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Jeopardy: Update on Diabetes Pharmacotherapy

Susan Cornell, BS, PharmD, CDE, FAPhA, FAADE

Associate ProfessorMidwestern University - Chicago College of Pharmacy

• Describe the mechanism of action and unique features of the 6 classes of medications that are recommended by the ADA as second-line therapies for type 2 diabetes.

• Discuss contraindications and side effect considerations when recommending second-line therapies for type 2 diabetes.

• Given a patient case where the patient has reached the maximal dosage of metformin, select among second line treatment options for individualize care.

Objectives

Why is Glucose Control Important?

• 60% of people with type 2 diabetes have at least 1 complication because of diabetes

– Complications are often present at time of diagnosis

AACE. State of diabetes complications in America. 2007. http://multivu.prnewswire.com/mnr/AACE/2007/docs/Diabetes_Complications_Report.pdf

(accessed 2016 Aug 20).

http://multivu.prnewswire.com/mnr/AACE/2007/docs/Diabetes_Complications_Report.pdf

β-cell Decline in Prediabetes and T2DM

DeFronzo RA. Diabetes. 2009; 58:773-95.

Ch

ange

in in

sulin

/ c

han

ge g

luco

se /

IR

Normal glucose tolerance

Impaired glucose tolerance

Type 2 diabetes

IR = insulin resistance

The Ominous Octet: Circa 2008

musclee

Pancreas- ß-cellPancreas – α-cell

Liver

GI tract-stomach/small

intestine

Peripheral tissue

Brain

Kidney

Cornell S et al. Postgrad Med. 2012; 124:84-94.Defronzo RA. Diabetes. 2009; 58:773-95.

Fat cells(adipose tissue)

Hyperglycemia

Treatment Approach to T2DM• Dietary changes

• Reduce consumption of calories• Reduce consumption of simple carbohydrates

• Increase physical activity

• Medications• Improve or replace insulin secretion• Reduce insulin resistance• Reduce glucagon secretion• Reduce hepatic glucose production• Increase urinary glucose excretion

DeFronzo RA et al. Diabetes Care. 2013; 36(suppl 2):S127-38.

Insulin (1)

Bolus insulin

– Insulin lispro

• U100

• U200

– Insulin aspart

– Insulin glulisine

– Insulin human inhaled

– Regular human insulin

Basal insulin

– Insulin NPH

– Insulin detemir

– Insulin degludec

• U100

• U200

– Insulin glargine

• U100

• U300

Oral Medications (9)

– -glucosidase inhibitors (AGI)

– Biguanides

– Bile acid sequestrants (BAS)

– Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins)

– Dopamine agonists

– Glinides

– Sulfonylureas (SU)

– Sodium Glucose Co-Transporter-2 inhibitors (SGLT-2i)

– Thiazolidinediones (TZDs or glitazones)

Non-insulin injectable agents (2)

– Glucagon-like peptide-1 (GLP-1) agonists

– Amylinomimetic

12 Pharmacotherapy Options

Cornell S et al. Postgrad Med. 2012;124:84-94. www.pdr.net (accessed 2016 June 30). .

ADA Standards of Medical Care in Diabetes (2015)

• Inzucchi SE et al. Diabetes Care. 2015; 38:140-9.

Garber AJ. Endocr Pract. 2016; 22:84-113.

Oral Agents

• Affordable

• Possible weight loss benefit

• Low risk of hypoglycemia

• GI side effects can be managed

• Risk of lactic acidosis far less than feared

• Effectively lowers BG and A1c

– Though not sustainable as monotherapy

Metformin:Current Cornerstone of Therapy

Rational Choices for second-line add-on to Metformin

Drugs that target different metabolic defects

Combine medications that work at different tissue sites for synergy

Drugs that target fasting and postprandial glucose control

Select therapies that support patient goals Low hypo risk

Weight neutral, loss

Sulfonylureas

• Glimepiride – Amaryl ®

• 1mg, 2mg, 4mg• Once daily

• Glipizide – Glucotrol ®

• 5mg, 10mg• Once to twice daily

– Glucotrol XL ®• 2.5mg, 5mg, 10mg• Once daily

• Glyburide – Micronase ®

• 1.25mg, 2.5mg, 5mg• Once to twice daily

– Diabeta ®• 1.25mg, 2.5mg, 5mg• Once to twice daily

– Glynase ®• 1.5mg, 3mg, 6mg• Once to twice daily

Sulfonylureas: 1st Generation

Titrate every 2-4 weeks based on FPG

Sulfonylureas• Stimulates insulin release from the pancreas

– Long acting stimulation (>6 hours)

