American Diabetes Association requires the following...Second Sentence: ›Ongoing patient...
Transcript of American Diabetes Association requires the following...Second Sentence: ›Ongoing patient...
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In compliance with the accrediting board policies, the
American Diabetes Association requires the following
disclosure to the participants:
Discuss the American Diabetes Association Anti-
hyperglycemic therapy recommendations for T2DM
Understand the importance of co-morbidities when
choosing therapy
Review the recent CV risk reduction findings in regard to
anti-hyperglycemic therapies
Discuss how to keep the patient centered in your choice of anti-hyperglycemic medication
Second Sentence:
› Ongoing patient self-management
education and support are critical to
preventing acute complications and
reducing the risk of long-term
complications.
Standards of Medical Care in Diabetes -2018 Diabetes Care 2018;41(Suppl.1):S1-S2.
Antihyperglycemic therapy in type 2 diabetes: general recommendations. *If patient does not tolerate or has contraindications to metformin, consider agents from another class in Table 8.1. #GLP-1 receptor agonists and
DPP-4 inhibitors should not be prescribed in combination.
American Diabetes Association Dia Care 2018;41:S73-S85
©2018 by American Diabetes Association
Combination injectable therapy for type 2 diabetes.
American Diabetes Association Dia Care 2018;41:S73-S85
©2018 by American Diabetes Association
Medication Centric
Inattentive to Diabetes Life Cycle
Less focused on Co-morbid conditions
Promotes Polypharmacy
What are Patients Thinking?
Cost
Side Effects
Hassle Factors
Future Implications
What are Physicians Thinking?
Efficacy
Side Effect Profile
Tolerability
Coverage
Economics
Safety
Efficacy
Co-Morbid
Conditions
Patient
Co-Morbid
Conditions
Patient
Cardiovascular Risk – Underlying CVD,
Stroke, MI, PVD
Renal Risk – Diabetic nephropathy, declining
renal Fx
GI Tolerability – Underlying GI conditions
Obesity -
Endocrine – Thyroid, PCOS, others
Obesity: 1999-2004 (NHANES) Type 2 patients
27% overweight and 61% were obese
Dyslipidemia: 99% eligible for lipid lowering therapy
1999-2004 (NHANES) 46% had elevated lipids
HTN: 67% of T2DM patients were being treated or
had HTN
Chronic Kidney Disease: ~40% of patients with
diabetes
Cardiovascular Disease:
Depression, Sleep Disorders, Cancers
(NHANES) 1999-2004
14% of patients with
T2DM had no co-morbidity
http://outpatient.aace.com/type-2-diabetes/management-of-common-comorbidities-of-diabetes
SafetyPatient
Can I take this medication with the other
medications that I am already taking?
Will this medication affect other health
problems that I am having?
I see the ads on TV. They scare me.
EconomicsPatient
Will my insurance cover this new medicine?
Can I afford to take this with all of my other
medications?
If I get a coupon or co-pay card, how long will
it last?
Is the benefit that I will get be worth the
money that I am spending?
EfficacyPatient
Will it work?
Will it be worth it?
HTN
Hyperlipidemia
Obesity
Social – elderly, frail, falls risk
CVD – stroke, MI, CAD, PVD, CHF
CKD
GI – GERD, Gall Bladder, NASH, Pancreatitis, IBS,
Crohn’s, Ulcerative Colitis
Endocrine – obesity, PCOS, Thyroid, Adrenal
Choosing Medications While
Giving Consideration to
Co-Morbid Conditions
HTN – SGLT-2 Inhibitors
› Volume Contraction and possible hypotension need to be considered.
› Canagliflozin noted with SBP reductions of 3.3 and 5.0 mm/Hg at 26 weeks1
› Empagliflozin: Mean Arterial Pressure reductions of 2.3 and
2.1 mm/Hg at 24 weeks2
› Dapagliflozin: reduced mean seated SBP -10.4 vs -7.3
mm/Hg and mean 24 hr ambulatory SBP -9.6 vs -6.7 mm/Hg at 12 weeks
1. https://www.google.com/search?q=Invokana+PI&oq=Invokana+PI&aqs=chrome.0.69i59j0j69i60j0l3.2423j0j7&sourceid=chrome&ie=UTF-8 (Accessed
1/13/2018)
2. Chilton R, et.al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes
Obesity Metabolism 2015;17(12):1180-1193.
Weber, MA et.al Effects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin-angiotensin system blockade. Blood Pressure 2016;25(2):93-
103.
