DM Egregious Eleven

Diabetes Mellitus
By Andrew S. Bzowyckyj, Pharm.D., BCPS, CDE
Reviewed by: Christie Schumacher, Pharm.D., BCPS, BCACP, BC-ADM, CDE; and Heather L. Peterson, Pharm.D., BCPS
LEARNING OBJECTIVES
1. Apply the current treatment guidelines to a specific patient with type 2 diabetes.
2. Evaluate the appropriateness of non-insulin therapies in patient-specific situations.
3. Construct a treatment plan for a patient needing to convert between different insulin regimens.
4. Design a patient-specific regimen incorporating a fixed-ratio combination of a basal insulin and glucagon-like peptide-1
receptor agonist.
5. Assess the safety and efficacy of non-insulin therapies in a patient with type 1 diabetes.
INTRODUCTION
ABBREVIATIONS IN THIS CHAPTER
The prevalence and incidence of type 2 diabetes (T2DM) continue
ADA American Diabetes Association
to rise. An estimated 9.4% of the U.S. population has diabetes, with
DKA Diabetic ketoacidosis
T2DM accounting for 90%–95% of cases. This figure includes 23.1
GLP-1 RA Glucagon-like peptide-1 receptor
agonist million individuals with diagnosed disease and 7.2 million individu-
SGLT2 Sodium-glucose cotransporter-2 als without diagnosed disease. An additional 84.1 million U.S. adults
T1DM Type 1 diabetes 18 and older had prediabetes in 2015 (CDC 2017). Compounding
these statistics is the national obesity rate, which was 39.8% of all
T2DM Type 2 diabetes
U.S. adults in 2015–2016, with higher rates noted in Hispanic (47%)
TDD Total daily dose
and non-Hispanic black (46.8%) subgroups (NCHS 2017). As a result,
Table of other common abbreviations. pharmacists in all patient care settings should work to decrease the
morbidity and mortality associated with diabetes in a cost-effective
and patient-centered manner. This chapter focuses on updates and
emerging therapies in achieving glycemic goals in T2DM, though inno-
vations in managing type 1 diabetes (T1DM) will also be discussed.
Ominous Octet and Egregious Eleven

In 2009, the pathophysiology of diabetes was introduced as the “omi-
nous octet,” which challenged clinicians to think beyond impaired
insulin secretion, increased hepatic glucose production, and
decreased glucose uptake as the main drivers of hyperglycemia, by
adding five additional pathophysiologic factors: (1) decreased incretin
effect, (2) increased renal glucose reabsorption, (3) neurotransmitter
dysfunction, (4) increased glucagon secretion, and (5) increased lip-
olysis. This broader approach to diabetes has contributed to the shift
from sulfonylureas that only target one pathophysiologic process
toward agents that target several areas (e.g., glucagon-like peptide-1
receptor agonists [GLP-1 RAs]). In 2016, three more pathophysiologic
mechanisms were incorporated, creating the “egregious eleven”:
(1) decreased beta cell function and mass, (2) abnormal microbi-
ota, and (3) immune dysregulation/inflammation (Schwartz 2016).
PSAP 2019 BOOK 3 • Endocrinology and Nephrology 7 Diabetes Mellitus

These newly identified targets have shifted the approach of 2015 position statement on managing hyperglycemia incor-
caring for individuals with diabetes toward a focus on patient- porates new evidence gathered since publication of the
specific causes of hyperglycemia and tailoring treatment previous version. Whereas the previous consensus state-
accordingly. ments focused predominantly on efficacy in reducing
hyperglycemia, tolerability, and safety, this update empha-
CLINICAL GUIDELINE UPDATES FOR sizes the need to consider a patient’s concurrent medical
HYPERGLYCEMIA MANAGEMENT conditions and other patient-specific factors when deciding
on the right drug for a patient (Figure 1). This position state-
2018 ADA/EASD Consensus Report
ment heavily emphasizes the role of drugs that target several
The 2018 American Diabetes Association (ADA)/European
pathophysiologic processes for optimizing patient outcomes,
Association for the Study of Diabetes (EASD) update to the
relegating sulfonylureas and thiazolidinediones only to when
cost is a significant barrier. More specific guidance for inten-
sifying a patient’s regimen to injectable therapies is also
available, starting with a consideration for adding a GLP-1 RA
BASELINE KNOWLEDGE STATEMENTS
before insulin in most people with diabetes unless the A1C is
Readers of this chapter are presumed to be familiar over 11%, symptoms of catabolism are present (e.g., weight
with the following: loss, polyuria, polydipsia) suggesting insulin deficiency, or
• General knowledge of the pathophysiology that if T1DM is a possibility. Additional guidance is provided on
leads to hyperglycemia in diabetes mellitus when to consider initiating basal and mealtime insulins and
• A1C, fasting, and postprandial glycemic goals which oral drugs to discontinue when transitioning a patient
defined by leading diabetes guidelines to injectable therapies (Table 1).
• Familiarity with the various oral and non-insulin
injectable agents and insulins used to treat Updates to Additional Diabetes-Specific
diabetes mellitus References
• Consequences of not achieving glucose goals, In 2018, the annual ADA standards of care became a “living”
including micro- and macrovascular complications
document, with updates added as new evidence becomes
Table of common laboratory reference values available rather than waiting until the next year to incorpo-
rate timely recommendations. The American Association of
Clinical Endocrinologists (AACE) and the American College
ADDITIONAL READINGS
of Endocrinology (ACE) also publish a comprehensive T2DM
The following free resources have additional back- management algorithm annually. All of these references
ground information on this topic: provide useful algorithms and flowcharts for obesity man-
• American Diabetes Association (ADA). Standards agement, prediabetes treatment, cardiovascular risk factor
of Medical Care in Diabetes – 2019. Diabetes Care modifications, hyperglycemia management, and adding and
2019;42(suppl 1):S61-S138. intensifying insulin (Table 2).
• Garber AJ, Abrahamson MJ, Barzilay JI, et al.
Consensus statement by the American Association
of Clinical Endocrinologists and American College UPDATES IN NON-INSULIN THERAPIES
of Endocrinology on the comprehensive type 2
Glucagon-like Peptide-1 Receptor Agonists
diabetes algorithm – 2019 executive summary.
Endocr Pract 2019;25:91-100. Six GLP-1 RAs are available in the United States: twice-daily
• Davies MJ, D’Alessio DA, Fradkin J, et al. exenatide immediate release (IR), once-daily liraglutide and lix-
Management of hyperglycemia in type 2 diabetes, isenatide, and once-weekly formulations exenatide extended
2018. A consensus report by the American release (XR), dulaglutide, and semaglutide. The GLP-1 RAs are
Diabetes Association (ADA) and the European injected subcutaneously, though a once-daily oral formulation
Association for the Study of Diabetes (EASD). of semaglutide is currently in development (Aroda 2018). These
Diabetes Care 2018;41:2669-701.
drugs act by increasing glucose-dependent insulin secretion,
• Schwartz SS, Epstein S, Corkey BE, et al. The time decreasing glucose-dependent glucagon secretion, slowing
is right for a new classification system for diabe-
gastric emptying, and increasing satiety. Benefits of these
tes: rationale and implications of the
beta-cell-centric classification schema. Diabetes agents include a low risk of hypoglycemia and the potential to
Care 2016;39:179-86. facilitate weight loss or prevent further weight gain.
• Dickinson JK, Guzman SJ, Maryniuk MD, et al. The
use of language in diabetes care and education. Efficacy
Diabetes Care 2017;40:1790-9. In clinical trials, GLP-1 RAs have reduced A1C values by
1%–1.5%, with liraglutide, dulaglutide, and semaglutide having

Diagnosis of T2DM:
Metformin and comprehensive lifestyle
(including weight management and physical activity)
Established No established
A1C above goal
ASCVD, HF, or CKD ASCVD or CKD
ASCVD HF or CKD Compelling Compelling need Cost is a

predominatesa predominates need to minimize to minimize weight major issuea
hypoglycemiaa gain or promote
weight lossa
GLP-1 RA with proven SGLT2i with evidence
ASCVD benefitb of reducing HF and/or
(liraglutide > CKD progression DPP-4i GLP-1 RA Sulfonylurea
semaglutide > (if eGFR adequate) GLP-1 RA (semaglutide > (2nd generation)
exenatide extended (canagliflozin ~ SGLT2i liraglutide > TZD
release; dulaglutide) dapagliflozin ~ TZD dulaglutide >
OR empagliflozin) exenatide >
SGLT2i with proven lixisenatide)
ASCVD benefit SGLT2i
(if eGFR adequate) If SGLT2i not tolerated
(empagliflozin > or contraindicated, add
canagliflozin) GLP-1 RA with proven
ASCVD benefit
(liraglutide >
semaglutide >
exenatide extended
release; dulaglutide)
Figure 1. Overall approach to selecting glucose-lowering drug in type 2 diabetes.