– Requires endogenous insulin to be affective; therefore better used early in the disease; if necessary

– Short durability

• Lowers fasting and postprandial glucoseDecreases A1c by 1.5-2% (~45-60 mg/dl)

• Most common side effects• Hypoglycemia• Weight gain

• may inhibit ischemic pre-conditioning

Cornell S, Lullo A. Diabetes Trends 2009.

Meglitinides

• Repaglinide– Prandin ®

• 0.5mg, 1mg, 2mg• Up to three times daily before meals

• Nateglinide– Starlix ®

• 60mg, 120mg• Up to three times daily before meals

Glinides

• Stimulates insulin release from the pancreatic beta cells

– Short acting stimulation (30 minutes to 4 hours)– Requires endogenous insulin to be affective; therefore

better used early in the disease; if necessary – Short durability

• Lowers postprandial glucose• Decreases A1c by 0.5-1% (~15-30 mg/dl; more postprandial)



TZD’s (Glitazones)

• Pioglitazone– Actos ®– 15mg, 30mg, 45mg– Once daily

• Rosiglitazone– Avandia ®– 2mg, 4mg, 8mg– Once to twice daily

TZD’s (Glitazones)

• Stimulates PPRA γ to increase GLUT-4 transporter production; thereby moving glucose from the blood into the peripheral tissue.

• Also reduces adipose fat– Can be used thru duration provided insulin is present

– Good durability

• Lowers fasting and postprandial glucose

• Decreases A1c by 1.0-1.5% (~30-45 mg/dl)

• Most common side effects

• Edema (swelling) usually in the legs

• Weight gain

• Possible ↑ risk of fractures.

• Takes 4-6 weeks (or more) to take affect and requires insulin (endogenous or exogenous) Cornell S, Lullo A. Diabetes Trends 2009.

DPP4 Inhibitors (gliptins)• Sitagliptin (Januvia ®)

– 25 mg, 50 mg, & 100 mg

– Once-daily dosing

– Dose adjustment in renal impairment

• Saxagliptin (Onglyza ® )– 2.5 mg & 5 mg



• Linagliptin (Tradjenta ®)– 5 mg


• Alogliptin (Nesina ®)– 6.25 mg, 12.5 mg, & 25 mg



DPP4 Inhibitors (gliptins)

• Inhibits DPP-4 enzyme in the GI tract that breaks down GLP-1 resulting in ↑ endogenous GLP-1. – glucagon suppression (from pancreatic alpha cell) results in ↓

liver glucose production– Enhances appropriate insulin and amylin secretion from the

pancreatic beta cells– Can be used thru duration provided insulin is present

• Promising durability

• Lowers postprandial glucose– Decrease A1c by 0.5 to 0.7% ( ~15-20 mg/dl; most postprandial)

• Most common side effects• Stuffy, runny nose• Headache• Upper respiratory tract infection

Cornell S. Dorsey VJ. Postgraduate

Medicine. 2012;124(4):84-94.

Sodium Glucose Co-Transporter-2 Inhibitors (SGLT-2i)

• Canagliflozin– Invokana ®

• 100mg & 300mg• taken once daily before first meal of the day.

• Dapagliflozin– Farxiga ®

• 5mg & 10mg• taken once daily (ideally, before first meal of the day).

• Empagliflozin– Jardiance ®

• 10mg & 25mg• taken once daily (ideally, before first meal of the day).

Sodium Glucose Co-Transporter-2 Inhibitors (SGLT-2i)

• ↓ renal glucose reabsorption in the early proximal tubule of the kidney

– Possibly reduces adipose fat - likely due to ↑ water and fat urination (elimination)

• Lowers fasting glucose– Decreases A1c by 0.7-1% (~20-30 mg/dl)

• Most common side effects- Weight loss- Vaginal and male genital infections - Rash- UTI- Frequent urination- Increased thirst - GI problems (when combined with metformin)

List JF, et al. Diabetes Care. 2009;32(4):650-657.