Hyperlipidemia:› SGLT-2 Class Medications: Can cause a slight
elevation in LDL Cholesterol (canagliflozin 4.5 to 8%)1(dapagliflozin 2.9%)2 (empagliflozin 4.6, 6.5%)3
› TZD Class Medications: Pioglitazone can cause a reduction in triglycerides (-9.9% to -12.3%), HDL Cholesterol (-18.1 to -20.3%), LDL Chol increased
(+5.2% to +9.6%)4
1. https://www.google.com/search?q=Invokana+PI&oq=Invokana+PI&aqs=chrome.0.69i59j0j69i60j0l3.2423j0j7&sourceid=chrome&ie=UTF-8 (Accessed
1/13/2018)
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202293s000lbl.pdf (Accessed 1/13/2018)
3. http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Jardiance/jardiance.pdf (Accessed 1/13/2018)
4. Spanheimer R et.al. Long-term lipid effects of pioglitazone by baseline anti-hyperglycemia medication therapy and statun use from the PROactive experience
(PROactive 14). Am J Cardiol 2009;104(2): 234-239.
Obesity:› Gain:
SU Class can cause weight gain
TZD Class can cause fluid retention and weight gain
Glinide Class can cause weight gain
Insulins
› Neutral:
DPP-4i Class
Biguanides – metformin
› Lose:
SGLT-2 Class
GLP-1 Class
Social – elderly, frail, falls risk, isolated
› Anything that is a hypoglycemia risk
SU’s
Insulins
Glinides
› Volume Depletion
SGLT-2’s
Economics –
Everything past metformin and SU’s tend to get
expensive
Try to simplify, limit or combine medications
Insured:
› Follow formulary as much as possible
› Use Coupon programs when you can
› Sample Access: try to limit to extreme or emergency situations
Cardiovascular Risk
Pre-2008 2008 The Present
CVD – TZD’s
› Pioglitazone – PROactive Trial
› 5238 Patients with evidence of macrovascular Dse.
› 34.5 month avg. time of observation
› Primary Endpoint: All-cause mortality, non-fatal MI, stroke, ACS, revascularization coronary or leg and
amputation
HR 0.90; CI 0.80-1.02, p=0.095
› Secondary Endpoint: All-cause mortality, non-fatal MI
and stroke
HR 0.84; CI 0.72-0.98, p = 0.027
Dormandy, JA, et.al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective
pioglitazone Clinical Trial In macrovascular Events): a randomized controlled trial. The Lancet 2005;366: 1279-1289.
CVD – TZD’s
› Rosiglitazone – RECORD Trial1
4447 Patients – HR for CV Death 0.84;CI 0.59-1.18, MI 1.14;
CI 0.80-1.63, Stroke 0.72; CI 0.49-1.06
Heart Failure Admission or death HR 2.10; CI 1.35-3.27.
Increased risk of long bone Fx, mainly women
› Nissen Meta-analysis2
42 trials, avg. age 56 y
Odds ratio for MI 1.43
Odds ratio of death 1.64
1. Home,PD, et.al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a
multicenter, randomized, open-label trial. The Lancet 2009;373:2125-2135.
2. Nissen, SE, et al. Effect of Rositglitaone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med 2007;356:
2457-2471.
CVD –
These events should include cardiovascular mortality, myocardial infarction, and stroke, and can include
hospitalization for acute coronary syndrome, urgent
revascularization procedures, and possibly other endpoints.
https://www.fda.gov/downloads/Drugs/Guidances/ucm071627.pdf
CVD –
What is 3 pt. MACE:
