5/7/2016 1 Diabetes Medication Update for Healthcare Professionals 21 May 2016 Joyce M. Vergili, EdD, RD, CDN, CDE, FAND Doctor of Education (Nutrition Education) Registered Dietitian | Certified Dietitian-Nutritionist Certified Diabetes Educator Fellow of the Academy of Nutrition and Dietetics [email protected]1 Overarching Objective This session will • increase your knowledge of 8 of the 12 classes of FDA- approved diabetes medications, with an emphasis on those approved since 2012 • enhance your confidence when – assessing and educating patients – discussing patients taking these medications with physicians and other healthcare professionals 2 Specific Objectives At the end of the program, you should be able to ... 1. explain the underlying metabolic defects of Type 2 diabetes for which medications have been developed: • insulin resistance • progressive decrease in insulin production • blunted incretin response • increased renal threshold for glucose 3
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5/7/2016
1
Diabetes Medication Update for Healthcare Professionals
21 May 2016
Joyce M. Vergili, EdD, RD, CDN, CDE, FAND Doctor of Education (Nutrition Education)
At the end of the program, you should be able to ...
3. accurately describe the mechanisms of action, safety, efficacy, contra-indications, and major patient-education teaching points for medications receiving FDA approval since 2012
At the end of the program, you should be able to ...
4. identify reliable resources for more information
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A SHORT HISTORY OF MEDICATION OPTIONS FOR TYPE 2 DIABETES
From the 1950’s until 1994, there were only 2 classes of diabetes medications:
• Sulfonylureas
• Insulin
1994: Metformin
1999: Thiazolidinediones
(Rosiglitazone [Avandia] & Pioglitazone [Actos])
. . . Fast forward . . .
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March 2013: Invokana (Canagliflozin) – an SGLT2 inhibitor 12 Classes of Meds
Oral
1. Biguanides (Metformin)
2. Sulfonylureas
3. Meglitinides
4. Thiazolidinediones (TZD)
5. -glucosidase inhibitors*
6. DPP-4 Inhibitors
7. Bromocriptine (Cycloset)*
8. Colesevalam (Welchol)*
9. Sodium-glucose co-transporter-2
(SGLT2) inhibitors
Injectable 10. GLP-1 Receptor Agonists
11. Pramlintide (Symlin)*
12 (a). Insulin
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Insulin
secretagogues
Inhalable 12 (b). Insulin
* α-glucosidase inhibitors,
colesevalam, bromocriptine,
pramlintide – generally not
recommended due to modest
efficacy, frequency of administration
and/or limiting side effects.
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Type 2 Diabetes (T2DM)
ADA. Diabetes Care. 2016;39 (Suppl 1), pg S13
Type 2 diabetes is due to a progressive
loss of insulin secretion on the
background of insulin resistance
Decreased glucose uptake by
muscles & adipose tissue
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Increased hepatic glucose output
Metabolic Defect #1 in T2DM:
Insulin Resistance
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Metabolic Defect #2 in T2DM: Progressive Loss of Insulin Secretion
By the time T2
diabetes is
diagnosed,
-cell function
may have
declined by
50% or more
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Decreased insulin secretion from
-cells of the pancreas
Metabolic Defect #2 in T2DM:
Progressive Loss of Insulin Secretion
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Metabolic Defect #3 in T2DM: Blunted Incretin Effect
Kendall DM et al. Am J Med. 2009;122:S37-S50.
• Progressive
deficiency of
GLP-1
(glucagon-like
peptide-1)
• Progressive
β-cell
resistance to
the action of
GIP (glucose-
dependent
insulinotropic
polypeptide )
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Incretins: GLP-1 (glucagon-like peptide-1) & GIP
(glucose-dependent insulinotropic polypeptide) • Proteins that are secreted by the small
intestine when food is ingested
• Stimulate β-cells to secrete insulin
• Inhibit glucagon secretion from α-cells
• Rapidly degraded by the enzyme dipeptidyl
peptidase-4 (DPP-4)
• In T2DM, incretin effect is blunted
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Kidneys:
Renal glucose threshold is
increased to ~200-250 mg/dL
from normal threshold of
~180 mg/dL
Metabolic Defect #4 in T2DM
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Medications that Address
the Metabolic Defect of
Insulin Resistance
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Biguanides – ↓ hepatic glucose output
• Metformin (Glucophage, Glumetza, Fortamet)
“First line therapy,” if not contraindicated • Lowers A1C by ~1 to 1.2 percentage points • Contraindicated in hepatic impairment and HF • Until April, contraindicated in all patients
with renal impairment . . .