Wilding JP, et al. Diabetes Care. 2009;32(9):1656-1662.

SGLT2 Inhibitors: Comparisons

Canagliflozin Dapagliflozin Empagliflozin

Efficacy (A1c lowering)

Monotherapy ↓ 0.77 - 1.03% ↓ 0.8 – 0.9% ↓ 0.7 – 0.8%

Combination ↓ 0.79 - 0.94% ↓ 0.7 – 0.8% ↓ 0.7 – 0.8%

Dose and Frequency

100-300 mg once daily

5-10 mg once daily

10-25 mg once daily

Renal dose adjustment

CrCl <60 mL/min 100 mg once dailyUse not

recommended*No dosage adjustment

CrCl <45 mL/min Use not recommended

Invokana (canagliflozin) [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2013.Farxiga (dapagliflozin) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; August 2014.

Jardiance (empagliflozin) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2014.

Injectable Agents

GLP-1 Agonists

short-acting GLP-1 agonists

• Exenatide (Byetta ®)

– 5 mcg & 10 mcg

– Twice-daily dosing

• Lixisenatide (Adlyxin ®)

– 10 mcg & 20 mcg

– once-daily dosing

long-acting GLP-1 agonists

• Liraglutide (Victoza ®)

– 0.6 mg, 1.2 mg, & 1.8 mg


•Exenatide (Bydureon ®)

– 2 mg

– Once-weekly dosing

• Albiglutide (Tanzeum ®)

– 30mg & 50mg


• Dulaglutide (Trulicity ®)

– 0.75 mg & 1.5 mg


GLP-1 Agonists

• GLP-1 agonists “fix” 5 dysfunctional organs in T2DM– glucagon suppression from the pancreatic alpha cell

• Results in ↓ liver glucose production

– Enhances appropriate insulin and amylin secretion from the pancreatic beta cell• Results in brain satiety

– Regulates the GI tract to slow gastric emptying time

– Can be used thru duration provided insulin is present• Promising durability

• Short acting agonists lowers postprandial glucose– Decreases A1c by 0.8-1.5% (~20-45 mg/dl; most postprandial)

• Long acting agonists lowers fasting and postprandial glucose– Decreases A1c by 0.8-1.8% (~20-50 mg/dl)

• Most common side effects– Weight loss– Stomach upset– Caution in patients at risk for pancreatitis

Cornell S. Dorsey VJ. Postgraduate

Medicine. 2012;124(4):84-94.

Differences in GLP-1 agonists Exenatide BID

Lixisenatide Liraglutide Exenatide QW

Albiglutide Dulaglutide

Dose 5 & 10 mcg BID(within 30-60 min of am/pm meal)

10 & 20 mcg (within 60 min of same meal once daily)

0.6 mg initial, then ↑ to 1.2 & 1.8 mgOnce daily, anytime

2 mg weekly 30mg & 50mg weekly

0.75 mg & 1.5 mgweekly

Max dose 10 mcg BID 20 mcg daily 1.8 mg daily 2mg weekly 50 mg weekly 1.5 mg weekly

Half- life 2-4 hours 2-4 hours 13 hours 5 days 5 days 5 days

Homology to GLP-1

53% 50% 97% 53% 97% 90%

Antibodies 44% 69.8% 8.6% 44% 2.5% 2%

FPG or PPG effects

PPG PPG Both, FPG & PPG Both, FPG & PPG

Both, FPG & PPG

Both, FPG & PPG

FPG = fasting plasma glucose; PPG = postprandial plasma glucose

High-Concentration or Low Volume Glargine (U300)

• Available only in a pen

– U-300: 450 units/pen, max 80 units/inj

– Can be used for patients on small and large volumes of insulin

• Offers a smaller depot surface area, leading to a reduced rate of absorption

• Provides flatter and prolonged pharmacokinetic and pharmacodynamic profiles and more consistency

– Half-life is ~23 hours

– Steady state in 4 days

– Duration of action ≤36 hours1. Garber AJ. Diabetes Obesity Metab; published online 31 Oct 2013].

