340201

−This Clinical Resource gives subscribers
additional insight related to the Recommendations published in−
January 2017 ~ Resource #330104
Comparison of GLP-1 Agonists

Ozempic (semaglutide) and Bydureon BCise (extended-release exenatide) are the newest glucagon-like peptide-1 (GLP-1) receptor agonists approved
for type 2 diabetes. The first GLP-1 agonist, exenatide (Byetta), marketed in 2005, required twice-daily dosing. Since then, newer agents with longer
half-lives and extended-release formulations have been developed allowing for once-daily, and even once-weekly, dosing. While all GLP-1 receptor
agonists reduce A1C and fasting blood glucose concentrations, only some have evidence of improved cardiovascular outcomes. See our chart,
Diabetes Medications and Cardiovascular Impact, for more on their cardiovascular impact. All of the agents carry a warning about the risk of
worsening renal function, the rare occurrence of pancreatitis, and a possible association with thyroid C-cell tumors in rodents. Some carry an
additional precaution about the potential for gallbladder disease. The exact role in therapy for the GLP-1 receptor agonists is evolving as we learn
more about potential cardiovascular benefits. For most patients, GLP-1 agonists should be reserved for those who require two or more diabetes
medications to maintain a desired A1C. See our algorithm, Management of New-Onset Type 2 Diabetes, for more information. The chart below
compares the GLP-1 receptor agonists for type 2 diabetes currently available in the U.S.
Abbreviations: BID = twice daily; ESRD = end-stage renal disease; g = gauge; GI = gastrointestinal; SQ = subcutaneously.
Druge Dosing Availability and Storage Rates of Nauseac Use in Renal/Hepatic Avg.
Requirements and Injection Site Impairment Short-
Cost/montha Reactions term
Weight
A1C
Lossb
reductionb
Dulaglutide • Start with 0.75 mg SQ once Single-dose pens and prefilled Nausea: • No dosage changes ~2.5 kg
(Trulicity) weekly, with or without syringes (includes needles): 0.75 mg: 12.4% necessary in patients
meals. • 0.75 mg 1.5 mg: 21.1% with renal
~$675 • Increase to 1.5 mg once • 1.5 mg (placebo-controlled impairment.
(0.75 mg and weekly, if needed for • Reconstitution not necessary. trials, monotherapy • Monitor renal
1.5 mg doses) additional A1C lowering. • Keep refrigerated. or add-on therapy) function in patients
• Delayed doses: • May store at room temperature with significant GI
A1C: ~1.5% o If ≥3 days until the next for up to 14 days, if needed. Injection site adverse effects.
scheduled dose, give right reactions: 0.5% • Hepatic impairment
away. is not expected to
o If <3 days until next affect blood
scheduled dose, skip and concentrations.
give at next scheduled
weekly dose.
More. . .
Copyright © 2017 by Therapeutic Research Center
3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com ~ NursesLetter.com
(Clinical Resource #330104: Page 2 of 8)
Weight
A1C
Lossb
reductionb
Exenatide • Start with 5 mcg SQ BID. Multi-dose pens (60 doses per pen): Nausea: • Not recommended ~2 kg
(Byetta) • Increase to 10 mcg BID after • 5 mcg/dose Monotherapy: 8% in ESRD or severe
one month, if needed for • 10 mcg/dose Add-on therapy: renal impairment.
~$710 additional A1C lowering. • Pen needles not supplied with ≤44% • Use with caution in
(5 mcg and • Inject within 60 minutes prior pens. patients with renal
10 mcg doses) to morning and evening meals • No mixing needed. Injection site transplantation or
(or before the two main meals • Keep refrigerated. reactions: <2% moderate renal
A1C: ~1% of the day, ≥6 hours apart). • After first use, can be kept at impairment.
• Delayed doses: Give missed room temperature. • Hepatic impairment
dose as soon as able and • Discard 30 days after first use. is not expected to
resume normal dosing. affect blood
concentrations.
Exenatide • 2 mg SQ once weekly at any Bydureon Nausea (pooled rate • Not recommended Bydureon:
extended- time of day, with or without Single-dose vial: of monotherapy or in severe renal ~2.5 kg
release meals. • 2 mg (Comes with prefilled as add-on to other impairment or
(Bydureon, • Delayed doses: diluent syringe, vial connector, agents): ESRD. Bydureon
Bydureon o If ≥3 days until the next and 23 g needle.) • 11.3% • Use with caution in BCise:
BCise) scheduled dose, give right Single-dose dual chamber pen: (Bydureon) patients with renal ~1.4 kg
away. • 2 mg (One chamber with • 8.2 % transplantation or
~$660 o If <3 days until next medication and one with (Bydureon moderate renal
scheduled dose, skip and diluent, comes with 23 g BCise) impairment.
A1C:1,4 give at next scheduled needle.) • Hepatic impairment
~1.5% weekly dose. • Both the vial and the pen Injection site is not expected to
(Bydureon) dosage forms must be reactions (post- affect blood
~1.4% reconstituted immediately prior marketing reports of concentrations.
(Bydureon to use. serious injection site
BCise) • Keep refrigerated. reactions with or
without SQ nodules):
• Can be kept at room
• 17.1%
temperature for up to four
Continued… weeks, if needed.
(Bydureon)
More. . .
Weight
A1C
Lossb
reductionb
Exenatide Bydureon BCise Injection site
extended- Single-dose autoinjector: reactions:
release, • Keep refrigerated. • 23.9% (Bydureon
continued • Can be kept at room BCise)
temperature for up to four
weeks, if needed (unmixed).
• Store flat in original packaging,
protected from light.
• Remove from refrigerator about
15 minutes prior to mixing.
• Shake vigorously to mix for at
least 15 seconds.
Liraglutide • Start with 0.6 mg SQ once Multi-dose pens (6 mg/mL, 3 mL): Nausea: 20% • Use caution when ~2.5 kg
(Victoza) daily for one week (to reduce • Each pen delivers doses of 0.6 (pooled data from initiating or
nausea, not effective for mg, 1.2 mg, or 1.8 mg placebo- and active- escalating doses in
~$540 for glycemic control), increase to • Needles not supplied with pens. controlled trials) patients with renal
1.2 mg daily 1.2 mg once daily. • No mixing needed. impairment.
• Can increase to 1.8 mg once • Keep refrigerated. Injection site • Use caution in
~$805 for daily if needed for additional • After first use, can be stored at reactions: 2% patients with hepatic
1.8 mg daily A1C lowering. room temperature. (injection site rash, impairment.
• Administer at any time of • Discard 30 days after first use. erythema)
A1C: ~1.5% day, with or without meals.
• Delayed doses: Give missed
dose as soon as able and
resume normal dosing.
More. . .
Weight
A1C
Lossb
reductionb
Insulin • Start with 16 units insulin Multi-dose pens Nausea: 7.8% • Use caution when ~2.5 kg
degludec/ degludec/0.58 mg liraglutide (3 mL): initiating or versus
liraglutide SQ once daily, with or • Insulin degludec (100 units/mL) Injection site escalating doses in insulin
(Xultophy without food. and liraglutide (3.6 mg/mL) reactions: 2.6% patients with renal degludec3
100/3.6) • Adjust dose by 2 units • Each pen delivers doses from (hematoma, pain, impairment.
(2 units of insulin degludec 10 units to 50 units with each hemorrhage, • Has not been studied
~$990 for max and 0.072 mg of liraglutide) injection erythema, nodules, in patients with
daily dose every three to four days • Keep refrigerated. swelling, hepatic impairment.
• Maximum daily dose is 50 • After first use, store at room discoloration,
A1C: ~1% units insulin degludec/1.8 mg temperature. pruritus, warmth,