Insulin resistance: Increased
hepatic glucose output
Metabolic Defect:
Medication to Address:
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Metformin-containing Drugs: Drug Safety Communication - Revised Warnings for Certain Patients With Reduced Kidney
Function
• After reviewing medical literature, FDA concluded that metformin can be used safely in some patients with mild or moderate kidney impairment
• FDA is requiring changes to metformin labeling:
– Metformin is contraindicated if eGFR <30 mL/min
– Starting metformin if eGFR is between 30 and 45 mL/min is not recommended
– Obtain an eGFR at least annually
– In pts on metformin whose eGFR later falls <45, assess benefits and risks
When food is ingested, the intestines secrete the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide)
Glucose
Incretin hormones stimulate insulin secretion in a glucose-dependent manner
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Incretin Hormones are then Degraded by DPP-4
DPP-4 is an enzyme that rapidly breaks down the incretins (half-life of incretins is only ~2 minutes)
DPP-4
Insulin
Glucagon
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Incretin-Based Therapies: DPP-4 Inhibitors (oral)
Glucose DPP-4
DPP-4 inhibitors slow down the inactivation of incretin
hormones, thereby prolonging their survival.
The resulting higher concentration of active incretins • increases insulin secretion in a glucose-dependent manner • suppresses glucagon secretion.
“Smart secretagogues”
DPP-4 inhibitors (see hand-out packet, pg 3)
In general Sitagliptin Saxagliptin Linagliptin Alogliptin Efficacy ↓ A1C by
~0.75
percentage
points
↓ A1C by
~0.7 to 0.8
percentage
points
↓ A1C by
~0.5 to 0.9
percentage
points
↓ A1C by
~0.4 to 0.7
percentage
points
↓ A1C by ~0.4 to 0.6 percentage points
Advantages Low risk of
hypoglycemia Weight neutral
No dose change
needed for ↓
renal function
High selectivity for DPP-4 enzyme
Dosing Once daily,
without regard to
time of day,
without regard to
food (take same
time everyday)
100 mg in
normal renal 50 mg / 25
mg in
moderate /
severe renal
impairment
5 mg in
normal renal
function 2.5 in renal
impairment
5 mg/day for all
– no dose
adjustment
needed in renal
disease
25 mg in normal renal
12.5 mg / 6.25 mg in moderate / severe renal impairment
Sodium-glucose co-transporter-2 • SGLT2 actively transports glucose across the proximal
convoluted tubule of the kidney so it can be reabsorbed into the blood
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Sodium-glucose co-transporter-2
• The renal glucose threshold in someone without
diabetes is ~180 mg/dL
• In diabetes, the renal glucose threshold is
increased to ~200-250 mg/dL
• When the maximum capacity of the renal tubule to
reabsorb glucose is exceeded, glucose is excreted
into the urine
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When SGLT2 is blocked
• Renal threshold is lowered
• Less glucose is reabsorbed by the kidneys
• More glucose is excreted into the urine
• Plasma glucose decreases
http://www.invokanahcp.com/mechanism-of-action
GLUCOSE
Invokana (Canagliflozin) blocking SGLT2
from reabsorbing glucose from kidney
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SGLT2 inhibitors • ↓ A1C by ~0.5 to 1 percentage point
Renal Function • eGFR must be > 45 mL/min (Invokana &
Jardiance) and > 60 mL/min (Farxiga)
Advantages • Low risk of hypoglycemia (~3%) • ↓ weight (~3 to 5 lb)
– 1/3 is LBM (including fluid) & 2/3 is fat loss
– ~50 to 70 g gluc (≈ 200-280 kcal) “spilled” into urine/day
• ↓ systolic BP by ~3 to 5 mm Hg 64
SGLT2 inhibitors
Disadvantages
• ↑ LDL by ~3 to 8%
– Canagliflozin (Invokana) ↑ HDL by ~8%
– Empagliflozin (Jardiance) associated with significantly lower rates of all-cause and cardiovascular death; lower hospitalizations for heart failure (Garber, 2016)
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SGLT2 inhibitors
Most common side effects • Genital yeast infections • UTI • Increased urination • Dehydration hypotension • Hyperkalemia (Invokana only)
