Yehuda Handelsman, MD, FACP, FNLA, MACE Courtyard by Marriott, Saturday, April 7, 2018, Sherman Oaks, CA AACE Diabetes Algorithm- Focus on: SGLT2-inhibitors and GLP1-ra Therapies California Chapter of the American Association of Clinical Endocrinologists Presents: Hot Topics in Diabetes and Endocrinology for Primary Care
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Yehuda Handelsman, MD, FACP, FNLA, MACECourtyard by Marriott, Saturday, April 7, 2018, Sherman Oaks, CA
AACE Diabetes Algorithm- Focus on:
SGLT2-inhibitors and GLP1-ra Therapies
California Chapter of the American Association of Clinical Endocrinologists
Presents:
Hot Topics in Diabetes and Endocrinology for Primary Care
Yehuda Handelsman, MD, FACP, FNLA, MACE
Medical Director & Principal investigator
Metabolic Institute of America
Chair
AACE/ACE Diabetes & lipid Scientific Committees
President
Pacific Lipids association
Program Chair & Director
“Heart in Diabetes” 7/13-15/2018, Philadelphia, PN16th WCIRDC 11/29-12/1/2018, Los Angeles, CA
Solo practice
Endocrinology, Diabetes & Metabolism
Tarzana, California
Handelsman Disclosures Research grant- Amgen, AZ, BMS, BI, Gan & Lee, Grifolis, Hamni,
Foley RN, et al. J Am Soc Nephrol. 2005;16:489-495.
x 2.8
x 2.3
x 1.7
x 2.1
x 2.0
x 2.5
8
Type 2 Diabetesis a
Cardiovascular Disease
Treat All Risk Factors
Handelsman Y, 1998
A: Total deaths during 13.3 years (primary endpoint)B: Death from cardiovascular disease, nonfatal stroke, nonfatal myocardial
infarction, CABG, PCI, revascularization for atherosclerotic obstructive disease, outbreak of cardiovascular events including leg amputation (secondary combined endpoint)
C: Number of each event constituting the combined endpoint (bar for A and B indicates SE)
*Outbreak of cardiovascular events, etc. was compared between the standard therapy group (conventional multi-factor treatment applied) and the intensive therapy group (treatment applied with goal set at HbA1c < 6.5%, fasting total cholesterol < 175mg/dL, fasting triglycerides < 150mg/dL, systolic blood pressure < 130 mmHg and diastolic blood pressure < 80 mmHg).
10
Intensive Intervention in T2DM Reduced CV
Death and Improved Vascular Complications
Gaede P. et al.: N Engl J Med. 358(6): 580-591, 2008
*p<0.0001 vs comparator. Exenatide ER, exenatide extended release; IGlar, insulin glargine.Ahmann A et al. Presented at the 77th Scientific Sessions of the American Diabetes Association, 9–13 June 2017, San Diego, CA, USA. Poster Number 1080-P.
*p<0.0001 vs comparator. BW, body weight; exenatide ER, exenatide extended release; IGlar, insulin glargine.Lingvay I et al. Presented at the 77th Scientific Sessions of the American Diabetes Association, 9–13 June 2017, San Diego, CA, USA. Oral presentation 243-OR.
SUSTAIN 1monotherapy
SUSTAIN 2vs sitagliptin
SUSTAIN 3vs exenatide ER
SUSTAIN 4vs IGlar
SUSTAIN 5add-on to basal insulin
Treatment duration: 30 weeks 56 weeks 56 weeks 30 weeks 30 weeksBW at baseline: 92 kg 89 kg 96 kg 93 kg 92 kg
*
* *
**
*
*
*
*
Safety Considerations
with GLP1 Receptor AgonistsGI adverse
events
• Common • Usually dose dependent and transient• Usually reduced with dose titration
Pancreatitis
• Pancreatitis has been reported with postmarketing use of some of incretin agents, although no causal relationship has been established
• Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents
• Labeling for all incretins states these agents should be immediately discontinued if pancreatitis is suspected• Labeling for GLP-1 receptor agonists suggests consideration of other therapies for patients with a history of
pancreatitis
Pancreatic
cancer
• Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents
• Further assessments required from long duration-controlled studies or epidemiological databases
Medullary
thyroid
cancer
• Animal data showed an increased incidence of C-cell tumors with liraglutide and exenatide ER treatment, but confirmatory population studies are lacking
• Labeling for liraglutide and exenatide ER:• Patients should be counseled regarding medullary thyroid carcinoma and the signs/symptoms of thyroid
tumors• Contraindicated in patients with personal/family history of MTC or multiple endocrine neoplasia
syndrome type 2
Renal
impairment
• Renal Impairment has been reported postmarketing, usually in association with nausea, vomiting, diarrhea,
or dehydration. Use caution when initiating or escalating doses in patients with renal impairment. Exenatide
is contraindicated in patients with severe renal insufficiency or ESRD
ER, extended release.
Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.
ADA/EASD/IDF statement concerning the use of incretin therapy and pancreatic disease [news release]. Alexandria, VA: American Diabetes
Association, European Association for the Study of Diabetes, International Diabetes Federation; June 28, 2013.
Invokana [Package Insert] Janssen Pharmaceuticals, Inc. Titusville, NJ.; Lavalle-gonzález FJ, Januszewicz A, Davidson J, et al. Diabetologia. 2013; StenlöfK, Cefalu WT, Kim KA, et al. Diabetes Obes Metab. 2013;15(4):372-82; Burki TK. Lancet. 2012;379(9815):507.
Mechanism
Inhibits sodium-glucose transport protein subtype 2 (SGLT2) which is responsible for at least 90% of glucose reabsorption in the kidney causing blood glucose is eliminated in the urine
Efficacy On Average A1C 0.7-1.1%
AdvantagesInsulin-independent glucose reduction, Low risk of hypoglycemia, Weight loss (to 4% BW), Blood pressure-lowering
with SGLT2 InhibitorsPlacebo-Adjusted Change from Baseline
(Not Head-to-Head Trials)
*Absolute change from baseline (active-controlled trial).
1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. 3. Roden M, et al. Lancet
Diabetes Endocrinol. 2013;1:208-219. 4. Cefalu WT, et al. Lancet. 2013;382:941-950. 5. Nauck MA, et al. Diabetes Care. 2011;34:2015-2022. 6.
Haring HU, et al. Diabetes Care. 2014;37:1650-1659. 7. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473. 8. Wilding JPH, et al. Ann Intern
Med. 2012;156:405-415. 9. Rosenstock J, et al. Diabetes Care. 2014;37:1815-1823.
Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs
Can1 Dap2 Emp3 Can4 Dap5 Emp6 Can7 Dap8 Emp9
Baseline A1C
(%)
8.1 7.8 7.9 8.1 8.2 7.9 8.2 8.6 8.3
Pla
ce
bo
-ad
juste
d
A
1C
(%
)
*
*
1.1
-0.9
-0.4
-0.66-0.52 -0.57
-0.86
-0.64
-0.46
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
Ertugliflozin Mono: Change in A1C Over Time
Ertugliflozin + MET: Change in A1C over Time
A1C
(%
) C
hange f
rom
Baselin
e (
LS
Mean, ±
SE
)
Ertugliflozin + Sita: Change in A1C
Weight Change
with SGLT2 InhibitorsAbsolute Change from Baseline
(Not Head-to-Head Trials)
W
eig
ht
(kg
)
Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs
Can1 Dap2 Emp3 Can4 Dap5 Emp6 Can7 Dap8 Emp9
-3.4
-4.0
-1.4
-3.2 -3.2
-1.6
-2.48 -2.46-2.04
-4.5
-4
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. 3. Roden M, et al. Lancet
Diabetes Endocrinol. 2013;1:208-219. 4. Cefalu WT, et al. Lancet. 2013;382:941-950. 5. Nauck MA, et al. Diabetes Care. 2011;34:2015-2022. 6.
Haring HU, et al. Diabetes Care. 2014;37:1650-1659. 7. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473. 8. Wilding JPH, et al. Ann Intern
Med. 2012;156:405-415. 9. Rosenstock J, et al. Diabetes Care. 2014;37:1815-1823.
Overseas phase III clinical study - A metformin combination study (D1690C00012)
Changes in body composition from the baseline(24 and 102 weeks after start of treatment)
Bolinder J. et al.: Diabetes Obes Metab. 16(2): 159-169, 201445
-5.0
-4.5
-4.0
-3.5
-2.0
-1.5
-0.5
Ch
an
ge
(24 Weeks)
Placebo + MET
(n=86)
Farxiga 10 mg + MET
(n=83)
(102 Weeks)
Placebo + MET
(n=71)
Total lean tissue mass
Total fat mass
0.0
-1.0
-2.5
-3.0
Farxiga 10 mg + MET
(n=66)
-0.65
-0.40
-2.16
-1.00
-1.46
-0.90 -2.80
-1.30
(kg)
Subjects: Patients with type 2 diabetes mellitus poorly controlled as to blood glucose by uncombined metformin (MET) therapy [182 patients included in safety analysis; 180 patients included in efficacy analysis (FAS)]
Methods: A randomized, double-blind, placebo-controlled, multicenter, parallel-group comparative study. Subjects were allocated at random to the Forxiga 10 mg + MET group and the placebo + MET group. Once daily treatment (combined with MET 1,500 mg/day) in the morning was continued for 102 weeks, and mean adjusted change in body composition at 24 and 102 weeks after the start of treatment was analyzed.
