New Treatment Guidelines & Emerging Issues in Diabetes

Candis M. Morello, Pharm.D., CDE, FCSHP, FASHP Professor of Clinical Pharmacy Associate Dean for Student Affairs University of California, San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences Ambulatory Care Pharmacist Specialist and Director, Diabetes Intense Medical Management Clinic Veterans Affairs San Diego Healthcare System

Disclosure Dr. Morello has no conflicts of interest to disclose.

Learning Objectives 1. Describe the newest American Diabetes Association treatment guidelines for helping patients achieve their glycemic goals. 2. Identify emerging safety precautions as well as cardiovascular effects of specific diabetes medications. 3. Using a case-based approach provide personalized care incorporating the latest treatment guidelines and therapeutic issues.

Diabetes Today: New Era Diabetes ◦Target pathophysiology by combining treatment options

Current treatment guidelines Clearer picture of second line agents? ◦SGLT2 inhibitor data & safety update ◦GLP1-agonist data & safety update

Case

CASE

68 yo male, T2DM since 2000 presents to clinic. PMH:

T2DM, HTN, hyperlipidemia with CAD, morbid obesity, osteoporosis, GERD, microalbuminuria

DM Meds: metformin 1gm BID, glipizide 10mg daily Other Daily Meds: fosinopril 40mg, aspirin 81mg, atorvastatin 80mg, omeprazole 20mg, alendronate 10 mg

ROS:

Polyuria Q 20 min & nocturia 4-6x/nt; affecting productivity,

Other: No SMBG, afraid of needles, married, retired, no family history of cancer or heart disease Current

A1C

Wt

BMI

BP

LDL

TG

HDL

TC

GFR

Labs:

9.8

280

36

134/78

65

140

35

165

88

Hyperglycemia in T2D:Pathophysiological Defects & Other Contributors

Schwartz SS, Epstein S, Corkey BE, et al. The time is right for a new classification system for diabetes Rationale and implications of the b-cell–centric classification schema. Diabetes Care. 2016;39:179– 186.

FDA-Approved Diabetes Therapies Oral

–Sulfonylureas ◦ Glipizide , Glimepizide

–Biguanide ◦ Metformin

–Non-sulfonylurea insulin secretagogues ◦ Repaglinide, Nateglinide

–Alpha-glucosidase inhibitors ◦ Acarbose, Miglitol

–Thiazoladinediones ◦ Rosiglitazone, Pioglitazone

–DPP4 Inhibitors ◦ Sitagliptin (Januvia) ◦ Saxagliptin (Onglyza) ◦ Linagliptin (Tradjenta) ◦ Alogliptin (Nesina)

SGLT-2 Inhibitors

–Insulin ◦ Rapid acting

– Insulin Powder

◦ Insulin lispro, Insulin aspart, Insulin glulisine (Apidra)

• Rapid acting (Afrezza)

◦ Short acting ◦ Regular insulin

◦ Intermediate acting ◦ NPH

◦ Long acting ◦ Insulin detemir (Levemir) ◦ Insulin glargine (Lantus ;U100 & U300) ◦ Insulin degludec (Tresiba ; U100 & U300)

–Amylin analog ◦ Pramlintide (Symlin)

–GLP-1 Receptor Agonist (incretin mimetic) ◦ Exenatide (Byetta), Liraglutide (Victoza)

–GLP-1 Receptor Agonist ONCE WEEKLY ◦ Exenatide (Bydureon),

◦ Canagliflozin (Invokana)

◦ Albiglutide (Tanzeum)

◦ Dapagliflozin (Farxiga)

◦ Dulaglutide (Trulicity)

◦ Empagliglozin (Jardiance)

Inhaled

Injectable

Rev090916CMM

How Diabetes Medications Target Pathophysiologic Defects of Diabetes: Combining Medications is Key! Brain: GLP-1 RA, amylin Muscles and tissues: TZD, Metformin (insulin sensitivity), Insulin (peripheral glucose uptake)