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SGLT2 inhibitors Use with caution in • Patients > 65-75 years old
– Higher incidence of adverse reactions related to volume depletion (hypotension, postural dizziness, syncope, dehydration)
– Higher incidence of UTIs (Jardiance)
– Lower efficacy (Invokana)
• Patients at risk for hyperkalemia (on ACEi or ARB) (Invokana)
• Patients with h/o bladder cancer, bladder cancer risk factors, hematuria (Farxiga)
• Patients in whom DKA may develop
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SGLT2 inhibitors: DKA & UTI FDA Warnings (5/15/15 & 12/4/15) • DKA
– From Mar 2013 to May 2015, FDA identified 73 cases of ketoacidosis in pts with T1 or T2 DM treated w/ SGLT2i
– All patients required hospitalization or treatment in an ED – Ketoacidosis not immediately recognized – BG levels were below
those typically seen in DKA (“euglycemic DKA”) • UTI
– FDA also identified 19 cases of life-threatening blood infections (urosepsis) and kidney infections (pyelonephritis) that started as UTIs between Mar 2013 and Oct 2014.
– All pts were hospitalized; few required dialysis. • An FDA safety review has resulted in adding warnings to the labels
of SGLT2 inhibitors about the risks of too much acid in the blood and of serious UTIs.
Pancreatitis, N/V, injection site rxns, gastro-paresis; monitor renal function
Nausea, hypo-glycemia
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Summary of Diabetes Medications
Most medications for Type 2 diabetes address the underlying pathophysiologic defects
– Progressive ↓ in insulin secretion
– Insulin resistance
– ↑ hepatic glucose output
– Blunted incretin response
– ↑ renal glucose threshold
• Other medications (not discussed in this presentation)
– Modify physiologic processes related to nutrient absorption
(α-glucosidase inhibitors) or have mechanisms of action
that are not completely understood (Cycloset, Welchol)
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↓ insulin secretion
↓ GLP-1 &
resistance to GIP
↓ glucose uptake
hepatic glucose
production
Stimulate the satiety center
↑ renal
glucose
threshold
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Metformin
Insulin
secret-
agogues
TZD
Incretin-based therapies
SGLT2 inhibitors
↓ rate of gastric emptying
GL
P-1
glucose uptake
↓ hepatic glucose
production
Insulin secretion
↓ renal
glucose
threshold Insulin secretion &
↓ glucagon secretion
GLP-1 GLP-1
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• Metformin, unless contraindicated, is considered first-line therapy
• If Metformin is contraindicated or poorly tolerated, or if pt needs dual or triple therapy, medications should be chosen on the basis of factors such as
– Efficacy
– Complementary mechanisms of action
– Risks / potential side effects (hypoglycemia, wgt gain, nausea, DKA,
pancreatitis, heart failure)
– Cardiovascular outcomes
– Cost / insurance coverage
– Dosing frequency (QD, TID, QW) or complexity
– Consideration of patient’s goals and values
Summary of Guidelines
Reliable resources for more information
• ADA Position Statements
• AACE Consensus Statement
• NIH’s Daily Med website
• Prescribing Information
• DiabetesPro SmartBrief (email alerts)
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Position & Consensus Statements • Inzucchi SE et al. Management of hyperglycemia in type 2
diabetes: A patient-centered approach – Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), Diabetes Care, 2012; 35(12): 1364-1379.
• Inzucchi SE et al. Management of hyperglycemia in type 2 diabetes, 2015: A patient-centered approach (update to the above position statement), Diabetes Care 2015;38:140-149.
• Garber et al. Consensus statement by the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) on the comprehensive type 2 diabetes management algorithm - 2016 Executive Summary 2016, Endocrine Practice 2016;22(1):84-113.
Inzucchi, Diabetes Care 2015;38:140-149
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See hand-out packet, pg 1
Garber et al, Consensus statement by AACE and ACE - 2016 Executive Summary 2016, Endocrine Practice