Cardivascular Death
Non-fatal MI
Non-fatal Stroke
https://www.fda.gov/downloads/Drugs/Guidances/ucm071627.pdf
Study EXAMINE1 CARMELINA2 SAVOR3 TECOS4
DPP-4i Alogliptin linagliptin saxagliptin sitagliptin
N 5380 7003 16492 14671
Duration 40 months,
median 18 months2013-2018 2.1 years 3.0
Resulted 2013 Ant. 2018 2013 2015
Primary
Endpoint
MACE MACE MACE MACE
HR 0.95; CI upper
limit 1.16
TBD 1.00; CI 0.89-
1.12
0.98; CI 0.88-
1.09
Results Non-inferior
p<0.001
TBD Non-inferiority
p<0.001
Non-inferior
P<0.001
1. White,W, et al. Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes. N Engl J Med 2013; 369:327-335.
2. https://clinicaltrials.gov/ct2/show/NCT01897532 (Accessed 2/2/2018)
3. Green, JB. et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2015; 373:232-242.
Study CANVAS1 DECLARE2 EMPA-Reg3
SGLT-2 Canagliflozin Dapagliflozin Empagliflozin
N 10142 17276 7020
Duration 188.2 weeks 3.1 years
Resulted2017
Mid-2018
(anticipated)
2015
Primary EndpointMACE
MACE MACE
HR0.86;CI 0.75-0.97
TBD 0.86; CI 0.74-.099
ResultsNon-inferior
p<0.001
Superior p=0.02
TBD Superiority
p=0.04
1. Neal,B et.al. Canagliflozin and Cardiovasculary and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377:644-657.
2. https://clinicaltrials.gov/ct2/show/NCT01730534 (Accessed 2/1/2018)
3. Zinman, B et.al. Empagliflozin, Cardiovascular Outcomesn and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373:2117-2128.
Study CANVAS1 DECLARE2 EMPA-Reg3
SGLT-2 Canagliflozin Dapagliflozin Empagliflozin
N 10142 17276 7020
Duration 188.2 weeks 3.1 years
Resulted 2017Mid-2018
(anticipated)2015
Primary Endpoint MACE MACE MACE
HR 0.86;CI 0.75-0.97 TBD 0.86; CI 0.74-.099
ResultsNon-inferior
p<0.001
Superior p=0.02
TBDSuperiority
p=0.04
1. Neal,B et.al. Canagliflozin and Cardiovasculary and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377:644-657.
2. https://clinicaltrials.gov/ct2/show/NCT01730534 (Accessed 2/1/2018)
3. Zinman, B et.al. Empagliflozin, Cardiovascular Outcomesn and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373:2117-2128.
Study ELIXA1 EXSCEL2 LEADER3 REWIND4 SUSTAIN-65
GLP-1RA Lixisenatide Exenatide LR Liraglutide Dulaglutide semaglutide
N 6068 5400 9340 8300 2735
Duration 25 month
median3.2 years 3.8 years Up to 6.5
years104 weeks
Resulted 2015 2017 2016 2019 2016
Primary
Endpoint
MACE + hosp
for unstable
angina
MACE Time to
event MACE
Time to
event
MACE
Time to event
MACE
HR 1.02; CI 0.89-
1.17
0.91;CI 0.83-
1.000.87; CI
0.78-0.97
TBD 0.74; CI
0.58-0.95
Results Non-inferior
P<0.001
Non-inferior
P<0.001
Non-inferior
P<0.001
Superior P<0.01
TBD Non-inferior
p<0.001
1. Pfeffer,MA et.al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med 2015;373:2247-2257.
2. Holman,RR et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2017;377:1228-1239.
3. Marso, SP et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016;375:311-322.
4. ClinicalTrial.gov: https://clinicaltrials.gov/ct2/show/NCT01394952 (Accessed Jan 31st, 2018)
5. Marso SP et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016;375:1834-1844.
Study ELIXA1 EXSCEL2 LEADER3 REWIND4 SUSTAIN-65
GLP-1RA Lixisenatide Exenatide LR Liraglutide Dulaglutide semaglutide
N 6068 5400 9340 8300 2735
Duration 25 month
median3.2 years 3.8 years Up to 6.5
years104 weeks
Resulted 2015 2017 2016 2019 2016
Primary
Endpoint
MACE + hosp
for unstable
angina
MACE Time to
event MACE
Time to
event
MACE
Time to event
MACE
HR 1.02; CI 0.89-
1.17
0.91;CI 0.83-
1.000.87; CI
0.78-0.97
TBD 0.74; CI
0.58-0.95
Results Non-inferior
P<0.001
Non-inferior
P<0.001
Non-inferior
P<0.001
Superior P<0.01
TBD Non-inferior
p<0.001
1. Pfeffer,MA et.al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med 2015;373:2247-2257.
2. Holman,RR et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2017;377:1228-1239.
3. Marso, SP et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016;375:311-322.
4. ClinicalTrial.gov: https://clinicaltrials.gov/ct2/show/NCT01394952 (Accessed Jan 31st, 2018)
5. Marso SP et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016;375:1834-1844.
CVD – CV Risk Reduction› Canagliflozin
› Empagliflozin
› Liraglutide
CV Risk: PVD and SGLT-2i
› Lower Extremity Amputation1
CANVAS Trial – higher risk of amputations at
toes, feet or legs with canagliflozin (6.3 vs. 3.4
participants with amputations/ 1000 pt. yrs.) (HR
1.97)
Highest absolute risk was with patients who had
a previous amputation or PVD.