2. Owens DR, et al. Diabetes Metab Res Rev. 2014;30(2):104-19. 3. Steinstraesser A, et al. Diabetes Obes Metab. 2014 Feb 26. .

PK and PD of U300 Insulin Glargine vs U100 Insulin Glargine1

U300 glargine displays a more even and prolonged PK/PD profile compared with U100 glargine, offering blood glucose control beyond 24 hours

LLOQ

0

GIR

[mg

/kg-1

/min

-1] 3

1

Time (h)

2

36

Gla-100 0.4 U/kg-1

Gla-300 0.4 U/kg-1

24181260 30

0

INS

[µU

/mL-1

]

25

5

15

20

10

N=30

1. Becker RH, et al. Diabetes Care. 2014;pii:DC_140006.

U-100 and U-200 Insulin Degludec

• Available only in a pen– U-200: 600 units/pen, max 160 units/inj– U-100: 300 units/pen, max 80 units/inj

• Can be used for patients on small and larger volumes of insulin

• Provides flatter and prolonged pharmacokinetic and pharmacodynamic profiles and more consistency– Duration of action >42 hours– Half-life ~25 hours

• Detectable for at least 5 days

– Steady state in 3-4 days

1. Garber AJ. Diabetes Obesity Metab; published online 31 Oct 2013]. 2. Owens DR, et al. Diabetes Metab Res Rev. 2014;30(2):104-19.

Basal Insulin DegludecFlat, stable profile of both 100 unit/mL

and 200 unit/mL formulations

GIR = glucose infusion rate.1. Heise T, et al. ADA. 2012, Oral 349 Abstract (Trial: NN1250-1987).

2. Nosek L, et al. IDF 2011: P-1452; Diabetologia. 2011;54(suppl. 1):S429 (1055-P); Diabetes. 2011;60(suppl. 1A):LB14.

Glu

co

se In

fusio

n R

ate

2

0

Day 6 Day 7

4

1

3

5

IDeg 100 U/mL 0.4 U/kg




Mean 24-Hour GIR Profile of the Two Insulin DegludecFormulations at Steady State

Half-life atSteady State

IDeg 200 U/mL0.6 U/kg

MeanHalf-life(hours)

26.2 h

n = 21

n = 37n = 16n = 22

Side Effects and Contraindications

Adverse Reaction

Sitagliptin

100 mg†1

Saxagliptin

2.5 mg‡2

Saxagliptin

5 mg‡2

Linagliptin

5 mg‡3

Alogliptin

25 mg‡§4

Headache 5.1–5.9 6.5 6.5 – 4.2

Nasopharyngitis 5.2–6.3 – – 7.0 4.4

URTI 5.5–6.3 – 7.7 – 4.2

UTI – – 6.8 – –

Frequently Reported ADEs in Patients Receiving a DPP-4i

Adverse Reactions Reported Core Phase 3 Placebo-Controlled Studies, %*

*Excluding hypoglycemia. †Data from multiple core studies. ‡Pooled data from core studies.§URTI = upper respiratory tract infection; UTI = urinary tract infection.

1. Januvia® (sitagliptin). Prescribing information.

2. Onglyza® (saxagliptin). Prescribing information..

3. Tradjenta® (linagliptin). Prescribing information.

4. Nesina™ (alogliptin). Prescribing information.

5. Deacon. Diabetes Obes Metab. 2011;13:7–18.

No differences in the overall safety profiles of the

various DPP-4 inhibitors have so far emerged.5

Agent

Approximate ex Vivo

DPP-4 Inhibition, %1

Metabolism EliminationMaximum

24 H

Postdose

Sitagliptin 97 80 Not appreciably

metabolized2

Primarily renal (~79%

excreted unchanged by

kidney)2

Saxagliptin 80 70 Hepatically transformed to

active metabolite, chiefly by

CYP3A4/53

Primarily renal (24% as

parent compound, 36% as

metabolite); also hepatic3

Linagliptin 80 70 ~90% eliminated

unchanged; exposure

decreased by strong

CYP3A4 or P-gp inducers4

Primarily enterohepatic

(80%); renal, 5%4

Alogliptin 90 75 Not appreciably

metabolized5

Primarily renal (up to 71%

excreted unchanged by

kidney)5

Pharmacologic and PK Characteristics of DPP-4i

1. Deacon. Diabetes Obes Metab. 2011;13:7–18.

2. Januvia® (sitagliptin). Prescribing information..

3. Onglyza® (saxagliptin). Prescribing information.

4. Tradjenta® (linagliptin). Prescribing information. .


CYP = cytochrome P450; P-gp = P-glycoprotein.