Liver: Metformin, Insulin, GLP-1 RA, amylin analog, DPP-4 Inh (↓ Hepatic glucose output)output)

Stomach: GLP-1 RA and amylin analog (slows gastric emptying)

Gut:

analog (satiety)

Mouth: GLP-1 RA, amylin analog

(reduced

caloric intake)

Pancreas/Alpha cells: GLP-1 RA, amylin analog, DPP-4 Inh ( postprandial glucagon secretion)

Pancreas/Beta cells: SFU, Glinides (insulin secretion) GLP-1 RA, DPP-4 Inh (glucose-dependent insulin secretion)

Gut (other):

GLP-1 RA

Kidneys:

AGI /BAS (delays CHO breakdown/absorption)

SGLT-2 inh (increases glucose urinary output)

Key- black orals, grey injectables. Image developed from images at: www.topnews.in/healthcare/node?page=12, www.jamesgillespiesps.ik.org, www.beyondbiology.org/beyondbiology.org/index on 6/18/10.Revised 9/7/16 ©CMMorello

ADA 2016Diabetes Diagnosis- new emphasis Diagnostic Criteria# OR

FPG*

≥ 126 mg/dL

Casual Glucose

≥ 200 mg/dL**

A1C

≥ 6.5%

OGTT post 75 gm glucose load

≥ 200 mg/dl at 2 hrs

OR OR

# in the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing. * Fasting: no food for 8 hours **accompanied by polyuria, polydipsia, or unexplained weight loss

ADA Standards of Medical Care in Diabetes-2016. Diabetes Care 2016;39(supp 1).

Guidelines for Glycemic Control 2016:

ADA/EASD Goals

AACE/ACE Goals

6.5 if NO concurrent serious illness ¬ at risk for < 7.0% hypoglycemia (individualization)* > 6.5 if concurrent serious illness and at risk for hypoglycemia

HbA1C Preprandial glucose Postprandial glucose

80-130 mg/dL

< 180 mg/dL

110 140

* ADA A1C goal Individualization is key:  Tighter targets (6.0 - 6.5%) for younger, healthier  Looser targets (7.5 - 8.0%+) for older, comorbidities, hypoglycemia prone, etc.

-

Avoidance of hypoglycemia

ADA Standards of Medical Care in Diabetes-2016. Diabetes Care 2016;39(supp 1). AACE/ACE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM 2016 Endocr Pract.2016;22:84-113

ADA: Selecting a Personalized A1C Goal

Frail or high fall risk

Consider A1C 6-6.5%

Consider A1C 7.5-8% or higher

ADA. 6. Glycemic Targets. Diabetes Care 2015;38(suppl 1):S37. Figure 6.1; adapted with permission from Inzucchi SE, et al. Diabetes Care, 2015;38:140-149

2012 T2DM Treatment General Recommendations & Algorithm

From Figure 2 in Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ADA T2D 2015 Treatment: A Patient Centered Approach

ADA. 7. Approaches to Glycemic Treatment. Diabetes Care 2015;38(suppl 1):S43. Figure 7.1; adapted with permission from Inzucchi SE, et al. Diabetes Care, 2015;38:140-149

Diabetes & Complications- U.S. Health Impact 7th leading cause of death Renal Disease

Life expectancy ↓ 5 to 10 yr

Diabetes

Blindness

Amputations

Nerve Damage in 60% to 70% of patients

*Diabetes is the leading cause of renal failure, new cases of blindness, and nontraumatic amputations

Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Accessed on 9/7/16

Cardiovascular disease 2-4 times

T2D & CHD: Increasing Prevalence Globally, 387 million people are living with diabetes1

• At least 68% of people >65 years with diabetes die of heart disease2 Mortality risk associated with diabetes (n=820,900)3 Hazard ratio (95% CI) (diabetes vs no diabetes)

3

This will rise to 592 million by 20351

2

1

0 CV death

1. IDF DIABETES ATLAS 6TH EDITION 2014 HTTP://WWW.IDF.ORG/DIABETESATLAS; 2. CENTERS FOR DISEASE CONTROL AND PREVENTION 2011; 3. SESHASAI ET AL. NEJM 2011;364:829-41

All-cause mortality

Diabetes is associated with significant loss of life years 7

Men

Non-vascular deaths

Years of life lost

6

Vascular deaths

5

4

4

3

3

2

2

1

1

0

0

0 40

50

60

70

80

90

Women

6

5

Age (years)

.