more than liraglutide.d • Discard 21 days after first use. mass)
insulin • Delayed doses: Give missed
degludec dose as soon as able and
resume normal dosing
schedule.
Lixisenatide • Start with 10 mcg SQ once Multi-dose pens (14 doses per pen): Nausea: 25% • Monitor for GI ~ 2 kg
(Adlyxin) daily for 14 days. • 10 mcg adverse effects and
• Increase to 20 mcg once • 20 mcg Injection site changes in renal
~$590 for the daily. • Needles not supplied with pen. reactions: 4% function in patients
20 mcg daily • Administer within one hour • No mixing needed. (pain, pruritus, with severe renal
dose prior to the first meal of the • Keep refrigerated prior to first erythema) impairment.
day. use. • Hepatic impairment
A1C: ~1% • Delayed doses: Give missed • After first use, store at room is not expected to
dose as soon as able and temperature. affect blood
resume normal dosing • Discard 14 days after first use. concentrations.
schedule.
More. . .
Weight
A1C
Lossb
reductionb
Insulin Uncontrolled on <30 units of Multi-dose pens Nausea: 10% • Monitor for GI ~1.4 kg
glargine/ basal insulin or lixisenatide: (3 mL): adverse effects and versus
lixisenatide • Start with 15 units (15 units • Insulin glargine (100 units/mL) Injection site changes in renal insulin
(Soliqua insulin glargine/5 mcg and lixisenatide (33 mcg/mL). reactions: 1.7% function in patients glargine2
100/33) lixisenatide) SQ once daily. • Each pen delivers doses from (hematoma, pain, with severe renal
Uncontrolled on 30 units to 60 15 to 60 units per injection. hemorrhage, impairment.
~$815 for max units of basal insulin: • Needles not supplied with pen. erythema, nodules, • Increase the
daily dose • Start with 30 units (30 units • No mixing needed. swelling, frequency of glucose
insulin glargine/10 mcg • Keep refrigerated prior to first discoloration, monitoring in
A1C: 0.5% lixisenatide) SQ once daily. use. pruritus, warmth, patients with renal
more than • Adjust dose by 2 units • After first use, store at room injection-site mass) or hepatic
insulin (2 units insulin glargine/ temperature. impairment.
glargine alone 0.66 mcg lixisenatide) to • Discard 14 days after first use.
4 units (4 units insulin
glargine/1.32 mcg
lixisenatide) each week.
• Maximum daily dose is
60 units insulin glargine/
20 mcg lixisenatide per day.d
• Administer within one hour
before the first meal of the
day.
• Delayed doses: Give missed
dose as soon as able and
resume normal dosing
schedule.
More. . .
Weight
A1C
Lossb
reductionb
Semaglutide • Start with 0.25 mg SQ once Multi-dose pens Nausea: • No dosage changes ~4 kg
(Ozempic) weekly at any time of day (1.34 mg/mL, 1.5 mL): 0.5 mg: 15.8% necessary in patients
with or without meals. • Carton with 1 pen intended for 1 mg: 20.3% with renal
~$675 • Increase to 0.5 mg once 0.25 mg and 0.5 mg doses. (placebo-controlled impairment.
(0.5 mg and weekly after four weeks. • Carton with 2 pens intended for trials, monotherapy • Monitor renal
1 mg doses) • May increase to 1 mg once 1 mg doses. or add-on therapy) function in patients
weekly, if needed after at • No mixing needed. with significant GI
A1C:f ~1.5% least four weeks. • Keep refrigerated prior to first Injection site adverse effects.
• Delayed doses: use. reactions: 0.2% • Hepatic impairment
o If within 5 days of missed • After first use, can be stored at is not expected to
dose, give right away. room temperature. Discard 56 affect blood
o If >5 days since the dose days after first use. concentrations.
was missed, skip and give
at next scheduled weekly
dose.
Because clinical trials are conducted under widely varying conditions, rates of efficacy and adverse effects seen in the clinical trials of a medication
cannot be directly compared to those of another medication and may not reflect the rates seen in clinical practice.
a. Wholesale average cost of 30-day supply. Medication pricing by Elsevier, accessed January 2018.
b. A1C reduction and weight loss based on results of FDA-approval clinical trials. A1C reduction and weight loss are average values and will
vary among patients.
c. Nausea is transient and usually dissipates within the first few weeks of therapy. Incidence of nausea is the rate reported in placebo-controlled
trials used for FDA approval, unless otherwise noted.
d. GLP-1 agonist and insulin fixed-dose combination products (e.g., Soliqua, Xultophy) have shown comparable rates of hypoglycemia
compared to similar doses of basal insulin alone.2,3
e. Albiglutide (Tanzeum) removed from chart due to discontinuation in late 2017.
f. Unpublished results from SUSTAIN 7, a head-to-head trial comparing semaglutide and dulaglutide, found semaglutide 1 mg may reduce A1C
by as much as 1.8%. Watch for more about this when the data are published in early 2018.5
More. . .
Information from U.S. prescribing information, unless otherwise noted: Trulicity (March 2015); Bydureon (September 2015); Bydureon BCise
(December 2017); Byetta (February 2015); Victoza (April 2016); Xultophy 100/3.6 (November 2016); Adlyxin (July 2016); Soliqua 100/33
(November 2016); Ozempic (December 2017).
Users of this resource are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical
judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national
organizations. Information and internet links in this article were current as of the date of publication.
More. . .
Project Leader in preparation of this clinical 3. Buse JB, Vilsboll T, Thurman J, et al. Contribution of
resource (330104): Beth Bryant, Pharm.D., BCPS, liraglutide in the fixed-ratio combination of insulin
degludec and liraglutide (IDegLira). Diabetes Care
Assistant Editor; last modified January 2018 2014;37:2626-33.
4. Wysham CH, Rosenstock J, Vetter ML, et al.
References Efficacy and tolerability of the new autoinjected
1. Bergenstal RM, Wysham C, Macconell L, et al. suspension of exenatide once weekly versus
Efficacy and safety of exenatide once weekly versus exenatide twice daily in patients with type 2 diabetes.
sitagliptin or pioglitazone as an adjunct to metformin Diabetes Obes Metab 2018;20:165-72.
for treatment of type 2 diabetes (DURATION-2): a 5. Novo Nordisk. Semaglutide superior to dulaglutide
randomised trial. Lancet 2010;376:431-9. on glucose control and weight loss in people with
2. Rosenstock J, Diamant M, Aroda VR, et al. Efficacy type 2 diabetes. August 16, 2017.
and safety of LixiLan, a titratable fixed-ratio https://www.novonordisk.com/bin/getPDF.2127298.p
combination of lixisenatide and insulin glargine, df. (Accessed January 12, 2018).
versus insulin glargine in type 2 diabetes
inadequately controlled on metformin monotherapy:
the LixiLan proof-of-concept randomized trial.
Diabetes Care 2016;39:1579-86.
Cite this document as follows: Clinical Resource, Comparison of GLP-1 Agonists. Pharmacist’s Letter/Prescriber’s
Letter. January 2017.
Evidence and Recommendations You Can Trust…
3120 West March Lane, Stockton, CA 95219 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249
Copyright  2017 by Therapeutic Research Center
Subscribers to the Letter can get clinical resources, like this one,
on any topic covered in any issue by going to PharmacistsLetter.com,
PrescribersLetter.com, PharmacyTechniciansLetter.com, or NursesLetter.com
−This Professional Resource gives subscribers
PHARMACIST’S LETTER / PRESCRIBER’S LETTER
August 2016 ~ Resource #320804
Diabetes Medications and Cardiovascular Impact