• Rare cases of acute pancreatitis and HSRs have been reported during clinical trials and the postmarketing period1–5

• Acute pancreatitis– Meta-analysis did not detect increased incidence vs comparators in core

trials5

– Patients should be monitored for signs and symptoms, especially at start of therapy1,2,4

– If pancreatitis is suspected, DPP-4 inhibitor should be discontinued promptly and management initiated1,2,4

• HSRs– Often occur within first 3 months of treatment1,2

– Discontinue agent and do not restart if serious HSR is suspected1–4

– Use caution when prescribing a DPP-4 inhibitor for a patient who had a HSR during treatment with a previous DPP-4 inhibitor1,2,4

Safety Issues with DPP-4i

HSR = hypersensitivity reaction.

1. Januvia® (sitagliptin). Prescribing information.

2. Onglyza® (saxagliptin). Prescribing information.

3. Tradjenta® (linagliptin). Prescribing information.


5. Monami et al. Curr Med Res Opin. 2011;27:57–64.

Head-to-Head Trial, Active Comparators

Incidence of Adverse Event, %

Nausea Vomiting Diarrhea

LEAD-6: liraglutide 1.8 mg, exenatide 10 μg 26, 28 6, 10 12, 12

DURATION-1: exenatide extended release 2 mg, exenatide 10 μg 26, 35 11, 19 14, 13

DURATION-5, exenatide extended release 2 mg, exenatide 10 μg 14, 35 5, 9 9, 4

DURATION-6, exenatide extended release 2 mg,

liraglutide 1.8 mg

9, 21 4, 11 6, 13

HARMONY-7, albiglutide 50 mg, liraglutide 1.8 mg 10, 29 5, 9 15, 14

AWARD-1, dulaglutide 0.75 & 1.5 mg, exenatide 10 μg 16, 28, 26 6, 17, 11 8, 11, 6

AWARD-6, dulaglutide 1.5 mg, liraglutide 1.8 mg 20, 18 7, 8 12, 12

GLP-1 agonist : GI Adverse Events

Buse. Lancet. 2009. Drucker. Lancet. 2008. Blevins. J Clin Endocrinol Metab. 2011.

Buse. Lancet. 2013. Pratley. Lancet

Diabetes Endocrinol. 2014. Wysham. Diabetes Care. 2014. Dungan. Lancet. 2014.

Handelsman. Endocr Pract. 2015.

In clinical practice, GI disturbances often resolve over time, but 5–10% of patients

discontinue treatment due to adverse effects.

Following dose titration instructions reduces risk of GI disturbances.

Patients with preexisting severe GI disease (eg, gastroparesis) should not use a GLP-1

agonists.

• Pancreatitis has been reported in association with GLP-1 agonist treatment

• Until more is known, providers should

– Observe patients carefully for pancreatitis signs and symptoms

– Discontinue agent if pancreatitis is suspected

– Not restart treatment if pancreatitis is confirmed

– Consider other glucose-lowering agents in patients with pancreatitis history

Pancreatic Safety for GLP-1

agonists

Byetta®. PI. Feb. 2015. Victoza®. PI. Mar. 2015.

Bydureon®. PI. Mar. 2015. Tanzeum™. PI. Mar. 2015.

Trulicity™. PI. Mar. 2015.

Egan. N Engl J Med. 2014. Butler. Diabetes Care. 2013.

