Managing T2D in 2017

Matt Bouchonville
Endocrinology Division
Family Medicine Resident School
February 8, 2017
 Objectives

• ADA 2017 guidelines – anything we need to

know this year?

• Emerging cardiovascular benefits of newer

diabetes therapies
What hasn’t changed? The “ABCs”
• A1c <7% for most patients
• Fasting & premeal BG targets (2015):
• 80-130 mg/dL

• Blood pressure targets (2015):

• 140/90 mmHg for most patients

• Cholesterol (statin) therapy (2015):

• Old = LDL target driven (<100 or <70 mg/dL)
• New = CVD risk driven
ADA 2017: Statin treatment
 (IMPROVE-IT)

Modest reduction
in composite CV
outcome with
addition of
ezetimibe to statin
post-ACS
What are some of the changes to
ADA recommendations?
 1. 42 year-old woman with type 2 diabetes
returns to clinic with BP 148/92 mmHg. She
has no microvascular complications. Which
of the following medications should be
started for hypertension?

A. Lisinopril
B. Losartan
C. Hydrochlorothiazide
D. Amlodipine
E. Any of the above are appropriate
 Answer

E. Any of the above

 Each of these classes
found to reduce CV
events in hypertensive
patients with diabetes in
two systematic reviews

*Note: ACE or ARB is still favored in the setting of

albuminuria
JAMA 2015;313:603-615.

BMJ 2016;352:i438.
 2. A 52 year-old man has long-standing
type 2 diabetes complicated by neuropathy.
A1c is 7.1% on metformin. Metformin use is
associated with deficiency of which of the
following vitamins?

A. Vitamin A
B. Vitamin B-12
C. Vitamin C
D. Vitamin D
E. Vitamin E
 Answer

B. Vitamin B-12
Long term metformin use was associated with an
increased risk of B12 deficiency (<203 pg/mL) in
the Diabetes Prevention Program Outcomes Study
(DPPOS)
J Clin Endocrinol Metab 2016;101(4):1754-61.
QUESTION
 3. A 34 year-old obese woman with family history of
type 2 diabetes and negative GAD antibodies
presents with new diagnosis of type 2 diabetes. A1c
is 10.1% and fasting BG is 312 mg/dL. In addition to
lifestyle management, which of the following
treatments might be most appropriate for this patient?

A. None (lifestyle management alone)

B. Metformin
C. Metformin plus glipizide
D. Metformin plus basal insulin
E. Armour thyroid
 Answer

D. Metformin plus basal insulin

Algorithm has been revised!
 What if baseline A1c >10% or

BG >300 mg/dL or

patient is markedly symptomatic or

if suboptimal control on max non-

insulin therapy?
Insulin glargine + TID lispro
vs
Insulin glargine + exenatide
Exenatide therapy:
• Less nocturnal hypoglycemia
• HbA1c Weight
Higher patient-satisfaction
• Increased risk GI side effects
 What if there are
contraindications to GLP-1
agonist therapy (i.e.
gastroparesis, history of
pancreatitis, financial barriers)?
 Adding rapid-acting insulin to basal
insulin: One meal? Two? All meals?

Endocr Pract 2011;17(3):395.

 Objectives

• ADA 2017 guidelines – anything we need to

know this year?

• Emerging cardiovascular benefits of newer

diabetes therapies
 SGLT2-
inhibitors
 FDA Approval
March 2013 – Canagliflozin (Invokana)

January 2014 – Dapagliflozin (Farxiga)

August 2014 – Empagliflozin (Jardiance)

Contraindications: Severe renal impairment

Adverse effects: Hypotension/dehydration, genital

mycotic infections, hyperkalemia, DKA?, fractures?
• 1,450 T2D patients uncontrolled (mean A1c
7.8%) on metformin
• Randomized to canagliflozin 100 mg, 300 mg,
or glimepiride (titrated up to 6-8 mg/day)
• 52 week core period plus 52 week extension
Diabetes Care 2015;38:355-364.
Similar A1c reduction (slightly
better in CANA 300 mg)

Diabetes Care 2015;38:355-364.

Significant weight loss in CANA
groups

Sulfonylurea

SGLT2I

Diabetes Care 2015;38:355-364.

Modest BP lowering effect of CANA

Sulfonylurea

SGLT2I

Diabetes Care 2015;38:355-364.

Less hypoglycemia in CANA groups
% Hypoglycemia

Diabetes Care 2015;38:355-364.