7

0 40

50

60

70

80

Age (years)

On average, a 50-year-old PWD and no vascular disease history will die 6 years earlier compared to someone without diabetes

SESHASAI ET. NEJM 2011;364:829-41

90

Impact of Intensive Therapy in Type 2 Diabetes Summary of Major Clinical Trials: BUT

Subset Evaluations Show Reduced CV Outcomes if shorter duration of DM, without significant pre-existing complications

Initial Trial

Long Term Follow-up

Study

Microvascular

Macrovascular

Mortality

UGDP

↔

↔

↔

UKPDS DCCT/EDIC* ACCORD ADVANCE

VADT Meinert CL. Diabetes. 1970;19(suppl):789-830. Goldner MG. JAMA. 1971;218(9):1400-1410. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865. Holman RR. N Engl J Med. 2008;359(15):1577-1589. DCCT Research Group. N Engl J Med. 1993;329;977-986. Nathan DM, et al. N Engl J Med. 2005;353:2643-2653.

↓ ↓

↓ ↓

↔ ↔

↓ ↓ ↔

↓ ↓ ↔ ↔ ↔

Gerstein HC, et al. N Engl J Med. 2008;358:2545-2559. Patel A, et al. N Engl J Med. 2008;358:2560-2572. Duckworth W, et al. N Engl J Med. 2009;360. Obesty Lecture by Saanley Schwartz, MD

*T1DM study.

↔ ↔

↓ ↔

↑(unadj.), ↔ (adj.)

↔ ↔ ↑- likely due to hypoglycemia and weight gain

T2D Landmark Studies: 2015 & 2016 FDA CV safety studies requirement: ◦cardiovascular safety study for a diabetes drug to show cardiovascular benefit, rather than just lack of harm

EMPA-REG: Empagliglozin LEADER: Liraglutide

SGLT-2 Inhibitors

Canagliflozin (Invokana)

Dapagliflozin (Farxiga)

J&J

Astra Zenica

Empagliflozin (Jardiance) Boehringer Ingelheim & Eli Lilly

FDA Approval March 2013

January 2014

August 2014

SGLT-2 Inhibitors MOA ◦ inhibit the reabsorption of glucose into the blood ◦ urine glucose output

SGLT2 Inh

-

Blocks approximately 50-80 grams of glucose per day from being reabsorbed into the blood

EMPA-REG OUTCOME® Trial design

Placebo (n=2333)

Randomized and treated (n=7020)

Empagliflozin 10 mg (n=2345)

Randomized, double-blind, placebo-controlled CV outcomes trial

Empagliflozin 25 mg (n=2342)

Screening (n=11531)

Study medication was given in addition to standard of care. Key inclusion criteria: ◦ Adults with type 2 diabetes and CV disease (heart attack, stroke, etc.) ◦ HbA1c 7–10%; eGFR ≥30 mL/min/1.73m2 (MDRD)

• 1° outcome = ‘3-point MACE’ (CV death, non-fatal MI, non-fatal stroke)

• Baseline characteristics all groups: mean age 63, male 71-72%, A1C 8% CV, CARDIOVASCULAR; BMI, BODY MASS INDEX; EGFR, ESTIMATED GLOMERULAR FILTRATION RATE; MDRD, MODIFICATION OF DIET IN RENAL DISEASE.

22

EMPA-REG OUTCOME:

3-point MACE and 4-point MACE Patients with event/analysed Empagliflozin Placebo 3-point MACE

490/4687

HR

(95% CI)

p-value

282/2333

0.86

(0.74, 0.99)*

0.0382

CV death

172/4687

137/2333

0.62

(0.49, 0.77)