The medication classes within each individual box are listed in alphabetical order, not in order of preference.
a
b
At the time of printing, the American Diabetes Association had not yet incorporated the dulaglutide data from the REWIND trial into
their treatment algorithm for patients with concurrent ASCVD.
ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; DPP-4i = dipeptidyl peptidase-4 inhibitor; HF =
heart failure; GLP-1 RA = glucagon-like peptide-1 receptor agonist; SGLT2i = sodium-glucose co-transporter-2 inhibitor; T2DM = type
2 diabetes; TZD = thiazolidinedione.
Information from: American Diabetes Association (ADA). Pharmacologic approaches to glycemic treatment: Standards of Medical
Care in Diabetes-2019. Diabetes Care 2019;42(suppl 1):S90-S102; Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and
cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind randomised placebo-controlled trial. Lancet 2019;394:121-30.
Table 1. Considerations When Combining Oral Therapy with Injectable Therapies
Oral Therapy Consideration (clinical judgment may supersede)
Metformin Continue metformin
TZD Discontinue TZD when initiating insulin OR reduce TZD dose
SU Discontinue or reduce dose of SU by 50% when basal insulin is initiated (if patient at risk of hypoglycemia)
Discontinue SU if mealtime insulin initiated or on a premix regimen
SGLT2i Continue SGLT2i
DPP-4i Discontinue DPP-4i if GLP-1 RA initiated
DPP-4i = dipeptidyl peptidase-4 inhibitor; GLP-1 RA = glucagon-like peptide-1 receptor agonist; SGLT2i = sodium-glucose
cotransporter-2 inhibitor; SU = sulfonylurea; TZD = thiazolidinedione.
Information from: Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus
report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care
2018;41:2669-701.

Table 2. Overview of Recommendations for Initiating and Titrating Insulin
2019 ADA Standards of Care & 2018 ADA/EASD 2019 AACE/ACE Comprehensive
Recommendation Consensus Report Diabetes Management Algorithm
Consider injectable A1C > 10% and/or 2% above target A1C > 9% and symptomatic
combination (i.e., basal Consider insulin as first injectable if:
insulin + GLP-1 RA or bolus • A1C very high (> 11%)
insulin) • Symptoms or evidence of catabolism (e.g., weight
loss, polyuria, polydipsia) that suggest insulin
deficiency
• Type 1 diabetes is a possibility
Basal Insulin
Starting dose 10 units/day or 0.1–0.2 unit/kg/day A1C < 8%: 0.1–0.2 unit/kg/day
A1C > 8%: 0.2–0.3 unit/kg/day
Dose titration • Set FBG target that correlates with A1C target Reassess q2–3 days
• Advise patient to increase by 2 units every 3 days FBG 110–139 mg/dL: Increase by 1 unit
until FBG target reached FBG 140–180 mg/dL: Increase by 10% of
total daily basal dose
FBG > 180 mg/dL: Increase by 20% of total
daily basal dose
Hypoglycemia If no clear cause, lower dose by 10%–20% BG < 70 mg/dL: Decrease by 10%–20% of
BG < 40 mg/dL: Decrease by 20%–40% of
Bolus/Prandial Insulin
Starting dose • 4 units or 10% of basal dose before largest meal 10% of basal dose or 5 units before
• If A1C < 8%, consider lowering basal dose by largest meal
4 units/day or 10% of basal dose
Dose titration • Increase dose by 1–2 units or 10%–15% twice Reassess q2–3 days
weekly 2-hour postprandial or next premeal
• Stepwise addition of prandial insulin every 3 mo if BG > 140 mg/dL consistently: Increase
A1C remains above target prandial dose by 1–2 units or 10%
BG = blood glucose; FBG = fasting blood glucose; q = every; TDD = total daily dose.
Information from: American Diabetes Association (ADA). Pharmacologic approaches to glycemic treatment: Standards of Medical
Care in Diabetes-2019. Diabetes Care 2019;42(suppl 1):S90-S102; Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus
statement by the AACE and ACE on the comprehensive type 2 diabetes management algorithm – 2019 executive summary. Endocr
Pract 2019;25:69-100.
larger A1C reductions than the other GLP-1 RAs in head-to- 1.5 mg weekly, respectively (Ahmann 2018; Pratley 2018). The
head trials (Htike 2017; Orme 2017). In addition, the weight order of magnitude from the most to the least weight loss
reduction with these drugs has been favorable. Liraglutide has is semaglutide, liraglutide, dulaglutide, exenatide, and lix-
a labeled indication for weight loss, even in individuals with- isenatide (Davies 2018).
out diabetes, marketed as Saxenda. The dosage is 3 mg daily An additional benefit of some GLP-1 RAs is their ability
for weight loss versus 1.8 mg daily for diabetes. The other to reduce the risk of major adverse cardiovascular events,
GLP-1 RAs have shown overall mean reductions in weight of a composite end point including cardiovascular death, non-
1–2 kg in randomized controlled trials compared with pla- fatal myocardial infarction, and nonfatal stroke (Table 3).
cebo, except for semaglutide (Htike 2017). In the SUSTAIN-3 Liraglutide and semaglutide may also prevent new or wors-
and SUSTAIN-7 trials, semaglutide 1 mg weekly had a mean ening nephropathy, according to secondary outcomes from
weight loss of 5.6 kg compared with 3 kg with exenatide XR their cardiovascular outcomes trials, with HRs of 0.78 (0.67–
2 mg weekly and 6.5 kg compared with 3 kg with dulaglutide 0.92) and 0.64 (0.46–0.88), respectively.

Patient Care Scenario
G.K. is a 68-year-old woman with newly diagnosed T2DM. obesity, and a myocardial infarction 2 years ago. Her
She has had difficulty tolerating metformin, even at low drug regimen consists of atorvastatin 80 mg daily, lisino-
doses of the XR formulation. She denies any overt symp- pril 40 mg daily, carvedilol 25 mg twice daily, and aspirin
toms of hyperglycemia. Her relevant clinical information 81 mg daily. Her physician has recommended an A1C tar-
includes A1C 10.8%, weight 128 kg (BMI 44.1 kg/m2), blood get of less than 7%, and G.K. is in agreement. What is the
pressure 132/78 mm Hg, and a history of hypertension, most appropriate regimen for her T2DM?
ANSWER
Using the ADA/EASD algorithm, this patient is a candi- semaglutide, dulaglutide), with the final decision made
date for the initial injectable combination, given her A1C on the basis of the patient’s preferred device charac-
above 10% and greater than 2% above her target. Options teristics and dosing frequency, in addition to insurance
include a GLP-1 RA, basal insulin, and/or prandial insulin. formulary. A fixed-ratio combination of basal insulin and
With an A1C above 9%, she should be offered a once-daily GLP-1 RA can be used if not cost-prohibitive, with deglu-
basal insulin (at least in the short term) because there is dec/liraglutide preferred, given the cardiovascular benefit
likely some form of insulin insufficiency. Given her history of liraglutide compared with lixisenatide. However, the
of cardiovascular disease and obesity, she is also a can- patient’s BMI suggests she needs more than 50 units/day
didate for a GLP-1 RA, preferably one with cardiovascular of insulin, which makes using a fixed-ratio combination
benefits. Bolus/prandial insulin is likely not needed at this difficult.
time, given the relatively low likelihood that she has T1DM Once the patient’s glucose values are closer to target
or insulin deficiency and the risk of further weight gain. range and the GLP-1 RA is at maximum tolerated dose,
For her basal regimen, a starting dosage of 10 units a sodium-glucose cotransporter-2 (SGLT2) inhibitor
once daily can be used, though a weight-based dose of with cardiovascular benefit can be added to her regimen
13–26 units once daily (0.1–0.2 unit/kg/day) is likely more if additional glucose lowering is still indicated, with the
appropriate, given her higher BMI. A GLP-1 RA with proven added benefit of providing additional cardiovascular risk
cardiovascular benefit would be preferred (i.e. liraglutide, reduction.
1. American Diabetes Association (ADA). Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2019.
Diabetes Care 2019;42(suppl 1):S90-S102.
2. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the AACE and ACE on the comprehensive type 2 diabetes man-
agement algorithm – 2019 executive summary. Endocr Pract 2019;25:69-100.
3. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American
Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018;41:2669-701.
Safety initiating GLP-1 RAs. Common symptoms include excessive