• Currently unknown whether GLP-1 agonists cause thyroid C-cell tumors in humans

• Liraglutide, exenatide extended release, albiglutide, and dulaglutide– Have boxed warning on thyroid C-cell tumor risk– Are contraindicated in patients with personal or family history

of MTC and in patients with MEN 2

• Prescribers should– Counsel patients about potential MTC risk– Inform them about thyroid tumor symptoms

• Stipulations do not apply to exenatide (twice daily)

Thyroid C-Cell Tumors

MEN 2 = multiple endocrine neoplasia syndrome type 2;

MTC = medullary thyroid carcinoma

Byetta®. PI. Feb. 2015.

Victoza®. PI. Mar. 2015.

Bydureon®. PI. Mar. 2015.

Tanzeum™. PI. Mar. 2015.

Trulicity™. PI. Mar. 2015.

Effect1

GLP-1

Agonists

DPP-4

Inhibitors

Increase beta-cell mass and proliferation ++ +

Reduce beta-cell apoptosis ++ +

Enhance glucose-dependent insulin secretion ++ +

Reduce hepatic glucose production ++ +

Improve fasting glucose ++ +

Improve postprandial glucose ++ +

Delay gastric emptying ++ –

Increase satiety and reduce food intake ++ –

Promote weight loss ++ –

Comparing the Effects of GLP-1 Agonists and DPP-4i

GLP-1 agonists are administered by subcutaneous injection;

DPP-4 inhibitors are administered orally.

1. Cornell. J Clin Pharm Ther. 2012;37:510–524.– = negligible effects; + = modest effects; ++ = pronounced effects.

• Most common side effects– Weight loss– Vaginal and male genital infections– Rash– UTI– Frequent urination– Increased thirst– GI problems (when combined with metformin)

SGLT-2 Inhibitors Adverse Effects

List JF et al. Diabetes Care. 2009; 32:650-7.

Wilding JP et al. Diabetes Care. 2009; 32:1656-62.

Mean difference Upper 95% CI Lower 95% CI

Canagliflozin -0.640 -0.768 -0.513

Dapagliflozin -0.592 -0.692 -0.491

Empagliflozin -0.564 -0.745 -0.384

SUMMARY -0.591 kg -0.663 -0.519 P<0.001

SGLT-2i - Weight EffectsMeta-analysis

- Mechanism: 1 gram glucose = 4 kcal. Loss of potentially 200-300 kcal/day- Maximum weight loss at approximately 6 months- Weight loss is, in general, maintained

Berhan A et al. BMS Endocr Disord. 2013; 13:58-69.

Mean 95% CI

Systolic BP

SGLT2i vs. placebo -3.77 -4.65 to -2.90

SGLT2i vs. active comparator

-4.45 -5.73 to -3.18

Diastolic BP

SGLT2i vs. placebo -1.75 -2.27 to -1.23

SGLT2i vs. other antidiabetics

-2.01 -2.62 to -1.39

Odds Ratio

Hypotension 2.68 114 to 6.29

SGLT-2i – Blood PressureMeta-analysis

Vasilakou D et al. Ann Int Med. 2013; 159:262-74.

• BP Lowering Mechanism• Not fully determined but

likely due to osmotic diuresis

• Orthostatic changes possibleupon initiation• Early 24-48 hour

increased sodium excretion

• Caution in combination with other diuretics

CV Effects of DPP-4i, GLP-1 agonists and SGLT-2I

Results of CV Outcomes Trials in T2DM

Drug Class Study Drug vs. placebo N Results (year published)

DPP-4i EXAMINE Alogliptin 5400 Neutral (2013)

SAVOR-TIMI Saxagliptin 16500 Neutral (2013)

TECOS Sitagliptin 14000 Neutral (2015)

CARMELINA Linagliptin 8300 Expected (2017)

GLP-1 agonist ELIXA Lixisenatide 14000 Neutral (2015)

LEADER Liraglutide 16500 Positive (2016)

EXSCEL Exenatide QW 5400 Expected (2018)

REWIND Dulaglutise 8300 Expected (2019)

SGLT-2i EMPA-REG Empagliflozin 7300 Positive (2015)

CANVAS Canagliflozin 4300 Expected (2017)

DECLARE dapagliflozin 22200 Expected (2019)

DPP4i = dipeptidyl peptidase 4 inhibitor GLP-1 = glucagon like peptide -1 SGLT-2i = sodium glucose cotransporter 2 inhibitor Adapted from: Handelsman Y. Endocrine Today. 2016

LEADER Results

• 9340 patients randomized and followed for 3.8 years.