1. Neal,B et.al. Canagliflozin and Cardiovasculary and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377:644-657.
CV Risk: PVD and SGLT-2i
› Reasonable Recommendations:
Diabetes Foot Exam
Check Pulses and document
Hx of PVD – if questions, check Art. Duplex
Hx of Amputations
Interval Changes in Foot Health
CKD Improve:
› ACE/ARB medication to improve renal function
› HTN Control
› BGM/A1c Control
Cautions:
› Metformin
› DPP-4’s (linagliptin ok here as it is gut cleared)
› SGLT-2i
› GLP-1RA
CKD – Stage Process 1-5 based on GFR
› Stage 1: 120-90 ml/min/1.73m2
› Stage 2: 89-60 ml/min/1.73m2
› Stage 3a: 59-45 ml/min/1.73m2
› Stage 3b: 44-30 ml/min/1.73m2
› Stage 4: 29-15 ml/min/1.73m2
› Stage 5: <15 ml/min/1.73m2
Cautions:
› Metformin
Cautions:
› Metformin
CKD – Safe Dosing for Metformin
› Stage 3a: 59-45 ml/min/1.73m2
› Stage 3b: 44-30 ml/min/1.73m2
CKD – Safe Dosing for Metformin
› Stage 2: per package
› Stage 3a: 500 mg am and 1 gm pm
› Stage 3b: 500 mg BID
› Stage 4: Withdraw medication/Contraindicated
› Stage 5: Contraindicated.
Metformin should be withdrawn in patients like
to experience acute kidney injury in the context
of severe pathologies
Lalau,JD, et.al. Metformin Treatment in Patients With Type 2 Diabetes and Chronic Kidney Disease Stages 3A, 3B,
or 4. Diabetes Care 2018; https://doi.org/10.2337/dc17-2231.
GI – GERD, Gall Bladder, NASH, Pancreatitis, IBS,
Crohn’s, Ulcerative Colitis, gastroparesis
GI – GERD, Gall Bladder, NASH, Pancreatitis, IBS,
Crohn’s, Ulcerative Colitis, gastroparesis
Metformin: GI Upset both upper and lower
TZD’s, GLP-1RA: Can be beneficial with NASH
DPP-4i: Small pancreatitis risk
GI – GERD, Gall Bladder, NASH, Pancreatitis, IBS,
Crohn’s, Ulcerative Colitis, gastroparesis
GLP-1RA: Pancreatitis contraindication
› Hx of pancreatitis
› Consider high triglycerides
› Active alcoholism
› Do not use with gastroparesis
Endocrine – obesity, PCOS
Obesity:
› Cautions: Insulins, SU’s, glinides, TZD’s
› Beneficial: SGLT-2i, GLP-1RA
PCOS: TZD’s may be of benefit here
HTN
Hyperlipidemia
Obesity
Social – elderly, frail, falls risk
CVD – stroke, MI, CAD, PVD, CHF
CKD
GI – GERD, Gall Bladder, NASH, Pancreatitis, IBS,
Crohn’s, Ulcerative Colitis
Endocrine – obesity, PCOS
Patient Cases:
› A –
› B –
› C –
SU’s Met -GITZD InsulinsGlin DPP-4iSGLT-
2i
GLP-
1RA
Case #1:
41 year old female patient with a Dx of T2DM for the past
7 years.
SU’s Met -GITZD InsulinsGlin DPP-4iSGLT-
2i
GLP-
1RA
Case #2:
68 year old female patient with a Dx of T2DM for the past
19 years.
SU’s Met -GITZD InsulinsGlin DPP-4iSGLT-
2i
GLP-
1RA
Case #3:
39 year old male patient with a Dx of T2DM for the past 4
years.
HTN
Hyperlipidemia
Obesity
Social – elderly, frail, falls risk
CVD – stroke, MI, CAD, PVD, CHF
CKD
GI – GERD, Gall Bladder, NASH, Pancreatitis, IBS,
Crohn’s, Ulcerative Colitis
Endocrine – obesity, PCOS
The Standards of Medical Care in Diabetes can serve as
a guide for us as we choose therapy for patients with diabetes
Co-Morbid Conditions play a critical role in the health of our patients with diabetes and their choice of medications/therapy
Specifically, consideration of CV risk for patients with diabetes is important in deciding therapy with your
patient