Type 2 diabetes is a known risk factor for cardiovascular disease.1,2 In addition, the combination of diabetes and cardiovascular disease increases the
risk of death.3 When considering glucose-lowering potential, side effects, cost, and outcomes; metformin remains the optimal first-line oral agent in
the management of type 2 diabetes for most patients.4,5 For a complete listing of available diabetes medications including expected A1C lowering and
adverse effects see our charts, Drugs for Type 2 Diabetes (U.S.) and Stepwise Treatment of Type 2 Diabetes (Canada). In 2008, the FDA issued
guidance for evaluating cardiovascular risk of medications used to manage type 2 diabetes.19 Since then, studies are evaluating cardiovascular
outcomes associated with diabetes medications. These studies will assist in prioritizing add-on medications choices for diabetes management. The
chart below summarizes the existing cardiovascular outcome data for medications used to treat type 2 diabetes.
Cardiovascular impact definitions listed in the chart include:

• Unknown = cardiovascular outcome data is currently unavailable.
• Improves Outcomes = published data demonstrates cardiovascular benefit with use in the treatment of type 2 diabetes.
• Worsens Outcomes = published data demonstrates cardiovascular harm with use in the treatment of type 2 diabetes.
• Neutral = published data demonstrates neither benefit nor harm in cardiovascular endpoints with use in the treatment of type 2 diabetes.
Abbreviations: ACS = acute coronary syndrome; CV = cardiovascular; DM = diabetes mellitus; MI = myocardial infarction.
Medicationsa Cardiovascular Impact Cardiovascular Outcomes Data

Alpha-glucosidase Unknown: • Acarbose: The ACE (Acarbose Cardiovascular Evaluation) trial (NCT00829660)
inhibitors • Acarbose is ongoing to evaluate if acarbose reduces CV morbidity and mortality in patients
• Acarbose (e.g., Precose • Miglitol with impaired glucose tolerance and established coronary heart disease or ACS.18
[U.S.], Glucobay [Canada])
• Miglitol
(e.g., Glyset [U.S.])
Amylin analog Unknown: • Pramlintide: Unable to identify any published or ongoing trials evaluating CV
• Pramlintide • Pramlintide impact.
(SymlinPen [U.S.])
More. . .
PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com
(Professional Resource #320804: Page 2 of 7)

Biguanide Improves Outcomes: • Metformin: A subanalysis of the UKPDS trial found good glycemic control with
• Metformin • Metformin metformin with about 10 years of use MAY reduce the risk of CV mortality,
(e.g., Glucophage, especially in obese patients, NNT = 14 [Evidence level A; high-quality RCT].21
Glycon [Canada]) o Pooled data demonstrate possible reduced CV mortality with a NNT = 56,
compared to other DM medications or placebo [Evidence level A; high-quality
meta-analysis].15
Dipeptidyl peptidase-4 Neutral: • Alogliptin: The EXAMINE trial found alogliptin use in patients with type 2 DM
(DPP-4) inhibitors • Alogliptin* and a history of a recent ACS, did not increase major adverse CV events, compared
• Alogliptin • Saxagliptin* to placebo [Evidence level A; high-quality RCT].10
(e.g., Nesina) • Sitagliptin o Alogliptin is associated with an increased risk of heart failure-related
• Linagliptin admissions, NNH = 167 [Evidence level A; high-quality RCT].10
(e.g., Tradjenta [U.S.]; • Saxagliptin: The SAVOR-TIMI 53 found saxagliptin use in patients with type 2
Unknown:
Trajenta [Canada])
• Saxagliptin
• Linagliptin DM at high risk for CV events; neither reduced nor increased the risk of CV death,
(e.g., Onglyza)
MI, or ischemic stroke, compared to standard therapy [Evidence level A; high-
• Sitagliptin *based on CV morbidity and quality RCT].11
(e.g., Januvia) mortality outcomes, but note o Saxagliptin was associated with an increased risk of heart failure-related
increased risk of heart admissions, NNH = 143 [Evidence level A; high-quality RCT].11
failure-related admissions. • Sitagliptin: The TECOS trial found adding sitagliptin to existing DM therapy did
not increase the major adverse CV events, hospitalization for heart failure, or other
adverse events compared to placebo [Evidence level A; high-quality RCT].12
• Linagliptin: CAROLINA, CARdiovascular Outcome study of LINAgliptin versus
glimepiride in patients with type 2 DM (NCT01243424) is ongoing to evaluate the
long-term impact of linagliptin versus glimepiride on CV morbidity and
mortality.14
Glucagon-like peptide-1 Unknown: • Albiglutide: HARMONY Outcomes (NCT02465515) is ongoing to evaluate the
(GLP-1) receptor agonists • Albiglutide effects of adding albiglutide to standard blood glucose lowering therapies on major
• Albiglutide • Dulaglutide cardiovascular events.22
(Discontinued end of 2017) • Dulaglutide: The REWIND (Researching Cardiovascular Events with a Weekly
• Dulaglutide Improves Outcomes: Incretin in Diabetes) trial (NCT01394952) is ongoing to evaluate if dulaglutide can
(e.g., Trulicity) • Liraglutide reduce major CV events in patients with type 2 diabetes.23
• Exenatide • Semaglutide • Exenatide: The EXSCEL trial found adding exenatide to conventional therapy in
(e.g., Byetta, Bydureon,
Bydureon BCise [U.S.]) type 2 DM patients with or without CV disease had a neutral effect on CV
Continued… outcomes.24
More. . .