– Fewer patients died from CV causes in the liraglutide group (219 patients) than in the placebo group (278) P=0.007.

– The rate of death from any cause was lower in the liraglutide group (381 patients) than in the placebo group (447) P=0.02.

– The rates of nonfatal MI, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group.

• Is this reproducible? – Is this a class effect? Will this change guideline recommendations?

Marso S et al. N Engl J Med 2016; 375:311-322

EMPA-REG Results• 7300 randomized to empagliflozin vs. placebo.

– Primary outcome was 3-point MACE: Time to first occurrence of CV death, non-fatal MI or non-fatal stroke

– Key secondary outcome was 4-point MACE: Same as primary + hospitalization for unstable angina

• Treatment duration 2.6 years, Observation time 3.2 years

• Results were impressive and unexpected– ↓ CV death by 38%

– ↓ all cause mortality by 32%

– ↓ heart failure hospitalization by 35%

– Number Needed to Treat to prevent one death in 3 years = 39

• Is this reproducible? – Is this a class effect? Will this change guideline recommendations?

Zinman B, et al. NEJM 2015.

Dosing Considerations

Biguanides (Metformin)

• Decreases liver glucose production– Can be used throughout duration of disease; if no contraindication– Good durability

• Lowers fasting glucose• Decreases A1c by 1.5-2% (~45-60 mg/dl)

• Most common side effects• Stomach and intestine distress• May reduce B-12 levels after long-term use• Favorable lipid profile improvements

– ↑ good cholesterol (HDL)– ↓ bad cholesterol (LDL) & ugly cholesterol (triglycerides).

• Caution in patients with renal & hepatic dysfunction– CrCl < 1.4 in women and < 1.5 in men


Metformin: Labeling changes

• eGFR between 30 to 45 mL/minute/1.73 m2.

– Not recommended

• eGFR below 30 mL/minute/1.73 m2

– Contraindictaed

• If a patient is already on metformin

– eGFR falls below 45 mL/minute/1.73 m2,

• Weigh benefits of continuation verse discontinuation.

– eGFR falls below 30 mL/minute/1.73 m2

• Discontinue metformin

• Stimulates insulin release from the pancreatic beta cell

– Long acting stimulation (>6 hours)– Requires endogenous insulin to be affective; therefore better

used early in the disease; if necessary

– Short durability


• may inhibit ischemic pre-conditioning

Sulfonylureas


AgentDose Frequency and

Timing

tmax

t1/2

Initial Dose

(Duration)

Regular

DoseElimination

Exenatide BID

BID; within 60 minutes

before morning and

evening meals

2.1 hours

2.4 hours

5 µg

(1 month)

5 µg or

10 µg

Mainly renal; not recommended for

patients with ESRD or severe renal

impairment

Liraglutide QD; any time of day8-12 hours

13 hours

0.6 mg

(1 week)

1.2 mg or

1.8 mg

Mainly metabolized by proteolytic

degradation; use caution in patients

with renal impairment

Exenatide QW QW; timing not specified2-7 weeks

N/A2 mg 2 mg Renal

Albiglutide QW; timing not specified3-5 days

6-7 days30 mg 30 mg N/A

Dulaglutide QW; timing not specified~70 hours

~4 daysN/A

0.75 mg or

1.5 mgN/A

LixisenatideQD; within 60 minutes

before breakfast

~2 hours

~3 hours

10 µg

(2 weeks)20 µg Renal

Pharmacologic and Pharmacokinetic Differences among GLP-1 Agonists

Byetta [package insert]. 2015.

Victoza [package insert]. 2015.

Bydureon [package insert]. 2015.

Gilbert MP, et al. Am J Med. 2009;122(suppl 6):S11-S24.

Bischoff LA, et al. Expert Opin Pharmacother. 2011;12(8):1297-1303.

St Onge EL, et al. Expert Opin Biol Ther. 2010;10(5):801-6.

Umpierrez GE, et al. Diabetes Obes Metab. 2011;13(5):418-425.