The most common adverse effects with GLP-1 RAs are nau- nausea, vomiting, and right upper quadrant stomach pain,
sea, vomiting, diarrhea, and cholelithiasis, occurring in a and patients should be educated to seek medical attention if
dose-dependent manner (Bettge 2017; Htike 2017; Monami these symptoms occur.
2017). The long-acting agents tend to be associated with Liraglutide, dulaglutide, semaglutide, and exenatide XR
less nausea and vomiting, but more diarrhea, although sema- have been associated with thyroid C-cell tumors in animal
glutide does come with a considerable amount of nausea studies. These drugs have a black box warning for the risk
at the highest dose (Bettge 2017). Whether incretin-based of developing thyroid C-cell tumors and are contraindicated
therapies, including GLP-1 RAs, increase the risk of acute in patients with a personal history of medullary thyroid carci-
pancreatitis remains controversial. Recent analyses of large noma or multiple endocrine neoplasia syndrome type 2.
randomized controlled trials have not shown an increased An emerging area of concern is the increased risk of ret-
risk of pancreatitis (Liu 2018; Saisho 2018; Monami 2017). inopathy complications with semaglutide. These include
A post hoc analysis of the LEADER trial was unable to iden- vitreous hemorrhage, onset of diabetes-related blindness,
tify predictors for which patients taking liraglutide were more need for treatment with an intravitreal agent, and retinal pho-
likely to develop pancreatitis (Steinberg 2017). Of interest, a tocoagulation, which all occurred at a higher incidence in the
history of pancreatitis was not a predictive factor because semaglutide group than in placebo in the SUSTAIN-6 trial (3%
the incidence of pancreatitis in patients who entered the trial vs. 1.8%; HR 1.76; 95% CI, 1.11–2.78) (Marso 2016). Trials are
with a history of pancreatitis was 1.4% and 5% for liraglutide under way to further investigate this finding.
and placebo, respectively. However, because spontaneous
postmarketing reports of pancreatitis have been submitted GLP-1 RA Devices
to the FDA, pancreatitis has been added as a precaution to In addition to efficacy, each pen’s specific characteristics
the labeling of each GLP-1 RA. The risk, as well as the symp- should be considered to ensure the patient can successfully
toms, of pancreatitis should be discussed with patients when use the device. Liraglutide, lixisenatide, exenatide IR, and

Table 3. Overview of CV Outcomes Trials Focused on GLP-1 RAs and SGLT2i Agents
No. of Median Trial MACE Outcomes

Trial Agent Study Population Patients Duration (95% CI)
GLP-1 RA
ELIXA Lixisenatide Age 30+ with ASCVD 6068 2.1 yr HR 1.02 (0.89–1.17)
LEADER Liraglutide a
Age 50+ with ASCVD; 60+ with 1+ CV 9340 3.8 yr HR 0.87 (0.78–0.97)
risk factor
EXSCEL Exenatide XR 73.1% had ASCVD; 26.9% did not 14,752 3.2 yr HR 0.91 (0.83–1.00)
SUSTAIN-6 Semaglutide Age 50+ with ASCVD, CHF, or stage 3297 2 yr HR 0.74 (0.58–0.95)
3–5 CKD; 60+ with 1+ CV risk factor
REWIND Dulaglutide Age 50+ with ASCVD; 55+ with ASCVD 9901 5.4 yr HR 0.88 (0.79–0.99)
or 1 CV risk factor; 60+ with 2+ CV
risk factors
HARMONY Albiglutideb Age 40+ with ASCVD 9463 1.6 yr HR 0.78 (0.68–0.90)
SGLT2i
CANVAS Canagliflozina Age 30+ with ASCVD; 50+ with 2+ CV 10,142 3.6 yrc HR 0.86 (0.75–0.97)
risk factors
EMPA-REG Empagliflozind Age 18+ with ASCVD 7020 3.1 yr HR 0.86 (0.74–0.99)
OUTCOME
DECLARE-TIMI 58 Dapagliflozin Age 40+ with ASCVD; men 55+ with 17,160 4.2 yr HR 0.93 (0.84–1.03)
2+ CV risk factors; women 60+ with
1+ CV risk factor
VERTIS-CV Ertugliflozin Age 40+ with ASCVD 8237 N/A Results expected 2020
a
Labeled indication to reduce the risk of major adverse CV events in adults with type 2 diabetes and established CV disease.
b
Removed from market in 2018 because of poor market penetration.
c
Data expressed as mean.
d
Labeled indication to reduce the risk of CV death in adults with type 2 diabetes and established CV disease.
ASCVD = atherosclerotic cardiovascular disease; CHF = chronic heart failure; CKD = chronic kidney disease; CV = cardiovascular;
MACE = major adverse cardiovascular events; N/A = not applicable.
Information from: Pfeffer MA, Claggett B, Diaz R. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl
J Med 2015;373:2247-57; Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2
diabetes. N Engl J Med 2016;375:311-22; Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular
outcomes in type 2 diabetes. N Engl J Med 2017;377:1228-39; Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular
outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834-44; Gerstein HC, Colhoun HM, Dagenais GR, et al.
Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind randomised placebo-controlled trial. Lancet
2019;394:121-30; Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2
diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet
2018;392:1519-29; Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N
Engl J Med 2017;377:644-57; Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2
diabetes. N Engl J Med 2015;373:2117-28; Cannon CP, McGuire D, Pratley R, et al. Design and baseline characteristics of the
evaluation of ertugliflozin efficacy and safety cardiovascular outcomes trial (VERTIS-CV). Am Heart J 2018;206:11-23; ClinicalTrials.
gov (https://clinicaltrials.gov/ct2/show/NCT01986881).
semaglutide all come in multiuse pens that use the same pen use with liraglutide, lixisenatide, and exenatide IR so that the
needles as insulin pens. This may increase patient accep- patient can administer the drug. Semaglutide is packaged
tance because patients may be more familiar with this type such that each box already contains pen needles.
of pen needle. These needles must be attached immediately Alternatively, dulaglutide and exenatide XR both come in
before and removed immediately after each dose, requiring a single-use formulations. Dulaglutide was the first GLP-1 RA
certain level of dexterity. A separate prescription should be to come in an autoinjector pen, which automatically recon-
sent for pen needles (or the current prescription updated) to stitutes the drug and contains a built-in needle that is never

seen by the patient. This device can be a good option for Empagliflozin and canagliflozin have additional labeled indi-
patients with limited dexterity because it is easier to use than cations for reducing cardiovascular death and major adverse
other GLP-1 RA devices. Finally, exenatide XR is available cardiovascular events, respectively, in adults with T2DM and
in two different single-use pens. The exenatide XR dual- established cardiovascular disease (see Table 3). In each of the
chamber pen is quite bulky compared with similar devices published SGLT2 inhibitor cardiovascular outcome trials, hospi-
and requires a series of steps to be completed before admin- talization for heart failure was reduced compared with placebo
istering the drug, including tapping the pen 80 times or more (canagliflozin HR 0.67; 95% CI, 0.52–0.87; empagliflozin HR 0.65;
to reconstitute the drug. The newest device, Bydureon BCise, 95% CI, 0.50–0.85; dapagliflozin HR 0.73; 95% CI, 0.61–0.88)
incorporates an autoinjector technology similar to dula- (Wiviott 2019; Neal 2017; Zinman 2015).
glutide. Now, the patient is responsible for only one step In CANVAS and DECLARE-TIMI 58, canagliflozin and dapagli-
– shaking the pen for at least 15 seconds before injecting. All flozin reduced renal secondary outcomes by 40% and 47%,
exenatide XR pens require a 23-gauge needle because of the respectively (a composite of renal effects, including a 40% reduc-
way the drug is formulated, which may be a significant draw- tion in estimated glomerular filtration rate [eGFR], initiation of
back from the patient’s perspective. However, the BCise pen renal replacement therapy, and renal death) (Wiviott 2019; Neal
has a preattached needle that is never seen by the patient, 2017). In EMPA-REG, empagliflozin was associated with a 46%
which may help patient-perceived tolerability. reduction in the composite outcome of doubling of the SCr con-
centration accompanied by an eGFR of 45 mL/minute/1.73 m2 or
Sodium-Glucose Cotransporter-2 Inhibitors less, initiation of renal replacement therapy, or death from renal
Currently, the sodium-glucose cotransporter-2 (SGLT2) disease (Wanner 2016). Empagliflozin was also associated with
inhibitor class includes canagliflozin, dapagliflozin, empagli- a 39% reduction in incident or worsening nephropathy and a 38%
flozin, and ertugliflozin. These agents work directly on the reduction in progression to macroalbuminuria (Wanner 2016).
SGLT2 receptors in the renal proximal tubules to inhibit glu- In CREDENCE, canagliflozin was associated with a 34% reduc-
cose reabsorption. In individuals without diabetes, SGLT2 tion in the composite outcome of doubling of serum creatinine
is responsible for ensuring glucose is appropriately reab- level, end-stage kidney disease, renal death, and cardiovascu-
sorbed, resulting in extremely low glucose concentrations lar death, in patients with a baseline eGFR of 30 to less than
in the urine. In the presence of longstanding hyperglycemia, 90 mL/minute/1.73 m2 and albuminuria (Perkovic 2019). The
the renal proximal tubules try to increase the SGLT2 transport hypothesized nephroprotective mechanisms include improved
maximum as a compensatory mechanism for preserving this glycemic management, normalization of glomerular hyperfiltra-
energy source, not necessarily realizing the blood glucose tion, diuretic effects, anti-inflammatory and antioxidative stress
concentrations are exceeding those necessary for normal effects, improved endothelial function, diminished sympathetic
physiologic processes (Mosley 2015; Cersosimo 2014). In nerve activity, and increased renal oxygen consumption and
addition, SGLT2 inhibition reduces the threshold for renal glu- energy production through increases in Hct and β-hydroxybutyr-
cose reabsorption, thereby promoting glucose excretion and ate (Mima 2018). In populations with renal impairment, SGLT2
decreasing blood glucose concentrations. inhibition was consistently associated with an initial decrease in
eGFR, followed by an increase and then a return to baseline, sug-
Efficacy gesting a benefit in patients with reduced renal function (Seidu
In clinical trials, these drugs reduce the A1C by about 0.5%– 2018). However, SGLT inhibitor use in severe renal impairment is
1% (Zaccardi 2016). The resultant glycosuria may facilitate not recommended because the glucose-lowering effects do not
weight loss through an overall reduction in calories being occur at eGFR values below 30 mL/minute/1.73 m2. The pack-
metabolized. With 4 calories lost for each gram of glucose age labeling provides some guidance, noting these drugs are not
excreted in the urine, SGLT2 inhibitors can lead to a poten- recommended for use in patients with an eGFR less than 45 mL/
tial net loss of 160–320 calories/day (Ribola 2017; Bays minute/1.73 m2 for canagliflozin, dapagliflozin, and empagliflozin
2014). However, weight loss with SGLT2 inhibitor use is not as or less than 60 mL/minute/1.73 m2 for ertugliflozin. However,
much as what is expected, potentially because of an adaptive updated ADA recommendations recommend clinicians consider
increase in the intake of calories (Ferrannini 2015). This risk using an SGLT2 inhibitor in patients with type 2 diabetes and kid-
may be mitigated using the SGLT2 inhibitor in combination ney disease as long as the eGFR is above 30 mL/minute/1.73 m2
with a GLP-1 RA. In addition to glucose-lowering and weight- to reduce the risk of CKD progression, cardiovascular events, or
loss benefits, these agents moderately reduce blood pressure. both, especially if albuminuria is present.
The hypothesized mechanisms for blood pressure reduction
Safety
include osmotic diuresis, mild natriuresis, weight reduction,
and indirect effects on nitric oxide release (Majewski 2015). Euglycemic Diabetic Ketoacidosis
Blood pressure reductions in clinical trials were 3–5 mm Hg Euglycemic diabetic ketoacidosis (DKA), characterized by an
in systolic blood pressure and 1–2 mm Hg in diastolic blood increased anion gap metabolic acidosis, ketonemia, and nor-
pressure (Zaccardi 2016). mal blood glucose concentrations, has been reported with