GLP-1 agonists, continued Neutral: • Liraglutide: The LEADER trial [Evidence level A; high-quality RCT] found
• Liraglutide • Exenatide adding liraglutide to standard care in patients with type 2 DM with CV disease or at
(e.g., Victoza, Saxendab) • Lixisenatide high CV risk over almost four years may reduce:13
• Lixisenatide (pending FDA o Death from CV causes, nonfatal MI, or nonfatal stroke, NNT = 53.
approval; Lyxumia) o Death from CV causes, NNT = 77.
• Semaglutide o Death from any cause, NNT = 71.
(e.g., Ozempic)
o Liraglutide did not reduce the individual rates of MI, nonfatal stroke, or
hospitalization for heart failure.
• Lixisenatide: The ELIXA trial found adding lixisenatide to conventional therapy
in type 2 DM patients with a recent ACS had a neutral effect on CV outcomes.29
• Semaglutide: The SUSTAIN-6 trial [Evidence level A; high-quality RCT] found
adding semaglutide to conventional therapy in type 2 DM patients with CV disease,
chronic kidney disease, or CV risk factors for about two years may reduce the
combined endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke
(NNT=44).30 However, when evaluated individually, only nonfatal stroke was
significant.30
Insulin Neutral: • Glargine: The ORIGIN trial found use of basal insulin glargine for over six years
• Glargine had a neutral effect on CV outcomes [Evidence level A; high-quality RCT].6
Meglitinides Unknown: • Nateglinide: No outcome data for inpatients with type 2 DM. However, the
• Nateglinide • Nateglinide NAVIGATOR trial found nateglinide use in patients with impaired glucose
(e.g., Starlix [U.S.]) • Repaglinide tolerance and at high risk for CV events had a neutral effect on cardiovascular
• Repaglinide outcomes [Evidence level A; high-quality RCT].25
(e.g., Prandin [U.S.],
GlucoNorm [Canada])
Sodium-glucose co- Unknown: • Canagliflozin: CANVAS (CANagliflozin cardioVascular Assessment Study)

transporter 2 (SGLT2) • Dapagliflozin [Evidence level A; high-quality RCT] found canagliflozin use for about 3.5 years
inhibitors • Ertugliflozin when added to standard glucose-lowering therapy in patients with type 2 diabetes
• Canagliflozin and very high CV risk (>70% of patients had atherosclerotic CV disease), may
(e.g., Invokana) Improves Outcomes: reduce the combined endpoint of CV mortality, nonfatal MI, or nonfatal stroke
• Dapagliflozin • Canagliflozin (NNT=333). However, when evaluated individually, these endpoints were no
(e.g., Farxiga [U.S.], longer significantly reduced.20
Forxiga [Canada])
• Empagliflozin
• Dapagliflozin: DECLARE-TIMI58 (NCT01730534) is ongoing to evaluate the
Continued…
impact of adding dapagliflozin to current DM therapy on MI, ischemic stroke, and
More. . .

SGLT2 inhibitors, continued CV death.26
• Empagliflozin • Empagliflozin: The EMPA-REG OUTCOME trial [Evidence level A; high-
(e.g., Jardiance) quality RCT] found empagliflozin use for about three years, when added to
• Ertugliflozin standard glucose-lowering therapy in patients with type 2 DM and underlying CV
(e.g., Steglatro [U.S.]) disease, may reduce:7
o Hospitalization due to heart failure (NNT = 71).
o CV death rates (NNT = 45).
o Overall death rates (NNT = 39).
o Empagliflozin did not reduce the individual rates of MI or stroke.
• Ertugliflozin: The VERTIS CV Study (NCT01986881) is ongoing to evaluate the
impact of adding ertugliflozin in patients with existing vascular disease to current
DM therapy on cardiovascular death, nonfatal MI, and nonfatal stroke in patients
with type 2 diabetes.31
Sulfonylureas (first Unknown: • Tolbutamide: use has been associated with increased CV mortality compared to
generation) • Chlorpropamide diet alone or diet plus insulin.16
• Chlorpropamide • Tolazamide
• Tolazamide
• Tolbutamide Worsens Outcomes:
• Tolbutamide
Sulfonylureas (second Unknown: • Glimepiride: CAROLINA, CARdiovascular Outcome study of LINAgliptin

generation) • Gliclazide versus glimepiride in patients with type 2 DM (NCT01243424) is ongoing to
• Gliclazide (Canada) • Glipizide evaluate the long-term impact of glimepiride on CV morbidity and mortality.14
• Glipizide • Glimepiride
• Glimepiride • Glyburide
• Glyburide
Thiazolidinediones Improves Outcomes:* • Pioglitazone: The IRIS trial found use of pioglitazone for about five years in
• Pioglitazone • Pioglitazone patients with prediabetes and a history of stroke (with mild impairment) or
(e.g., Actos) transient ischemic attack may reduce the risk of a future stroke or MI (NNT = 36)
• Rosiglitazone Neutral:* [Evidence level A; high-quality RCT].8
(e.g., Avandia) • Rosiglitazone • Pioglitazone: The primary endpoint in the PROactive trial was not improved with
pioglitazone. A secondary endpoint found use of pioglitazone for about three years
Continued… *based on CV morbidity and
More. . .

Thiazolidinediones, mortality outcomes, but note in patients with type 2 DM and macrovascular disease (e.g., MI, stroke, PCI) may
continued increased risk of heart failure reduce the risk of all-cause mortality, non-fatal MI, and stroke (NNT = 50)
associated with use. [Evidence level A; high quality RCT].27
o Subgroup analysis found use of pioglitazone for about three years in patients
with type 2 diabetes and a previous stroke may reduce the risk of recurrent fatal
or nonfatal stroke (NNT = 22) [Evidence level A; high quality RCT].28
• Rosiglitazone: The RECORD trial found adding rosiglitazone to metformin or a
sulfonylurea for at least five years did not affect overall CV morbidity or mortality
[Evidence level A; high-quality RCT].9
• Pioglitazone and Rosiglitazone are known for their associated risk of heart failure
with a meta-analysis determining an NNH of approximately 50 patients treated
with either agent for approximately two years [Evidence level A; high-quality
meta-analysis].17
a. Many of these are also available as combination products with other medications like metformin or pioglitazone with different brand names.
b. Saxenda contains the same active ingredient as Victoza, but at higher doses and is indicated for weight loss, NOT the treatment of diabetes.
More. . .
Levels of Evidence 9. Home PD, Pocock SJ, Beck-Nielsen H, et al.