 SGLT2 inhibitor-associated AEs
CANA CANA
GLIM
100 mg 300 mg
Genital
Male 1.9% Male 9.5% Male 9.1%
mycotic
Female 2.7% Female 13.9% Female 15.6%
infections

UTI 6.8% 10.6% 8.7%

Osmotic
diuresis- 2.1% 5.8% 6.6%
related AEs*
*including dry mouth, nocturia, urgency, polyuria, thirst
Diabetes Care 2015;38:355-364.
Is there any cardiovascular benefit
of SGLT2 inhibitor therapy?

EMPA-REG Trial
• 7,020 T2D patients with CVD
Primary outcome:
• Mean age 63 yrs, A1c ~8%, BMI ~31
Composite of death from cardiovascular
• Randomized to empagliflozin 10mg, 25mg, or
causes, nonfatal MI, nonfatal CVA
placebo (double blind)
N Engl J Med 2015;373:2117-2128.
Modest A1c reduction with EMPA

Placebo

Empagliflozin
29% of placebo,
23% of EMPA
discontinued tx
prematurely

N Engl J Med 2015;373:2117-2128.

Modest reduction (14%) in primary
outcome
Placebo

Empagliflozin

N Engl J Med 2015;373:2117-2128.

CV Death reduced by 38%

Placebo

Empagliflozin

N Engl J Med 2015;373:2117-2128.

HF Hospitalization reduced by 35%

Placebo

Empagliflozin

N Engl J Med 2015;373:2117-2128.

 What is the explanation for the
reduction in CV death?
No difference in rates of MI or CVA

Only 10% with HF at baseline

Diuretics (excepting aldosterone antagonists)

have not been shown to reduce mortality
 What is the explanation for the
reduction in CV death?

Related to modest BP reduction (~4 mmHg)?

Related to modest weight loss (~2 kg)?

Unidentified mechanism?
 DKA occurred in ≤ 0.1% of
subjects in all groups

• Warning: SGLT2 inhibitors may

result in diabetic ketoacidosis
May 2015 • Based on 20 reports
• Several other cases reported
since
 • Warning: Canagliflozin may
increase fracture risk
Sept 2015
• Canagliflozin associated with
reduced total hip BMD,
increased fracture rate
• Recent meta-analysis 38
RCTs (38K pts) reported no
increased fracture rate

J Clin Endocrinol Metab 2016;101(1):157 and 44.

Diabetes Obes Metab 2016;PMID 27407013.

GLP-1 agonists
GLP-1 Modulates Numerous Functions

GLP-1: Secreted
Promotes satiety and
upon the reduces appetite
ingestion of food

Alpha cells:
 Postprandial
glucagon secretion

Beta cells: Liver:

Enhances glucose-  Glucagon reduces
dependent hepatic glucose output
insulin secretion
Stomach:
Helps regulate
gastric emptying
Data from Flint A, et al. J Clin Invest. 1998;101:515-520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422
Data from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Data from Drucker DJ. Diabetes. 1998;47:159-169
GLP-1 is normally degraded by the
DPP-4 Enzyme
GLP-1 agonist
DPP-4 inhibitor (resistant to
DPP-4
Meal degradation)
DPP-4
Enzyme

Release of Rapid Inactivation Inactive GLP-1

Active GLP-1
 GLP-1 agonists

• Exenatide
• Liraglutide
• Dulaglutide
• Albiglutide
• Lixisenatide
Is there any cardiovascular benefit
of GLP-1 agonist therapy?

LEADER Trial
• 9,340 T2D patients with high CVD risk
• Mean age 64 yrs, A1c 8.7%, BMI 32.5
• Randomized to liraglutide 1.8mg or placebo
(double blind)
Modest A1c reduction compared to
placebo

Placebo

Liraglutide

N Engl J Med 2016;375:311-322.

Modest weight reduction compared to
placebo

Placebo

Liraglutide

N Engl J Med 2016;375:311-322.

CV death reduced by 22%

Placebo

Liraglutide

N Engl J Med 2016;375:311-322.

 Other findings of LEADER Trial

• All cause death reduced by 15%

• Total myocardial infarctions reduced by 14%
• No significant difference in nonfatal MI,
stroke, or hospitalization for heart failure

N Engl J Med 2016;375:311-322.

 LEADER Trial: Adverse events
associated with liraglutide
• No difference in overall AEs
• Less severe hypoglycemia
• More discontinuation of therapy due to
nausea (1.6% vs 0.4%)
• No difference in pancreatitis
• No difference in pancreatic cancer after 3.8
years? (13 vs 5 cases; p=0.06)
N Engl J Med 2016;375:311-322.
 Objectives

• ADA 2017 guidelines – anything we need to

know this year?

• Emerging cardiovascular benefits of newer

diabetes therapies
Questions?