Safety: The incidence of adverse reactions was 19.8% (18/91) in the Forxiga 10 mg + MET group and 14.3% (13/91) in the placebo + MET group.
Adjusted mean change (95% CI)
FAS
(including data after hyperglycemia rescue therapy) MET: Metformin
Note) The starting dose level of Forxiga Tablet in Japan is 5 mg/day. Before use, reference to the latest package insert is needed.
Blood Pressure Changes
with SGLT2 Inhibitors
46
Absolute Change from Baseline
(Not Head-to-Head Trials)
1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Ferrannini E, et al. Diabetes Care. 2010;33:2217-
2224. 3. Roden M, et al. Lancet Diabetes Endocrinol. 2013;1:208-219. 4. Cefalu WT, et al. Lancet. 2013;382:941-
950. 5. Nauck MA, et al. Diabetes Care. 2011;34:2015-2022. 6. Haring HU, et al. Diabetes Care. 2014;37:1650-
1659. 7. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473. 8. Wilding JPH, et al. Ann Intern Med.
2012;156:405-415. 9. Rosenstock J, et al. Diabetes Care. 2014;37:1815-1823.
Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs
Can1 Dap2 Emp3 Can4 Dap5 Emp6 Can7 Dap8 Emp9
-5.0-4.6
-6.4
-3.6-4.3
-6.7
-5.0 -5.2
-3.8
-8
-7
-6
-5
-4
-3
-2
-1
0
S
ys
toli
c B
P (
mm
Hg
)
Hypoglycemia with SGLT2 Inhibitors
Percentage of Patients Reporting Hypoglycemia
(Not Head-to-Head Trials)
1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. 3. Roden M, et al. Lancet
Diabetes Endocrinol. 2013;1:208-219. 4. Cefalu WT, et al. Lancet. 2013;382:941-950. 5. Nauck MA, et al. Diabetes Care. 2011;34:2015-2022. 6.
Haring HU, et al. Diabetes Care. 2014;37:1650-1659. 7. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473. 8. Wilding JPH, et al. Ann Intern
Med. 2012;156:405-415. 9. Rosenstock J, et al. Diabetes Care. 2014;37:1815-1823.
Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
• Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
• To reduce the risk of major adverse CV events (CV death, non-fatal MI, or non-fatal stroke) in adults with type 2 diabetes mellitus and established CV disease
• Not for treatment of type 1 diabetes or diabetic ketoacidosis
• Has not been studied in combination with prandial insulin
Indications and usage
Victoza® [package insert]. Princeton, NJ: Novo Nordisk Inc.; August 2017
Contraindications
• Liraglutide is contraindicated in patients with:• Personal or family history of MTC or MEN2
• History of serious hypersensitivity to liraglutide or any product component
Initiate dosing at 0.6 mg/day for 1 week to reduce GI
symptoms
Increase dose to 1.2 mg/day after 1
week
Increase dose to 1.8 mg/day, if 1.2 mg does not result in
acceptable glycemic control
Dose initiation and titration
Limitations of use
Not recommended as first line language removed
Language “not studied in patients with hx of pancreatitis – consider other antidiabetic therapies” removed. Added “unknown if patients with a hx of pancreatitis are a higher risk of pancreatitis with Victoza”
Warnings and Precautions: Added “Acute Gallbladder disease: if cholelithiasis or cholecystitis are suspected, gallbladder sutdies are indicated”
Liraglutide- New Indication post LEADER
Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1607141
Sustain 6: Cardiovascular Outcomes
EMPA-REG
Primary outcome: 3-point MACE
59
HR 0.86
(95.02% CI 0.74, 0.99)
p=0.0382*
Cumulative incidence function. MACE, Major Adverse
Cardiovascular Event; HR, hazard ratio.
* Two-sided tests for superiority were conducted (statistical
significance was indicated if p≤0.0498)
EMPA-REG: Renal function over time
BL, baseline; PBO, placebo; EMPA, empagliflozin; FU, follow-up; LMDT, last measurement during treatment. Wanner C et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1515920.
CVReal: Absolute Rates of CV Events in Patients reated with SGLT-2i- Secondary & Primary Prevention
Cavender M at al.. Presented at ADA Scientific Sessions; June 9 – May 13, 2017; San Diego, CA.
Summary: DM Contemporary Care
• Identify individual treatment goals
• Institute personalized comprehensive care for people with diabetes
▪Start intensive lifestyle modification for glycemic control while concomitantly starting medications
▪Choose medications based on safety, efficacy and characteristics
▪Monitor every three months intensify/advance treatment as needed
• Per the AACE Algorithm Consider GLP1ra and SGLT2i as first options with metformin based on safety efficacy in reducing glucose and positive effect on CV risk parameters especially weight and blood pressure