In accordance with the trend towards Evidence-Based Rosiglitazone evaluated for cardiovascular outcomes
in an oral agent combination therapy for type 2
Medicine, we are citing the LEVEL OF EVIDENCE diabetes (RECORD): a multicentre, randomized,
for the statements we publish. open-label trial. Lancet 2009;373:2125-35.
Level Definition 10. White WB, Cannon CP, Heller SR, et al. Alogliptin
A High-quality randomized controlled trial (RCT) after acute coronary syndrome in patients with type 2
High-quality meta-analysis (quantitative diabetes. N Engl J Med 2013;369:1327-35.
systematic review) 11. Scirica BM, Bhatt DL, Braunwald E, et al.
B Nonrandomized clinical trial Saxagliptin and cardiovascular outcomes in patients
Nonquantitative systematic review with type 2 diabetes mellitus. N Engl J Med
Lower quality RCT 2013;369:1317-26.
Clinical cohort study 12. Green JB, Bethel A, Armstrong PW, et al. Effect of
Case-control study sitagliptin on cardiovascular outcomes in type 2
Historical control diabetes. N Engl J Med 2015;373:232-42.
Epidemiologic study 13. Marso SP, Daniels GH, Brown-Frandsen K, et al.
C Consensus Liraglutide and cardiovascular outcomes in type 2
Expert opinion diabetes. N Engl J Med 2016 Jun 13. [Epub ahead
D Anecdotal evidence of print]. Doi: 10.1056/NEJMoa1603827.
In vitro or animal study 14. ClinicalTrials.gov. CAROLINA: cardiovascular
Adapted from Siwek J, et al. How to write an evidence-based clinical outcome study of linagliptin versus glimepiride in
review article. Am Fam Physician 2002;65:251-8. patients with type 2 diabetes. June 21, 2016.
https://clinicaltrials.gov/show/NCT01243424.
(Accessed June 29, 2016).
Project Leader in preparation of this professional 15. Selvin E, Bolen S, Yeh HC, et al. Cardiovascular
resource (320804): Beth Bryant, Pharm.D., BCPS, outcomes in trials of oral diabetes medications: a
Assistant Editor; last modified January 2018. systematic review. Arch Intern Med 2008;168:2070-
80.
16. Meinert CL, Knatterud GL, Prout TE, Klimt CR. A
References study of the effects of hypoglycemic agents on
1. Sarwar N, Gao P, Seshasai SR, et al. Diabetes vascular complications in patients with adult-onset
mellitus, fasting blood glucose concentration, and diabetes. II. mortality results. Diabetes
risk of vascular disease: a collaborative meta- 1970;19:S789-830.
analysis of 102 prospective studies. Lancet 17. Singh S, Loke YK, Furberg CD. Thiazolidinediones
2010;375:2215-22. and heart failure: a teleo analysis. Diabetes Care
2. Beckman JA, Creager MA, Libby P. Diabetes and 2007;30:2148-53.
atherosclerosis: epidemiology, pathophysiology, and 18. ClinicalTrials.gov. Acarbose cardiovascular
management. JAMA 2002;287:2570-81. evaluation trial (ACE). March 2016.
3. Di Angelantonio E, Kaptoge S, Wormser D, et al. https://clinicaltrials.gov/ct2/show/NCT00829660.
Association of cardiometabolic multimorbidity with (Accessed June 30, 2016).
mortality. JAMA 2015;314:52-60. 19. FDA. Guidance for Industry. Diabetes
4. Inzucchi SE, Bergenstal RM, Buse JB, et al. mellitus―evaluating cardiovascular risk in new
Management of hyperglycemia in type 2 diabetes, antidiabetic therapies to treat type 2 diabetes.
2015: a patient-centered approach: update to a December 2008. http://www.fda.gov/downloads/
position statement of the American Diabetes Drugs/GuidanceComplianceRegulatoryInformation/G
Association and the European Association for the uidances/UCM071627.pdf. (Accessed July 11,
Study of Diabetes. Diabetes Care 2015;38:140-9. 2016).
5. Goldenburg R, Clement M, Hanna A, et al. 20. Neal B, Perkovic V, Mahaffey KW, et al.
Pharmacologic management of type 2 diabetes: Canagliflozin and cardiovascular and renal events in
2016 interim update. Can J Diabetes 2016;40:193-5. type 2 diabetes. N Engl J Med 2017 June 12. Doi:
6. ORIGIN trial investigators, Gerstein HC, Bosch J, et 10.1056/NEJMoa1611925. [Epub ahead of print].
al. Basal insulin and cardiovascular and other 21. Effect of intensive blood-glucose control with
outcomes in dysglycemia. N Engl J Med metformin on complications in overweight patients
2012;367:319-28. with type 2 diabetes. UK Prospective Diabetes
7. Zinman B, Wanner C, Lachin JM, et al. Study (UKPDS) Group. Lancet 1998;352:854-65.
Empagliflozin, cardiovascular outcomes, and 22. ClinicalTrials.gov. Effect of albiglutide, when added
mortality in type 2 diabetes. N Engl J Med to standard blood glucose lowering therapies, on
2015;373:2117-28. major cardiovascular events in subjects with type 2
8. Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone diabetes. March 2016.
after ischemic stroke or transient ischemic attack. https://clinicaltrials.gov/ct2/show/NCT02465515?term
New Engl J Med 2016;374:1321-31.
More. . .
=albiglutide+cardiovascular&rank=1. (Accessed July patients with type 2 diabetes in the PROactive Study
12, 2016). (PROspective pioglitAzone Clinical Trial In
23. ClinicalTrials.gov. Researching cardiovascular macroVascular Events): a randomised controlled
events with a weekly incretin in diabetes (REWIND). trial. Lancet 2005;366:1279-89.
May 2016. 28. Wilcox R, Bousser MG, Betteridge OJ, et al. Effects
https://clinicaltrials.gov/ct2/show/NCT01394952?term of pioglitazone in patients with type 2 diabetes with
=dulaglutide+cardiovascular&rank=1. (Accessed or without previous stroke: results from PROactive
July 12, 2016). (PROspective pioglitAzone Clinical Trial In
24. Holman RR, Bethel MA, Mentz RJ, et al. Effects of macroVascular Events 04). Stroke 2007;38:865-73.
once-weekly exenatide on cardiovascular outcomes 29. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in
in type 2 diabetes. N Engl J Med 2017;377:1228-39. patients with type 2 diabetes and acute coronary
25. Holman RR, Haffner SM, McMurray JJ, et al. Effect syndrome. N Engl J Med 2015;373:2247-57.
of nateglinide on the incidence of diabetes and 30. Marso SP, Bain SC, Consoli A, et al. Semaglutide
cardiovascular events. N Engl J Med and cardiovascular outcomes in patients with type 2
2010;362:1463-76. diabetes. N Engl J Med 2016;375:1834-44.
26. ClinicalTrials.gov. Multicenter trial to evaluate the 31. ClinicalTrials.gov. Cardiovascular outcomes
effect of dapagliflozin on the incidence of following ertugliflozin treatment in type 2 diabetes
cardiovascular events (DECLARE-TIMI58). June mellitus participants with vascular disease, The
2016. VERTIS CV Study (MK-8835-004). April 7, 2017.
https://clinicaltrials.gov/ct2/show/study/NCT0173053 https://clinicaltrials.gov/ct2/show/NCT01986881.
4?term=dapagliflozin+cardiovascular&rank=1. (Accessed January 7, 2018).
(Accessed July 12, 2016).
27. Dormandy JA, Charbonnel B, Eckland DJ, et al.
Secondary prevention of macrovascular events in
Cite this document as follows: Professional Resource, Diabetes Medications and Cardiovascular Impact.
Pharmacist’s Letter/Prescriber’s Letter. August 2016.

Subscribers to the Letter can get professional resources, like this one,
PrescribersLetter.com, or PharmacyTechniciansLetter.com
−This Clinical Resource gives subscribers
July 2017 ~ Resource #330711