SGLT2 inhibitor use (Rawla 2017; Peters 2015). Individuals (Kumar 2017). Maintaining good hygiene in the perineum and
with euglycemic DKA have nausea, vomiting, and malaise but genital regions is essential for avoiding this condition.
lack hyperglycemia, which often delays recognition because
the symptoms are nonspecific (Lupsa 2018). Most eugly- Risk Mitigation Strategies
cemic DKA episodes have occurred in individuals with A thorough medical history and medication review should
T1DM using SGLT2 inhibitors off-label, but these episodes be done before initiating an SGLT2 inhibitor, including ask-
can also occur in people with T2DM (Palmer 2016; Peters ing about a history of UTIs, acute kidney injury, DKA, chronic
2015). Risk factors for developing euglycemic DKA include genitourinary conditions (e.g., benign prostatic hypertrophy,
serious illness, surgical stress, alcohol binge, low carbohy- urinary incontinence), and drugs that may cause hypovole-
drate intake, and decreased insulin production/availability mia (e.g., loop diuretics) or nephrotoxicity (e.g., NSAIDs). To
(Lupsa 2018). An additional emerging high-risk group are minimize adverse effects, patients should maintain adequate
those who deliberately restrict insulin in order to lose hydration and avoid excessive hyperglycemia.
weight (Staite 2018). Thiazide-like diuretics are generally not an issue when
adding an SGLT2 inhibitor; however, reducing the dose of a
Amputations
loop diuretic by 50% should be considered when adding an
SGLT2 inhibitor (Lupsa 2018). To minimize the risk of acute
The risk of lower-extremity amputations has also emerged
kidney injury, avoid initiating a thiazide-like diuretic, angioten-
from clinical trials and population-based analyses, specif-
sin-converting enzyme inhibitor, and SGLT2 inhibitor at the
ically with canagliflozin (including the addition of a black
same time, when possible. Finally, the patient’s blood pres-
box warning). In the CANVAS trial, the incidence of amputa-
sure and volume status must be sufficient to accommodate
tion in the canagliflozin group was almost double that in the
the addition of an SGLT2 inhibitor. If tolerability is a concern,
placebo group (6.3 per 1000 patient-years vs. 3.4 per 1000 using half of the traditional SGLT2 inhibitor starting dose can
patient-years, p<0.001) (Neal 2017). This increased incidence mitigate this risk, as can more frequent follow-ups.
of amputation did not occur in the EMPA-REG and DECLARE-
TIMI 58 trials, so it may not be a class effect. According to
Non-Insulin Therapies in the Inpatient Setting
analyses of the CANVAS program data, the highest-risk popu-
For noncritically ill patients receiving care in the hospital,
lations include those with a history of amputation, peripheral
insulin remains the preferred treatment. However, continuing
vascular disease, neuropathy, or foot ulcers (FDA 2017). a patient’s home regimen consisting of non-insulin therapies
is sometimes appropriate. Metformin plays a limited role in
Skeletal Fractures the inpatient setting, especially if the patient is at high risk of
Canagliflozin has also been associated with an increased dehydration or renal insufficiency or is likely to receive radio-
risk of skeletal fractures, according to data from the CANVAS contrast media or other nephrotoxic drugs. Similarly, SGLT2
program (15.4 per 1000 patient-years vs. 11.9 per 1000 patient- inhibitors should generally be avoided, given the risk of eug-
years) in addition to a phase IV postmarketing study required lycemic DKA during periods of prolonged fasting and surgical
by the FDA that showed a reduction in total hip bone mineral procedures (Lupsa 2018). Thiazolidinediones likely also do
density over 104 weeks (placebo-subtracted change of -0.9% not play a role in the inpatient setting, especially if used con-
and -1.2% in 100- and 300-mg groups, respectively) (Neal currently with insulin. Sulfonylureas can increase the risk of
2017; Bilezikian 2016). The clinical significance of this finding hypoglycemia; however, if the patient’s diabetes is already
is still unclear, given that a meta-analysis of trials involving well managed on a sulfonylurea, the patient is eating regu-
canagliflozin, dapagliflozin, and empagliflozin did not sup- larly scheduled meals and has a low risk of hypoglycemia,
port a harmful effect of SGLT2 inhibitors on bone (Tang 2016). and a relatively short admission is planned, it may be appro-
The 2019 AACE and ACE consensus statement removed the priate to continue sulfonylureas.
warning for bone safety with all SGLT2 inhibitors, citing the The dipeptidyl peptidase-4 inhibitors may play a role in the
inpatient setting, with recent literature supporting their use in
lack of data supporting this association (Garber 2019).
combination with basal insulin, resulting in glucose manage-
ment and frequency of hypoglycemia similar to a basal-bolus
Genitourinary Risks
insulin regimen (Garg 2017a; Pasquel 2017). Given the recom-
The increased risk of bladder cancer was identified during mendation to avoid saxagliptin or alogliptin in patients with
early trials with dapagliflozin, but this increased risk has not heart failure, sitagliptin or linagliptin would be preferable for
occurred in subsequent studies or in clinical practice (Lupsa an inpatient formulary. Although GLP-1 RAs may also play a
2018). All the SGLT2 inhibitors have a warning about the risk role in the inpatient setting, their GI-related adverse effects
of Fournier gangrene. The reported incidence of this condi- (e.g., nausea, vomiting, decreased appetite, early satiety) may
tion is 55 cases over a nearly 6-year period of postmarketing be problematic in hospitalized patients because of appetite
reports, making the identification of specific risk factors dif- suppression from their concurrent illness (Umpierrez 2013).
ficult. Obesity, immunosuppressed states, smoking, alcohol As these agents come off patent in the coming years, a lower
abuse, and end-stage renal or liver failure may increase risk cost may make them more appealing in the inpatient setting.

