulin)

PK/PD All agents: highly protein bound, Vd ~ 70-80L, metabolized by liver, renal and fecal elimination

Not recommended with eGFR < 30 mL/min/1.73 m2, 65%

bioavailable, t1/2~10-13 hours depending on dose

Not recommended with eGFR < 60 mL/min/1.73

m2, contraindicated with eGFR < 30

mL/min/1.73 m2, 78% bioavailable, t1/2~8-12.9

hours

Contraindicated with eGFR < 30 mL/min/1.73

m2, t1/2~12.4 hours

Contraindicated in eGFR < 30 mL/min/1.73 m2,

do not initiate if eGFR < 60 mL/min/1.73 m2, 100% bioavailable,

t1/2~16.6 hours

Interactions UGT inducers decrease canagliflozin concentration; can increase digoxin serum level

No major interactions, can increase/compound diuretic effects

Warnings Consider risk of amputation before initiation (history of amputation, PVD, neuropathy, foot ulcers), correct volume before initiation, risk of bone fracture

DKA risk possible with all agents, possible volume depletion, possible LDL increase

Same warnings for amputation and volume risk as canagliflozin

T2DM: type 2 diabetes mellitus; CV: cardiovascular; UTI: urinary tract infection; DKA: diabetic ketoacidosis; AKI: acute kidney injury; eGFR: estimated glomerular filtration rate; Vd: volume of distribution; t1/2: half-life

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