Christensen M, et al. Expert Opin Investig Drugs. 2011;20(4):549-557.

Hirsch IB. N Engl J Med. 2005; 352:174-83.

Flood TM. J Fam Pract. 2007; 56(suppl 1):S1-S12.

Becker RH et al. Diabetes Care. 2015; 38:637-43.

Pharmacokinetic Profile of Currently Available Basal Insulins

Plasma Insulin Levels

0 12 16 20 24842 14 18 22106

Intermediate (NPH)

Long (detemir)

Long (U-100 glargine)

Time (hr)

26 28 30 32 34 36

Ultra-long (degludec & glargine U-300)

Insulin Onset (hr) Peak (hr) Duration (hr) Appearance

Insulin Lispro U100 & U200 within 15 min 0.5- 1.5 3-5 Clear

Insulin Aspart within 15 min 1-3 3-5 Clear

Insulin Glulisine 0.25-0.5 0.5-1 4 Clear

Regular U100 0.5 – 1 2-4 5-8 Clear

Regular inhaled Within 5 min 20-40 minutes 3 Powder

Regular U-500 30 min 2-4 Up to 24 hr Clear

NPH 1-2 4-10 14+ Cloudy

Insulin Detemir 3-4 6-8 (though relatively flat) up to 20-24 Clear

Insulin Glargine U100 1.5 flat 24 Clear

Insulin Glargine U300 1.5 flat 26 Clear

Insulin Degludec U100 & U200 0.5 – 1 flat >30 Clear

Lispro Mix 50/50 0.25-0.5 0.5-3 14-24 Cloudy

Lispro Mix 75/25 0.25-0.5 0.5-2.5 14-24 Cloudy

Aspart Mix 70/30 0.1-0.2 1-4 18-24 Cloudy

Degludec/aspart Mix 70/30 0.23 – 1.2 2.3 >24 Cloudy

Note: Patient specific onset, peak, duration may vary from times listed in table, Peak and duration are often very dose dependent with shorter duration of actions with smaller doses and vice versa

Insulin Comparison

Weight

EffectHypoglycemia

β-Cell

Protection

CVD

BenefitsCost Other Considerations

AGIs Neutral Low risk Possible Possible $ to $$GI adverse effects (gas),

dose frequency

Amylinomimetic Loss Low risk Possible Yes $$GI adverse effects (nausea),

injectable, dose frequency

Bile acid

sequestrant

Neutral

or lossLow risk Possible Yes $$

GI adverse effects (constipation),

dose frequency

Biguanides Loss Low risk Possible Yes $GI adverse effects (diarrhea),

renal and hepatic impairment

DPP-4 inhibitors

(gliptins)Neutral Low risk Possible Yes $$$ Minimal adverse effects

Dopamine agonistNeutral

or lossLow risk Unknown Yes/no $$$

GI adverse effects (nausea),

hypotension, dizziness

GLP-1 agonists Loss Low risk Possible Yes $$$GI adverse effects (nausea),

injectable

InsulinGain or

loss

Risk—bolus

Low risk—basalPossible Possible $ to $$

Injectable, dose frequency

(bolus), increased SMBG

Secretagogues

sulfonylureas

and glinides

Gain Risk No No $ to $$

Immediate short-term response,

increased SMBG,

dose frequency (glinides)

SGLT-2 inhibitors Loss Low risk ?? Yes $$$Urinary tract and urogenital

infections

TZDs (glitazones) Gain Low risk Possible Yes/no $$

4-8 weeks for response,

redistribution of SC/visceral fat,

edema, bone loss, fracture,

bladder cancer

FPG = fasting plasma glucose; PPG = postprandial glucose; GI = gastrointestinal; SMBG = self-monitoring of blood glucose.

Unger J, et al. Postgrad Med. 2010;122(3):145-157. Cornell S, et al. Postgrad Med. 2012;124(4):84-94.

• Metformin is recommended as initial therapy for most patients with type 2 diabetes, but most patients require additional therapy, particularly as the disease progresses.

• Guidelines recommend several second-line treatment options including insulin, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors.

• A patient-centered approach to decision making is recommended including an evaluation of the mechanism of action, efficacy, unique benefits and safety of each option.

Key Points

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