INSULIN UPDATES 0.58; 95% CI, 0.46–0.74) compared with insulin glargine U-100
Basal insulin analog options for patients have dramatically (Lane 2017; Wysham 2017).
expanded with the addition of insulin degludec, resurgence of These ultra-long acting insulin analogs are only available
concentrated insulins, and introduction of biosimilar insulins. in pen form, with the exception of insulin degludec U-100,
which is also available in vials for pediatric patients requiring
Ultra-Long Acting Insulin Analogs less than 5 units each day (Table 4). Patients must be edu-
The triple-concentrated formulation of insulin glargine cated not to use an insulin syringe to obtain their insulin from
(U-300) results in a smaller depot surface area after injec- the pen because of the risk of inaccurate dosing, especially
tion, a flatter pharmacokinetic profile, and a longer duration with concentrated insulins (Bzowyckyj 2016).
of action than traditional insulin glargine (up to 36 hours).
Another new basal insulin analog is insulin degludec, with an Ultra-Rapid Insulin Analog
almost entirely flat pharmacokinetic profile and a duration of Fast-acting insulin aspart has the same molecular structure
action lasting at least 42 hours, allowing for a flexible dosing as traditional insulin aspart, with the addition of niacina-
schedule, consistent insulin concentrations throughout the mide (for faster absorption) and l-arginine (as a stabilizing
day and night, and less hypoglycemia than other basal insu- agent) resulting in a quicker onset and the ability to admin-
lins. In the SWITCH trials, insulin degludec was associated ister a dose as late as 20 minutes after starting a meal. In
with a lower incidence of hypoglycemia in T1DM (RR 0.89; the ONSET 1 trial, patients with T1DM were randomized to
95% CI, 0.85–0.94) and T2DM (RR 0.70; 95% CI, 0.61–0.80), fast-acting insulin aspart at mealtime, fast-acting insulin
as well as a lower incidence of nocturnal symptomatic hypo- aspart postmeal, or traditional insulin aspart at mealtime
glycemia in T1DM (RR 0.64; 95% CI, 0.56–0.73) and T2DM (RR (all in addition to insulin detemir). Mealtime was defined as
Table 4. Product Characteristics of Newer Insulin Products
Supplied as Units Max Dose for Shelf-life, Open

Pen, Vial, or Concentration per Pen Single Injection and Unrefrigerated
Generic Name Brand Name Both (units/mL) Device from Pen (units) (days)
Degludec Tresiba U-100 Both 100 300 80 56
Tresiba U-200 Pen 200 600 160 a

56
Glargine Toujeo Pen 300 450 80 56
Toujeo Max Pen 300 900 160a 56
Lantus Both 100 300 80 28
Basaglar Pen 100 300 80 28
Detemir Levemir Both 100 300 80 42
Lispro Humalog U-100 Both 100 300 60 28
Humalog U-100 Pen 100 300 30 b

28
Junior
Humalog U-200 Pen 200 600 60 28
Admelog Both 100 300 80 28
Aspart NovoLog Both 100 300 60 28
Glulisine Apidra Both 100 300 80 28
Fast-acting aspart Fiasp Both 100 300 80 28
Insulin human U-500 Humulin R U-500 Both 500 1500 300 c

28
a
Dosed in 2-unit increments.
b
Dosed in 0.5-unit increments.
c
Dosed in 5-unit increments.

0–2 minutes before a meal, and postmeal was 20 minutes patient’s entire insulin regimen should be discontinued, and
after the start of the meal. Compared with traditional insulin the recommended TDD of U-500 insulin should be divided out
aspart, postprandial plasma glucose at 1 and 2 hours after a over two or three doses. If given twice daily, 60% of the TDD
meal was significantly lower with fast-acting insulin aspart should be administered before breakfast, with the remainder
administered at mealtime (-21.21 mg/dL and -12.01 mg/dL, administered before dinner. If given three times daily, 40% of
respectively), but not when administered postmeal, with sim- the TDD should be administered before breakfast, 30% before
ilar rates of hypoglycemia between all groups (Russell-Jones lunch, and 30% before dinner. The pen formulation of U-500
2017). In the ONSET 2 trial, patients with T2DM were random- insulin is preferred to eliminate the need for dose conver-
ized to either fast-acting insulin aspart or traditional insulin sions. If a patient needs to use the vial formulation, the U-500
aspart administered at mealtime, with insulin glargine and insulin syringes should be co-prescribed with it.
metformin used as adjunctive therapies. Compared with tra-
Changing to NPH Insulin
ditional insulin aspart, this trial found that fast-acting insulin
aspart only improved 1-hour postprandial glucose (-10.63 With the rising costs of insulin and changes in insurance
mg/dL). In addition, postprandial hypoglycemia (0–2 hours) coverage, the cost of insulin analogs has become increas-
was higher in the fast-acting insulin aspart group (RR 1.60; ingly out of reach for patients. Therefore, patients may need
95% CI, 1.13–2.27; p=0.0082) (Bowering 2017). According to to change to neutral protamine Hagedorn (NPH) and regu-
the results of the ONSET trials, fast-acting insulin aspart may lar insulin for their lower price tag and OTC access. Patients
be more useful in the T1DM population through better post- changing from a basal insulin analog to NPH insulin can likely
prandial glucose management. Additional trials have been be changed on a unit-per-unit basis. Usually, changing to
completed or are in the process of evaluating the usefulness NPH insulin requires a twice-daily dosing schedule and a 20%
of fast-acting insulin aspart in insulin pumps. Preliminary dose increase. However, the dose increase should be deferred
results are promising, but further investigation is warranted during the transition to minimize the risk of hypoglycemia,
to evaluate the potential increased risk of hypoglycemia, especially for patients who are already achieving their glyce-
infusion site reactions, and premature infusion-set changes mic goals. Similarly, patients and clinicians may choose to
compared with insulin aspart (Klonoff 2019; Zijlstra 2018). change to a premixed insulin formulation (e.g., 70/30). In this
At the time of publication, use of fast-acting insulin aspart in situation, one approach is to calculate the patient’s current
insulin pumps is considered off-label. TDD of insulin from all sources, reduce the dose by 10%–20%
if the patient is at high risk of hypoglycemia, and divide that
Insulin Dosing Conversions amount evenly into two doses (Bhattacharyya 2014). The first
With the increase in commercially available insulin products, dose is administered before breakfast and the other before
additional complexity exists when changing between prod- dinner. During these transitions between insulin regimens,
ucts. Most patients administering their basal insulin once more frequent blood glucose monitoring and follow-up is rec-
daily can be converted to the same dose of the new basal ommended to adjust doses accordingly.
insulin, with a few exceptions. In clinical trials, patients tak-
Changing from a Premixed Insulin Regimen
ing U-300 insulin glargine needed higher doses to achieve
If changing from 70/30 insulin to a typical multidose injec-
the same glycemic goals compared with patients taking
tion regimen using insulin analogs, calculate the TDD of each
U-100 insulin glargine. Therefore, patients changing from
insulin separately and convert to their respective insulin
U-300 insulin glargine to an alternative basal insulin ana-
doses. For example, if a patient is taking 60 units of 70/30
log are advised to set their new basal insulin dose at about
twice daily, this would equate to 84 units of NPH insulin and
80% of their current dose. Patients changing to U-300 insulin
36 units of mealtime insulin (either rapid or regular). From
glargine or insulin degludec from a twice-daily dosing regi-
there, a 20% reduction in NPH insulin is warranted because
men of any basal insulin analog should decrease the dose by
the patient will be changing from twice-daily NPH to a once-
20% and administer the new insulin once daily.
daily basal analog, resulting in a dose of 67 units once daily.
Concentrated Insulins The patient’s mealtime dose should then be divided evenly
For patients requiring more than 200 units/day of insulin, between three meals, resulting in a bolus dose of 12 units
U-500 insulin regular can be considered. The starting dose three times daily with meals.
for U-500 depends on the patient’s current glucose concen- Subsequent Dose Adjustments
trations. If the A1C is less than 8% or the mean self-monitored
Questions have arisen regarding whether insulin detemir and
glucose concentrations within the past 7 days are less than
U-100 insulin glargine are truly comparable on a unit-per-
180 mg/dL, the patient’s total daily dose (TDD) of U-500
unit basis. If changing from U-100 insulin glargine to insulin
should start at 80% of his or her current TDD of insulin (Hood
detemir, a one-to-one dose conversion is advised, but note
2015). If the patient does not meet either criterion, the TDD of
that an eventual dose increase may be warranted to achieve
U-500 should be equal to his or her current TDD of insulin. The
the same glycemic goals (Wallace 2014). In addition, insulin

Table 5. Product Characteristics of Basal Insulin/GLP-1 RA Fixed-Ratio Combinations
Insulin Glargine and Lixisenatide Insulin Degludec and Liraglutide

Characteristic (Soliqua 100/33) (Xultophy 100/3.6)
Insulin concentration 100 units/mL 100 units/mL