i
Drugs for Type 2 Diabetes

Glucose control is the mainstay of therapy diabetes management. In recent years, a variety of new agents with novel mechanisms of action have been
approved for the treatment of type 2 diabetes. While this provides more options for the treatment of these patients, it may lead to confusion as to
which agents should be used. In general, both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists
(AACE) recommend that in addition to lifestyle modification, metformin is first-line for the treatment of type 2 diabetes in most patients.1,2,21 The
target A1C concentrations are 7% (ADA) or 6.5% (AACE), but the goal may be individualized in patients with other illnesses and in those at risk for
hypoglycemia.1,2,21 Therapy can be started with more than one agent in patients with an A1C ≥9% (ADA) or ≥7.5% (AACE). However, for patients
who fail metformin monotherapy, a broad variety of agents can be used in combination with metformin, or as monotherapy in those who cannot use
metformin.1,2,21 The choice of second-line and third-line agents varies based on patient characteristics, patient preferences, potential adverse effects
(e.g., hypoglycemia, weight gain), and cost. The table below summarizes the agents available in the U.S. for the treatment of type 2 diabetes,
including expected A1C reduction when added to metformin, cost, adverse effects, and other pertinent information (e.g., frequency of dosing,
cardiovascular benefits). For additional details on cardiovascular benefits associated with drugs for type 2 diabetes, see our chart, Diabetes
Medications and Cardiovascular Impact.
Abbreviations: BID = two times daily; CVD = cardiovascular disease; eGFR = estimated glomerular filtration rate; GI = gastrointestinal; MOA =
mechanism of action; TID = three times daily; UTI = urinary tract infection.
Drug or Drug Class Expected A1C drop Maximum daily Notable Adverse Effects Comments
when added to dose24 (Cost/30
metformin23 days)a
MOA
Alpha-glucosidase 0.6% (acarbose) Acarbose • GI (e.g., flatulence, • Weight neutral as monotherapy23
inhibitors 300 mg, divided TID diarrhea)23 • Taken with meals24
0.7% (miglitol, when (~$45) • Low risk of • Reduces postprandial glucose21
Acarbose (Precose, added to sulfonylurea, hypoglycemia when • Requires frequent dosing (e.g.,
generics) not metformin)36 Miglitol used as monotherapy23 TID)21
300 mg, divided TID • Beneficial in the treatment of
Miglitol (Glyset, MOA: slows intestinal (~$200) prediabetes (acarbose)9
generics) carbohydrate • Ongoing trial to assess potential for
digestion/absorption21,24 CVD benefit in patients with
impaired glucose tolerance22
More. . .
metformin23 days)a
MOA
Amylin analog ~0.36% when added to Pramlintide • GI (e.g., nausea, • Weight loss21
Pramlintide (Symlin) insulin with or without 120 mcg/dose (usually vomiting)21 • Increased feeling of fullness after
metformin and/or a 360 mcg/day; divided, • Hypoglycemia rare, meal21
sulfonylurea33 prior to major meals) unless insulin dose not • Injectable21
(~$2,000) reduced21 • Taken immediately before meals24
MOA: slows gastric • Reduces postprandial glucose21
emptying, increases the • Requires frequent dosing21
feeling of fullness, and
reduces postprandial
glucagon secretion21,24
Biguanide 1% to 1.5% as Metformin • B12 deficiency23 • Weight neutral21,23

Metformin monotherapy 2,000 to 2,550 mg, • GI (e.g., diarrhea, • Ameliorates insulin-associated
(Glucophage, divided BID to TID nausea, cramping)21,23 weight gain23
Glucophage XR) MOA: inhibits (~$10) • Lactic acidosis (rare) in • First-line after diet and exercise for
production of glucose, patients with most patients21
Available in combination
with alogliptin,
intestinal absorption of Metformin XR cardiovascular, renal, or • Beneficial in the treatment of
glucose, and increases 2,000 mg to 2,500 mg, hepatic dysfunction21,24 prediabetes10
canagliflozin, glimepiride,
glipizide, glyburide, insulin sensitivity in divided BID • Low risk of • May reduce cardiovascular
linagliptin, pioglitazone, muscle and fat21,24 (~$120) hypoglycemia when mortality, especially in obese
rosiglitazone, saxagliptin, used as monotherapy23 patients [Evidence level A, high-
sitagliptin, and quality RCT]23
repaglinide. See specific • Safe in patients with stable heart
agents.
failure and moderate renal
impairment:3,16,25,26
o Can be initiated in patients with
an eGFR >45 mL/min/1.73m2
o Discontinue if eGFR falls below
30 mL/min/1.73m2
More. . .
metformin23 days)a
MOA
Dipeptidyl peptidase-4 0.7% Alogliptin • May be associated with • Dosage modification with renal
(DPP-4) inhibitor 25 mg pancreatitis6,21 impairment needed (sitagliptin,
(“gliptins”) or incretin MOA: increases (~$195) • New or worsening heart saxagliptin, alogliptin)24
enhancer insulin secretion in failure (saxagliptin and • CYP3A4 interactions (saxagliptin,
response to elevated Linagliptin alogliptin)[Evidence linagliptin)24
Alogliptin (Nesina,
others, with metformin
blood glucose, 5 mg level A, high-quality • Reduces postprandial glucose23
[Kazano], with
decreases glucagon (~$380) RCT]7,8,13,17,21,23 • Weight neutral23
pioglitazone [Oseni]), secretion, increases • May cause severe joint • Generally well tolerated21
Linagliptin (Tradjenta, sense of fullness, and Saxagliptin pain12
with metformin slows gastric 5 mg • Low risk of
[Jentadueto], with emptying21,24 (~$385) hypoglycemia when
empagliflozin used as monotherapy21,23
[Glyxambi]) Sitagliptin
100 mg
Saxagliptin (Onglyza,
(~$380)
with metformin
[Kombiglyze XR])
Sitagliptin (Januvia, with

metformin [Janumet,
Janumet XR])
Glucagon-like, ~1% See our chart, • GI (diarrhea, nausea)21 • Weight loss21

peptide-1 (GLP-1) (See GLP-1 agonist Comparison of GLP-1 • May be associated with • Injectable21
agonist or incretin chart for individual Agonists, for dosing pancreatitis (rare)6,21 • Linked to thyroid cell cancer in
mimetic agents) and cost info • May be associated with rats21
Dulaglutide (Trulicity) gallbladder disease • Dosage modification with renal
MOA: increases
(liraglutide, dysfunction needed (albiglutide,
Exenatide (Byetta) and insulin secretion in
exenatide)18,19 dulaglutide)
exenatide extended- response to elevated
• Low risk of • Avoid in severe renal impairment
release (Bydureon, blood glucose,
Bydureon BCise)
hypoglycemia when (exenatide)
decreases glucagon
Continued… secretion, leading to
used as monotherapy21 • Reduces postprandial glucose21
More. . .
metformin23 days)a
MOA
GLP-1 agonists, reduced hepatic • May lead to retinopathy • CV benefit: liraglutide use in
continued glucose production and complications patients with high CV risk or CV
slowed gastric (semaglutide)41 disease for about four years may
Liraglutide* (Victoza, emptying21,24 reduce [Evidence level A; high-
with insulin degludec quality RCT]:19
[Xultophy]) o Death from CV causes (NNT =
77)
Lixisenatide (Adlyxin,
with insulin glargine
o Death from any cause (NNT =
[Soliqua]) 71)
• CV benefit: semaglutide use in
Semaglutide (Ozempic) patients with CV disease, chronic
kidney disease, or CV risk factors
for about two years may reduce the
combined endpoint of CV death,
nonfatal MI, or nonfatal stroke
(NNT=44) [Evidence level A; high-
quality RCT].40 When evaluated
individually, only nonfatal stroke
was significant.40
• In patients who need more than one
or two diabetes meds, combination
therapy with basal insulin and a
GLP-1 agonist is an emerging
strategy1
Insulin 0.9% to 1.1% No maximum dose23 • Hypoglycemia (educate • Consider initial therapy within
Various See our chart, patient to prevent, insulin plus metformin if blood
MOA: promotes Comparison of Insulins recognize, and glucose is ≥300 mg/dL and/or A1C
storage of glucose in and Injectable Diabetes manage)21 is ≥10%21
muscle and fat tissues, Meds, for cost info • Highest risk of weight
and inhibits production gain21,23
of glucose21,24
More. . .
metformin23 days)a
MOA
Meglitinide 0.7% Nateglinide • Hypoglycemia (educate • Requires frequent dosing21
Nateglinide (Starlix,
360 mg, divided TID patient to prevent, • Reduces postprandial glucose21
generics)
MOA: stimulates (~$120) recognize, and • Provides flexible dosing (e.g., can
pancreatic insulin manage)21 hold dose if skipping meal)21,23
Repaglinide (Prandin, secretion21,24 Repaglinide • Weight gain21 • Consider over sulfonylureas (less
others, with metformin 16 mg, divided TID hypoglycemia, better postprandial
[PrandiMet]) (~$75) control)2
Sodium-glucose co- 0.7% to 1% Canagliflozin • Genital fungal (yeast) • Weight loss21