GLP-1 RA concentration 33 mcg/mL 3.6 mg/mL
Insulin amount per pen 300 units 300 units
GLP-1 RA amount per pen 99 mcg 10.8 mg
Starting dose (naive to basal insulin or 15 units/5 mcg 10 units/0.36 mg
GLP-1 RA)
Starting dose (currently on basal insulin 15 units/5 mcg (if current basal insulin 16 units/0.58 mg (regardless of current
or GLP-1 RA) dose < 30 units daily) basal insulin dose)
30 units/10 mcg (if current basal insulin
dose = 30–60 units daily)
Dose titrations Increase/decrease by 2–4 units every Increase/decrease by 2 units every 3–4
week days
Max insulin dose per day 60 units 50 units
Max GLP-1 RA dose per day 20 mcg 1.8 mg
Shelf-life (open and unrefrigerated) 28 days 21 days
detemir may need to be administered twice daily to achieve therapy varies depending on the product and patient’s regi-
24-hour basal coverage, especially with doses of less than or men at baseline (Table 5).
equal to 0.4 unit/kg/day in T1DM (Wallace 2014).
When changing insulin regimens, the patient should be NON-INSULIN THERAPIES IN T1DM
notified that subsequent dose changes may be necessary. Currently, the only drugs approved for helping patients
People may respond to insulin products differently, so get- achieve glycemic goals in T1DM are insulin and pramlintide.
ting the dose “right” on the first try is unlikely. The highest
However, one study evaluating several T1DM exchange reg-
priorities when changing insulin regimens are to get the
istries found that 5.4% of patients were using an adjuvant
patient comfortable and to balance the risks of hypoglycemia
agent for their diabetes including metformin (3.5%), GLP-1
or hyperglycemia. Patients must be advised that subsequent
RAs (0.91%), and SGLT2 inhibitors (0.63%), with the use of
dose adjustments may be necessary so that they do not think
adjuvant therapy associated with older age, a higher BMI, and
their diabetes is suddenly worsening or perceive their new
a longer duration of diabetes (Lyons 2017). Reasons for using
drug to be ineffective. Finally, clinical judgment should always
non-insulin therapies in T1DM include the desire to provide
be used when changing the patient’s regimen. If patients are
insulin-sparing effects, combat weight gain, and reduce gly-
currently experiencing a consistent pattern of hyperglyce-
cemic variation throughout the day.
mia, they are at low risk of developing hypoglycemia and may
not need a dose reduction during the transition. Conversely,
patients with unexplained hypoglycemia may need an even Metformin
larger dose reduction than what was recommended during In the REMOVAL trial, patients 40 and older with T1DM for
the transition to maximize patient safety. at least 5 years and three or more cardiovascular risk fac-
tors were randomized to metformin 2000 mg/day or placebo
Basal Insulin/GLP-1 RA Fixed-Ratio Combinations (Petrie 2017). After 3 years, patients’ insulin doses and A1C
For patients looking to minimize their number of injections values were unchanged, and metformin did not significantly
or copays, a once-daily fixed-ratio combination product is a alter atherosclerosis progression. However, weight and LDL
potential solution. This product provides benefit to patients were significantly lower in the metformin group (-1.17 kg and
who require lower amounts of basal insulin with the synergis- -5.03 mg/dL, respectively) and eGFR was increased (4 mL/
tic effects of a GLP-1 RA. However, unlike insulin, GLP-1 RAs minute/1.73 m2) compared with placebo, suggesting that met-
have maximum daily doses, which limits the amount of drug formin’s role in T1DM is long-term weight management and
that can be administered each day. The approach to initiating renal benefits rather than glucose management (Petrie 2017).

GLP-1 RA Agents used an insulin pump (4.4% vs. 0.7%) than in patients using
In the ADJUNCT ONE treat-to-target trial comparing liraglu- multiple daily injections of insulin (2.1% vs. 0.5%).
tide with placebo, insulin doses after 1 year were reduced by In March 2019, the FDA issued a complete response let-
5% and 2% in the 1.8- and 1.2-mg groups, respectively, com- ter stating it would not approve the new drug application in
pared with a 4% increase in the 0.6-mg and placebo groups its current form, citing an 8-fold increase in DKA risk com-
(Mathieu 2016). Liraglutide 1.8 mg daily also resulted in an pared with placebo (95% CI, 3.1–19.9). The risk of DKA was
average 4-kg weight loss compared with a 0.9-kg weight consistent across all subgroups studied but was highest in
increase for the placebo group. Mean A1C was reduced in all subjects with a history of DKA, young age, high baseline A1C,
groups, with no significant difference between the individ- and insulin pump use (FDA 2019). Conversely, the European
ual groups. However, liraglutide was also associated with Medicines Agency Committee for Medicinal Products for
an increase in symptomatic hypoglycemia, especially at Human Use has issued positive opinions for sotagliflozin and
higher doses. Finally, the risk of hyperglycemia with ketosis dapagliflozin as adjunctive treatments with insulin for cer-
was significantly higher in the liraglutide 1.8-mg/day group tain adults with T1DM and under strict conditions, including
(Mathieu 2016). patients with a BMI above 27 kg/m2, high insulin requirements,
following up with an endocrinologist, and closely monitoring
SGLT2 Inhibitors their glucoses to prevent ketosis.
Use of SGLT2 inhibitors in T1DM also holds promise as a
potential therapeutic option, especially because of their Summary
insulin-independent mechanism of action. In the DEPICT 1 General concerns related to using non-insulin therapies
trial, dapagliflozin decreased A1C, total daily insulin dose, in T1DM include the additional costs, adverse effects, and
and glycemic variability (using continuous glucose monitor- treatment burden that comes with extra drugs. A proposed
ing to calculate the mean amplitude of glycemic excursions) strategy for mitigating the DKA risk in patients with T1DM
compared with placebo. However, these benefits were accom- receiving adjunctive treatment with SGLT inhibitors is imple-
panied by a numeric (but not statistical) increase in UTIs and menting the STICH protocol when patients have symptoms
severe hypoglycemia episodes, with similar rates of defi- of DKA: stop the SGLT inhibitor, inject bolus insulin, consume
nite DKA (Dandona 2017). In the EASE trials, empagliflozin 30 g of carbohydrates, and hydrate with water (Garg 2018).
reduced weight, A1C, total daily insulin dose, and systolic An additional factor to consider is how to adjust mealtime
blood pressure while increasing glucose time-in-range, all in insulin doses and insulin-carbohydrate ratios in the presence
a dose-dependent manner, in persons with T1DM. These ben- of these additional agents for patients who use customized
efits came with a similar rate of hypoglycemia, an increase in mealtime doses or preprogrammed insulin pumps. This will
genital infections at all doses, and more DKA with the 10- and be especially problematic as new closed-loop insulin pump
25-mg doses, but not at 2.5-mg daily dosage (Rosenstock systems are introduced to the market. The increased risk of
2018). hyperglycemia with ketosis is also cause for concern, given
that the incidence would likely be higher in clinical practice
Sotagliflozin when patients are not followed as closely as they would be
Sotagliflozin is a combined SGLT1/2 inhibitor, currently in in a clinical trial. Therefore, patients must be able to show
development specifically for use as an adjunct to insulin in peo- understanding that these drugs are being used adjunctively
ple with T1DM. In addition to inhibiting renal SGLT2 receptors, and do not replace their insulin. Finally, until these agents
sotagliflozin inhibits glucose reabsorption through SGLT1 in are labeled for use in T1DM, they will likely not be covered by
the small intestine. The inTandem trials used a primary multi- insurance.
component outcome of A1C lower than 7% with no episodes
of severe hypoglycemia and absence of DKA after randomiza-
USE OF LANGUAGE IN DIABETES
tion. The inTandem3 trial was the largest of the three (n=1402)
AND EDUCATION
and lasted 24 weeks (Garg 2017b). More patients achieved
the primary outcome when sotagliflozin 400 mg daily was The focus in diabetes care should be on the person living
added to insulin than when insulin alone was used (28.6% vs. with diabetes. Because many individuals have difficulty
15.2%), with similar rates of severe hypoglycemia (around 3%). attaining their diabetes-related goals, larger focus has
Decreases in mean total daily insulin dose (-5.25 units/day), been placed on the use of language and terminology when
weight (-2.9 kg), and systolic blood pressure (-3.5 mm Hg) also providing diabetes care and education. How health care pro-
occurred in the sotagliflozin group compared with placebo. fessionals talk to and about people with diabetes plays an
These benefits must be weighed against the higher incidence important role in engagement, conceptualization of dia-
of DKA in the sotagliflozin arm (3% vs. 0.6%). The incidence of betes and its management, treatment outcomes, and the
DKA also appeared to be higher in the patient subgroup that individual’s psychosocial well-being (Dickinson 2017). As
care providers, pharmacists must embrace strengths-based

Aroda VR, Rosenstock J, Terauchi Y, et al. Effect and safety
Practice Points of oral semaglutide monotherapy in type 2 diabetes –
The key updates in diabetes drug therapy include the PIONEER 1 trial. Poster abstract presented at: American
following: Diabetes Association Annual Meeting; June 2018;
Orlando, FL.
• Diabetes is a heterogeneous condition, which requires
customizing therapy approaches and goals to the patient’s Bays HE, Weinstein R, Law G, et al. Canagliflozin: effects in
specific comorbidities and expectations. overweight and obese subjects without diabetes mellitus.
• Although helping patients achieve their glycemic goals is Obesity 2014;22:1042-9.
still a priority, decreasing a patient’s overall cardiometabol-
ic risk is essential. Bettge K, Kahle M, Abd El Aziz MS, et al. Occurrence of nau-
• Sulfonylureas and thiazolidinediones have limited benefit sea, vomiting and diarrhea reported as adverse events in
in managing diabetes, and their role is limited to patients in clinical trials studying glucagon-like peptide-1 receptor
whom drug cost is a significant barrier. agonists: a systematic analysis of published clinical trials.
• GLP-1 RAs and SGLT2 inhibitors provide many benefits, Diabetes Obes Metab 2017;19:336-47.
including A1C reduction, weight loss, and reduced cardio-
vascular risk in patients with established atherosclerotic Bhattacharyya A, Shetty R, Rajkumar C, et al. Switching from
cardiovascular disease for some agents. basal or basal-bolus insulin to biphasic insulin aspart
30: results from the Indian cohort of the A1Chieve study.
• Preliminary evidence shows promise for SGLT2 inhibitors
to improve heart failure symptoms and renal outcomes. Indian J Endocrinol Metab 2014;18:480-5.
• Despite the benefits of using GLP-1 RAs and SGLT2 Bilezikian JP, Watts NB, Usiskin K, et al. Evaluation of
inhibitors, confirm the individual patient has no absolute
bone mineral density and bone biomarkers in patients
or relative contraindications to use of either class of drugs
with type 2 diabetes treated with canagliflozin. J Clin
before they are initiated.
Endocrinol Metab 2016;101:44-51.
• Non-insulin therapies play a limited role in the inpatient
setting; however, pharmacists should evaluate each pa- Bowering K, Case C, Harvey J, et al. Faster aspart versus
tient’s diabetes regimen on admission and discharge. insulin aspart as part of a basal-bolus regimen in inad-
• Off-label use of metformin, GLP-1 RAs, and SGLT inhibitors equately controlled type 2 diabetes: the ONSET 2 trial.
as adjunctive treatment for T1DM has had mixed results. Diabetes Care 2017;40:951-7.
Their use in T1DM is not widely recommended, though
specific patients may benefit, and more frequent monitor- Bzowyckyj AS. Embracing the insulin revolution in the
ing is required. ambulatory care setting. Diabetes Spectr 2016;29:140-5.
Centers for Disease Control and Prevention (CDC). 2017.