transporter 2 300 mg infections (male/female)2 • Do not use if eGFR
(SGLT2) inhibitors or MOA: blocks glucose (~$465) • UTI (may be severe), <45 mL/min/1.73m2 (canagliflozin,
“flozins” reabsorption in the ketoacidosis (rare)14 empagliflozin) or <60 mL/min/1.73m2
kidney, and increases Dapagliflozin • Dizziness, hypotension, (dapagliflozin, ertugliflozin)
Canagliflozin (Invokana, urinary excretion of 10 mg hypoglycemia (rare), • CV benefit: empagliflozin use in
with metformin increased LDL/urination21 patients with CVD for about three
glucose21,24 (~$465)
[Invokamet]) • Hyperkalemia, especially years may reduce [Evidence level A,
in patients with renal high-quality RCT]:20
Dapagliflozin (Farxiga) Empagliflozin impairment35
25 mg o Hospitalizations due to heart
• Fractures (rare, in failure (NNT = 71)
Empagliflozin (Jardiance, (~$465) susceptible patients)4
o CV death (NNT = 45)
with linagliptin • Decrease in BMD
[Glyxambi], with Ertugliflozin o Overall death (NNT = 39)
(canagliflozin)11
metformin [Synjardy]) o Empagliflozin use has NOT been
15 mg • May be associated with
shown to reduce individual rates of
(~$270) increased risk of bladder
Ertugliflozin* (Steglatro,
cancer (dapagliflozin)39
MI or stroke20
with metformin
• Acute kidney injury, may • CV benefit: CANVAS
[Segluromet], with (CANagliflozin cardioVascular
sitagliptin [Steglujan]) require dialysis
(canagliflozin, Assessment Study)[Evidence level A;
*expected to be available dapagliflozin)15 high-quality RCT] found canagliflozin
early 2018 • Amputations may occur in use for about 3.5 years when added to
about 6 of every 1,000 standard glucose-lowering therapy in
patients treated with patients with type 2 diabetes and very
Continued…
canagliflozin over 1 year, high CV risk (>70% of patients had
More. . .
metformin23 days)a
MOA
SGLT2 inhibitors, compared to about 3 in atherosclerotic CV disease), may
continued every 1,000 patients on reduce the combined endpoint of CV
other diabetes meds27,37 mortality, nonfatal MI, or nonfatal
• Canagliflozin use in stroke (NNT=333). However, when
patients at high CV risk for evaluated individually, these
about 3.5 years may endpoints were no longer significantly
increase risk of reduced.37
amputations, NNH ~77
[Evidence level A; high-
quality RCT]37,38
Sulfonylurea–first 0.8% Chlorpropamide • Hypoglycemia (educate • Discontinue when more complex
generation 750 mg24 patient to prevent, insulin regimens (e.g., basal plus
MOA: stimulates (~$230) recognize, and prandial insulins) are started1
Chlorpropamide pancreatic insulin
Tolazamide
manage)21 • Second-generation sulfonylureas
(Diabinese, generics) secretion21,24 o More common than preferred over first-generation
1,000 mg (doses
>500 mg divide BID)24 with second- sulfonylureas, due to lower risk of
Tolazamide
(~$630) generation hypoglycemia5
(Tolinase, generics)
sulfonylureas5 • Relatively short-lived efficacy1
Tolbutamide Tolbutamide • Weight gain5 • Avoid chlorpropamide in patients
(Orinase, generics) 3,000 mg (given once • Increased CV mortality with renal dysfunction or the
daily or divided up to (tolbutamide)29 elderly24
TID)24
(~$215)
Sulfonylurea-second 0.8% Glimepiride • Hypoglycemia, • Discontinue when more complex

generation 8 mg especially with renal insulin regimens (e.g., basal plus
Glyburide (Diabeta, MOA: stimulates (less than $10) dysfunction (educate prandial insulins) are started1
Glynase, Micronase, pancreatic insulin Glipizide IR patient to prevent, • Relatively short-lived efficacy1
generics, with metformin secretion21,24 40 mg (doses >30 mg recognize, and • For the elderly and those with
[Glucovance])
should be divided BID) manage)21 hepatic or renal dysfunction, start
(less than $10) o Less with glimepiride with low doses and titrate up21
Continued… versus glyburide5
More. . .
metformin23 days)a
MOA
Sulfonylureas, Glipizide XL • Weight gain
continued 20 mg o Less with glipizide
(less than $10) and glimepiride
Glipizide (Glucotrol, versus glyburide5
Glucotrol XL, generics, Glyburide
with metformin 20 mg (standard; doses
[Metaglip]) >10 mg can divide
BID);
Glimepiride (Amaryl, 12 mg (micronized
generics, with metformin product; once daily or in
[Amaryl M], with divided doses)
pioglitazone [Duetact], (~$11)
with rosiglitazone
[Avandaryl])
Thiazolidinedione 0.8% Pioglitazone • Low risk of • Glycemic control better sustained

(TZD) 45 mg hypoglycemia when over diabetes course than metformin
MOA: increases (~$14) used as monotherapy21 or sulfonylureas21
Pioglitazone (Actos, insulin sensitivity in • Edema21 • Pioglitazone may improve lipid
generics, with metformin muscle and fat21,24 Rosiglitazone • Weight gain21 profile (e.g., lowers triglycerides)21
[Actoplus Met or Actoplus 8 mg • Heart failure21 • Avoid in patients with symptomatic
Met XR], with glimepiride (~$325)
[Duetact], with alogliptin • Increased fracture risk21 heart failure21
[Oseni]) • Increased LDL • CV benefit: pioglitazone use for
(rosiglitazone)21 about three years in patients with
Rosiglitazone (Avandia, • Possible increased risk type 2 diabetes and macrovascular
with metformin of bladder cancer disease may reduce the risk of all-
[Avandamet], with (pioglitazone). Assess cause mortality, nonfatal MI and
glimepiride [Avandaryl]) stroke (NNT = 50)[Evidence level
risk factors and counsel
patients to report A; high-quality RCT]30
hematuria.31,34
More. . .
metformin23 days)a
MOA
Others – bile acid 0.5%32 Colesevelam • GI (e.g., constipation, • Lowers LDL cholesterol21
sequestrant 3.75 gm, given once nausea, bloating)21 • May decrease absorption of other
MOA: may reduce daily or divided BID • May increase meds21
Colesevelam (Welchol) hepatic glucose (~$600) triglycerides21
production, increase
• Rare hypoglycemia21
incretin levels, and
decrease glucose
absorption21
Others – dopamine 0.5% when added to Bromocriptine • Fatigue21 • Weight neutral28

agonist metformin and a 4.8 mg • Dizziness/syncope21 • CYP3A4 interactions24
sulfonylurea28 (~$650) • Nausea21
Bromocriptine (Cycloset)
MOA: may centrally • Rare hypoglycemia21
regulate metabolism,
increases insulin
sensitivity21
a. Approximate prices based on WAC for 30-day supply (of generic product if available, generic prices may vary considerably). If WAC not
available (chlorpropamide, tolazamide, tolbutamide), AWP for 30-day supply used.
More. . .
Levels of Evidence 6. Egan AG, Blind E, Dunder K, et al. Pancreatic safety

In accordance with the trend towards Evidence-Based of incretin-based drugs-FDA and EMA assessment.
N Engl J Med 2014;370:794-7.
Medicine, we are citing the LEVEL OF EVIDENCE 7. Scirica BM, Bhatt DL, Braunwald E, et al.
for the statements we publish. Saxagliptin and cardiovascular outcomes in patients
Level Definition with type 2 diabetes mellitus. N Engl J Med
A High-quality randomized controlled trial (RCT) 2013;369:1317-26.
High-quality meta-analysis (quantitative 8. Zannad F, Cannon CP, Cushman WC, et al. Heart
systematic review) failure and mortality outcomes in patients with type 2
B Nonrandomized clinical trial diabetes taking alogliptin versus placebo in
Nonquantitative systematic review EXAMINE: a multicentre, randomised, double-blind
Lower quality RCT trial. Lancet 2015;385:2067-76.
Clinical cohort study 9. Chiasson JL, Josse RG, Gomis R, et al. Acarbose
Case-control study for prevention of type 2 diabetes mellitus: the STOP-
Historical control NIDDM randomised trial. Lancet 2002;359:2072-7.
Epidemiologic study 10. Diabetes Prevention Program Research Group.
C Consensus Long-term safety, tolerability, and weight loss
Expert opinion associated with metformin in the Diabetes Prevention
D Anecdotal evidence Program Outcomes Study. Diabetes Care
In vitro or animal study 2012;35:731-7.
Adapted from Siwek J, et al. How to write an evidence-based clinical 11. FDA. Invokana and Invokamet (canagliflozin): drug
review article. Am Fam Physician 2002;65:251-8. safety communication – new information on bone
fracture risk and decreased bone mineral density.
September 10, 2015.
http://www.fda.gov/safety/medwatch/safetyinformatio
Project Leader in preparation of this clinical n/safetyalertsforhumanmedicalproducts/ucm461876.
resource (330711): Beth Bryant, Pharm.D., htm. (Accessed June 5, 2017).
Assistant Editor; last modified January 2018 12. FDA. FDA drug safety communication: FDA warns
that DPP-4 inhibitors for type 2 diabetes may cause
severe joint pain. August 28, 2015.
http://www.fda.gov/drugs/drugsafety/ucm459579.htm.
References (Accessed June 5, 2017).
1. Inzucchi SE, Bergenstal RM, Buse JB, et al. 13. Udell JA, Bhatt DL, Braunwald E, et al. Saxagliptin
Management of hyperglycemia in type 2 diabetes, and cardiovascular outcomes in patients with type 2
2015: a patient-centered approach. Diabetes Care diabetes and moderate or severe renal impairment:
2015;38:140-9. observations from the SAVOR-TIMI 53 trial.
2. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Diabetes Care 2015;38:696-705.
Consensus statement by the American Association 14. FDA. FDA drug safety communication: FDA revises
of Clinical Endocrinologists and American College of labels of SGLT2 inhibitors for diabetes to include
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management algorithm – 2017 executive summary. serious urinary tract infections. Last updated
Endo Pract 2017;23:207-38. January 2016.
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http://www.endocrinologynetwork.com/sglt2/sglt2- on/SafetyAlertsforHumanMedicalProducts/ucm50655
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m. (Accessed June 5, 2017).
More. . .
18. Faillie J, Yu OH, Yin H, et al. Association of bile duct diabetes II mortality results. Diabetes 1970;19:S789-
and gallbladder diseases with the use of incretin- 830.
based drugs in patients with type 2 diabetes mellitus. 30. Dormandy JA, Charbonnel B, Eckland DJ, et al.
JAMA Intern Med 2016;176:1474-81. Secondary prevention of macrovascular events in
19. Marso SP, Daniels GH, Brown-Frandsen K, et al. patients with type 2 diabetes in the PROactive Study
Liraglutide and cardiovascular outcomes in type 2 (PROspective pioglitAzone Clinical Trial In
diabetes. N Engl J Med 2016;375:311-22. macroVascular Events): a randomised controlled
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Cite this document as follows: Clinical Resource, Drugs for Type 2 Diabetes. Pharmacist’s Letter/Prescriber’s
Letter. July 2017.
Subscribers to the Letter can get clinical resources, like this one,
PrescribersLetter.com, PharmacyTechniciansLetter.com, or NursesLetter.com

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−This Clinical Resource gives subscribers

additional insight related to the Recommendations published in−

January 2017 ~ Resource #330104

Comparison of GLP-1 Agonists

Evidence and Recommendations You Can Trust…

Diabetes Medications and Cardiovascular Impact

Cardiovascular impact definitions listed in the chart include:

Medicationsa Cardiovascular Impact Cardiovascular Outcomes Data

Medicationsa Cardiovascular Impact Cardiovascular Outcomes Data

Medicationsa Cardiovascular Impact Cardiovascular Outcomes Data

Sodium-glucose co- Unknown: • Canagliflozin: CANVAS (CANagliflozin cardioVascular Assessment Study)

Medicationsa Cardiovascular Impact Cardiovascular Outcomes Data

Sulfonylureas (second Unknown: • Glimepiride: CAROLINA, CARdiovascular Outcome study of LINAgliptin

Medicationsa Cardiovascular Impact Cardiovascular Outcomes Data

Levels of Evidence 9. Home PD, Pocock SJ, Beck-Nielsen H, et al.

Evidence and Recommendations You Can Trust…

July 2017 ~ Resource #330711

Drugs for Type 2 Diabetes

Biguanide 1% to 1.5% as Metformin • B12 deficiency23 • Weight neutral21,23

Sitagliptin (Januvia, with

Glucagon-like, ~1% See our chart, • GI (diarrhea, nausea)21 • Weight loss21

Sodium-glucose co- 0.7% to 1% Canagliflozin • Genital fungal (yeast) • Weight loss21

Sulfonylurea-second 0.8% Glimepiride • Hypoglycemia, • Discontinue when more complex

Thiazolidinedione 0.8% Pioglitazone • Low risk of • Glycemic control better sustained

Others – dopamine 0.5% when added to Bromocriptine • Fatigue21 • Weight neutral28

Levels of Evidence 6. Egan AG, Blind E, Dunder K, et al. Pancreatic safety

Evidence and Recommendations You Can Trust…

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