National Diabetes Fact Sheet. Accessed January 10, 2019.
and person-first language to help achieve better health out-
comes. An example of strengths-based language is, “Lee Cersosimo E, Solis-Herrera C, Triplitt C. Inhibition of renal
takes her insulin 50% of the time because of cost concerns,” glucose reabsorption as a novel treatment for diabetes
patients. J Bras Nefrol 2014;36:80-92.
which is much more helpful than “Lee is noncompliant/non-
adherent” (Dickinson 2017). Similarly, person-first language Dandona P, Mathieu C, Phillip M, et al. Efficacy and safety of
encourages the statement “Lee has diabetes” rather than dapagliflozin in patients with inadequately controlled type
the commonly used disease-first phrase “Lee is diabetic” 1 diabetes (DEPICT-1): 24 week results from a multicenter,
double-blind, phase 3, randomized controlled trial. Lancet
(Dickinson 2017).
Diabetes Endocrinol 2017;5:864-76.
CONCLUSION Davies MJ, D’Alessio DA, Fradkin J, et al. Management

of hyperglycemia in type 2 diabetes, 2018. A consen-
Previously, the treatment regimen for an individual patient was sus report by the American Diabetes Association (ADA)
based almost entirely on glycemic management. However, and the European Association for the Study of Diabetes
with new research and updated guidelines, the emphasis (EASD). Diabetes Care 2018;41:2669-701.
has shifted to more patient-specific treatments. With recent
Dickinson JK, Guzman SJ, Maryniuk MD, et al. The use of
cardiovascular outcomes trial data, clinicians have more language in diabetes care and education. Diabetes Care
information on the cardiovascular and renal benefits of some 2017;40:1790-9.
GLP-1 RA and SGLT2 inhibitor classes.
Ferrannini G, Hach T, Crowe S, et al. Energy balance after
sodium-glucose cotransporter-2 inhibition. Diabetes Care
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(SUSTAIN 7): a randomized, open-label, phase 3b trial. inhibitors on fracture risk among type 2 diabetes patients:
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Self-Assessment Questions
1. A 54-year-old man with type 2 diabetes (T2DM) currently dosage for him. According to the AACE and ACE compre-
takes metformin 1000 mg twice daily and glipizide XR 10 hensive diabetes management algorithm, which one of
mg 2 tablets before breakfast. His eGFR is 65 mL/min- the following is the best insulin glargine dosage to rec-
ute/1.73 m2, A1C is 7.4%, and A1C goal is less than 7%. In ommend for this patient?
addition to T2DM, his medical history is significant for
A. 10 units daily
heart failure with reduced ejection fraction (New York
B. 14 units daily
Heart Association class II; American College of Cardi-
C. 28 units daily
ology/American Heart Association stage C) and gout.
D. 5 units twice daily
Which one of the following is best to recommend adding
to manage this patient’s T2DM? 5. A 38-year-old woman (weight 120 kg) presents to the clinic
for a T2DM follow-up. Basal insulin was added to her reg-
A. Empagliflozin 10 mg daily
imen 6 months ago, and her A1C has improved (current
B. Pioglitazone 15 mg daily
A1C is 7.4%; previously was 10.3%; goal is less than 6.5%).
C. Saxagliptin 5 mg daily
Almost all of her fasting blood glucose readings are at goal,
D. Insulin glargine 10 units daily at bedtime
although postprandial readings are almost always above
2. A 48-year-old man presents for a T2DM follow-up. He her goal range. The patient’s current T2DM regimen con-
has been taking metformin 1000 mg twice daily for a few sists of metformin 1000 mg twice daily, liraglutide 1.8 mg
months now, but his A1C continues to be above his per- daily, and U-300 insulin glargine 140 units daily. Which one
sonal goal of less than 7% (most recent A1C was 7.5%), of the following is best to recommend for this patient?
and his BMI is 25.3 kg/m2. His medical history is non-
A. Initiate insulin aspart 14 units before her largest meal
significant, and he has a strenuous job as a garbage
and decrease insulin glargine to 126 units daily.
collector. Which one of the following is best to recom-
B. Initiate insulin aspart 14 units before her largest
mend adding as next-step therapy for this patient?
meal and increase insulin glargine to 154 units daily.
A. Glipizide C. Initiate sitagliptin 100 mg daily and continue insulin
B. Sitagliptin glargine 140 units daily.
C. Insulin glargine/lixisenatide D. Initiate sitagliptin 100 mg daily and increase insulin
D. Insulin detemir glargine to 154 units daily.
3. A 49-year-old woman was referred for T2DM manage- 6. A 72-year-old woman presents to the clinic for T2DM man-
ment, having been given a diagnosis of T2DM about agement. She currently takes insulin degludec 30 units
1 year ago. She has been taking metformin 1000 mg daily and insulin aspart 12 units three times daily with
twice daily in addition to implementing lifestyle modifica- meals. Prebreakfast and predinner glucose readings
tions for the past 6 months. Her A1C today is 10.6%, and have generally been in her goal range (80–130 mg/dL),
her goal is less than 6.5%. She has occasional polyuria but she notes prelunch hypoglycemia (50s–70s) about
(about three or four times per week) but has not noticed three or four times per week. She denies any changes in
any other symptoms of hyperglycemia. She has no other eating habits or exercise patterns on those days and can-
chronic medical conditions. Which one of the following is not identify a cause. Which one of the following is best to
the best approach to intensifying this patient’s regimen? recommend for this patient’s hypoglycemia?
A. Add insulin detemir and glipizide. A. Skip breakfast dose of insulin aspart.
B. Add insulin degludec and insulin lispro. B. Decrease insulin degludec to 25 units daily.
C. Add insulin aspart and dulaglutide. C. Decrease prebreakfast insulin aspart to 10 units.
D. Add insulin glargine and semaglutide. D. Change insulin aspart to fast-acting insulin aspart.
4. A 29-year-old man (weight 140 kg [308 lb]) has a medical 7. A 59-year-old woman presents for follow-up. She has
history that includes T2DM; he currently takes metformin a longstanding history of T2DM with A1C values previ-
1000 mg twice daily and liraglutide 1.8 mg daily. His most ously over 10%. Her A1C has decreased to 8.1% recently,
recent A1C was 9.4%, despite consistent use of his med- and her current weight is 110 kg (242 lb) (BMI 40.3 kg/m2).
ications and after generally healthy eating and exercise She takes metformin 1000 mg daily, insulin glargine
plans. His physician wants to initiate insulin glargine and 60 units daily, and insulin lispro 20 units three times daily
requests your advice on the most appropriate starting with meals, missing doses about two or three times per

week. Her C-peptide concentration is 0.4 ng/mL (normal C. 55 units before breakfast and dinner
range 0.5–3 ng/mL) with a corresponding glucose con- D. 60 units before breakfast and dinner
centration of 182 mg/dL. The patient is requesting a
11. A 52-year-old man will be admitted to the hospital today
modification to her diabetes regimen to help facilitate
for cardiac monitoring. His home regimen includes
some weight loss. Which one of the following is best to
40 units of 70/30 NPH insulin/aspart before breakfast
recommend for this patient?
and dinner. The comparable medications on your hospi-
A. Initiate empagliflozin 10 mg daily, titrated to 25 mg tal formulary include insulin glargine and insulin lispro.
daily. Assuming the patient will have the same insulin needs in
B. Change insulin lispro to fast-acting insulin aspart the hospital as he does at home, which one of the follow-
20 units three times daily with meals. ing is best to recommend for this patient?
C. Change insulin glargine to glargine/lixisenatide
A. Insulin glargine 45 units daily and insulin lispro
30 units/10 mcg daily.
8 units three times daily with meals
D. Initiate semaglutide 0.25 mg weekly, titrated to
B. Insulin glargine 56 units daily and insulin lispro
1 mg weekly.
12 units three times daily with meals
8. A 62-year-old woman with T2DM was admitted to the hos- C. Insulin glargine 22 units twice daily and insulin
pital yesterday for a heart failure exacerbation. Her home lispro 12 units three times daily with meals
diabetes regimen consists of insulin glargine 48 units D. Insulin glargine 28 units daily and insulin lispro
at bedtime, insulin lispro 10 units three times daily with 8 units three times daily with meals
meals, canagliflozin 300 mg every morning, and dulaglu-
12. A 28-year-old woman (BMI 53 kg/m2) presents with con-
tide 1.5 mg weekly (last dose administered yesterday).
cerns about her insulin copays. She currently takes
Which one of the following is best to recommend holding
U-100 insulin glargine 80 units twice daily and insu-
during this patient’s inpatient hospitalization?
lin glulisine 66 units three times daily with meals. Her
A. Insulin glargine insurance formulary covers insulin regular U-500 in pen
B. Canagliflozin form at a lower copay than the insulin analogs. Her most
C. Insulin lispro recent A1C is 7.3% and preprandial glucose concentra-
D. Dulaglutide tions are all generally less than 150 mg/dL. Which one of
9. A 38-year-old man with T2DM has been referred for ini- the following is best to recommend for this patient?
tiation of a glucagon-like peptide-1 receptor agonist A. Insulin regular U-500 215 units before breakfast and
(GLP-1 RA). The patient expresses a serious concern 145 units before dinner
about needles. When asked for more specifics, he notes B. Insulin regular U-500 140 units before breakfast and
he is distressed when he needs to attach the needle and 140 units before dinner
remove the cap before injection. Which one of the follow- C. Insulin regular U-500 115 units before breakfast and
ing GLP-1 RAs would be most appropriate to recommend 85 units before lunch and dinner
for this patient? D. Insulin regular U-500 215 units before breakfast and
A. Dulaglutide 105 units before lunch and dinner
B. Liraglutide 13. A 63-year-old woman with T2DM and a history of a myo-
C. Semaglutide cardial infarction 1 year ago currently takes metformin
D. Lixisenatide XR 500 mg 2 tablets twice daily and insulin glargine
10. A 43-year-old woman (weight 130 kg [286 lb]) recently lost 24 units daily with no dosage changes in the past 6
her job and her insurance. She is concerned because she months. Her current A1C is 8.3%. Which one of the fol-
has been doing well with diabetes (fasting glucose read- lowing is best to recommend for changing the patient’s
ings of 80–100 mg/dL and most recent A1C was 6.4%), but current insulin regimen to a basal insulin/GLP-1 RA
now her current insulins will be too expensive and she will fixed-ratio combination?
have to change to a less costly alternative. The patient cur- A. Insulin degludec/liraglutide 10 units daily
rently takes insulin glargine 64 units daily and insulin aspart B. Insulin degludec/liraglutide 16 units daily
15 units three times daily with meals for T2DM. Which one C. Insulin glargine/lixisenatide 15 units daily
of the following regimens using 70/30 (NPH insulin/regu- D. Insulin glargine/lixisenatide 30 units daily
lar) would be best to recommend for this patient?
A. 35 units before breakfast and dinner
B. 45 units before breakfast and dinner

14. Which one of the following patients with type 1 diabetes with meals, does not miss any doses, and is using con-
(T1DM) is the best candidate for using an SGLT2 inhibitor tinuous glucose monitoring. He states that his glucose
as adjunctive therapy to insulin? concentrations vary significantly throughout the day,
with no identified cause. He believes this is contributing
A. A 24-year-old man with a BMI of 23 kg/m2, taking
to his A1C of 7.6% because his fasting glucose concen-
0.6 unit/kg/day of insulin, and using continuous
trations are almost always within range. He denies an
glucose monitoring
overactive appetite or snacking and reports consuming
B. A 26-year-old woman with a BMI of 32 kg/m2, taking
appropriate portions at his meals. However, he is con-
0.7 unit/kg/day of insulin, and checking glucose
cerned because he has experienced a gradual weight
concentrations two or three times daily
gain without any changes in exercise or eating patterns
C. A 39-year-old man with a BMI of 29 kg/m2, taking
(current BMI is 23.8 kg/m2, up from 21.7 kg/m2 1 year
1.6 unit/kg/day of insulin, and using continuous
ago). Which one of the following is best to add to this
glucose monitoring
patient’s regimen?
D. A 41-year-old woman with a BMI of 31 kg/m2, taking
1 unit/kg/day of insulin, and checking glucose A. Liraglutide 0.6 mg daily, titrated to 1.8 mg daily
concentrations two or three times weekly B. Metformin 500 mg daily, titrated to 1000 mg twice
daily
15. A 34-year-old man (weight 82 kg) with a medical history
C. Dapagliflozin 5 mg daily, titrated to 10 mg daily
of T1DM presents to be evaluated for adjunctive non-
D. Pioglitazone 15 mg daily, titrated to 45 mg daily
insulin therapy. He currently takes insulin degludec
40 units daily and insulin lispro 15 units three times daily

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Diabetes Mellitus

By Andrew S. Bzowyckyj, Pharm.D., BCPS, CDE

Ominous Octet and Egregious Eleven

PSAP 2019 BOOK 3 • Endocrinology and Nephrology 7 Diabetes Mellitus

PSAP 2019 BOOK 3 • Endocrinology and Nephrology 8 Diabetes Mellitus

ASCVD HF or CKD Compelling Compelling need Cost is a

Figure 1. Overall approach to selecting glucose-lowering drug in type 2 diabetes.

Table 1. Considerations When Combining Oral Therapy with Injectable Therapies

Oral Therapy Consideration (clinical judgment may supersede)

Metformin Continue metformin

TZD Discontinue TZD when initiating insulin OR reduce TZD dose

SGLT2i Continue SGLT2i

DPP-4i Discontinue DPP-4i if GLP-1 RA initiated

PSAP 2019 BOOK 3 • Endocrinology and Nephrology 9 Diabetes Mellitus

PSAP 2019 BOOK 3 • Endocrinology and Nephrology 10 Diabetes Mellitus

Safety initiating GLP-1 RAs. Common symptoms include excessive

PSAP 2019 BOOK 3 • Endocrinology and Nephrology 11 Diabetes Mellitus

No. of Median Trial MACE Outcomes

PSAP 2019 BOOK 3 • Endocrinology and Nephrology 12 Diabetes Mellitus

PSAP 2019 BOOK 3 • Endocrinology and Nephrology 13 Diabetes Mellitus

PSAP 2019 BOOK 3 • Endocrinology and Nephrology 14 Diabetes Mellitus

Table 4. Product Characteristics of Newer Insulin Products

Supplied as Units Max Dose for Shelf-life, Open

Degludec Tresiba U-100 Both 100 300 80 56

Tresiba U-200 Pen 200 600 160 a

Glargine Toujeo Pen 300 450 80 56

Toujeo Max Pen 300 900 160a 56

Lantus Both 100 300 80 28

Basaglar Pen 100 300 80 28

Detemir Levemir Both 100 300 80 42

Lispro Humalog U-100 Both 100 300 60 28

Humalog U-100 Pen 100 300 30 b

Humalog U-200 Pen 200 600 60 28

Admelog Both 100 300 80 28

Aspart NovoLog Both 100 300 60 28

Glulisine Apidra Both 100 300 80 28

Fast-acting aspart Fiasp Both 100 300 80 28

Insulin human U-500 Humulin R U-500 Both 500 1500 300 c

PSAP 2019 BOOK 3 • Endocrinology and Nephrology 15 Diabetes Mellitus

PSAP 2019 BOOK 3 • Endocrinology and Nephrology 16 Diabetes Mellitus

Insulin Glargine and Lixisenatide Insulin Degludec and Liraglutide

Insulin concentration 100 units/mL 100 units/mL

PSAP 2019 BOOK 3 • Endocrinology and Nephrology 17 Diabetes Mellitus

PSAP 2019 BOOK 3 • Endocrinology and Nephrology 18 Diabetes Mellitus

Centers for Disease Control and Prevention (CDC). 2017.

CONCLUSION Davies MJ, D’Alessio DA, Fradkin J, et al. Management

PSAP 2019 BOOK 3 • Endocrinology and Nephrology 19 Diabetes Mellitus

PSAP 2019 BOOK 3 • Endocrinology and Nephrology 20 Diabetes Mellitus

Steinberg WM, Buse JB, Ghorbani MLM, et al. Amylase,

PSAP 2019 BOOK 3 • Endocrinology and Nephrology 21 Diabetes Mellitus

PSAP 2019 BOOK 3 • Endocrinology and Nephrology 22 Diabetes Mellitus

PSAP 2019 BOOK 3 • Endocrinology and Nephrology 23 Diabetes Mellitus

PSAP 2019 BOOK 3 • Endocrinology and Nephrology 24 Diabetes Mellitus

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