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Emily Weidman-Evans, Pharm.D., BC-ADM

Associate Professor & Clinical Pharmacist

“I read on the internet”… Things your patients will ask about their new diabetes medications

ObjectivesPharmacist Objectives: Counsel a patient on research related to potentially severe adverse effects of

SGLT- 2 inhibitors. Counsel a patient on research related to potentially severe adverse effects of

incretin drugs (DPP-4 inhibitors or GLP – 1 analogs). Counsel a patient on research related to potentially severe adverse effects of

basal insulins. Educate patients and providers on appropriate alternative drug choices, in

keeping with the American Diabetes Association Standards of Care.Pharmacy Technician Objectives: Identify potentially severe adverse effects of SGLT-2 inhibitors that need to

be discussed with the pharmacist. Identify potentially severe adverse effects of incretin drugs (DPP- 4

inhibitors or GLP – 1 analogs) that need to be discussed with the pharmacist. Identify potentially severe adverse effects of basal insulins that need be

discussed with the pharmacist.

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A quick note to start…about ethics??? Autonomy vs. beneficence vs. non-maleficence…

Are there more serious side effects with new drugs???

Maybe…but…Required post-marketing studiesDTC advertisingMore people using them more

exposureLegal commercials

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SGLT-2 inhibitorsThe Good The Bad Lower A1c (~0.5%)

Lower CVD Empagliflozin (Jardiance) >

Canagliflozin (Invokana)

Slow CKD progression* Empagliflozin and

canagliflozin

Decrease HF hospitalizations Empagliflozin and

canagliflozin

Low hypoglycemic risk

UTIs and genital fungal infections

Euglycemic DKA

Lower limb amputations

Necrotizing genital fasciitis

Fractures

*Do not use if GFR <30.

Euglycemic DKA—Why does it happen?

http://care.diabetesjournals.org/content/38/9/1638

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Euglycemic DKA—How common is it? As of May 2015, 101 cases per 500,000 patient years 0.0002 per person-year For every year you are on this, you have a 2-in-

1,000,000 chance of developing this adverse effect.

http://care.diabetesjournals.org/content/38/9/1638

Euglycemic DKA—Who’s MOST at risk?

Insulin reductions (or low circulating insulin)

Low caloric and fluid intake

Intercurrent illness

Alcohol use

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Euglycemic DKA—What can we do about it?

Don’t change insulin dose drastically

Avoid no- or low-carbohydrate diets

Stay hydrated

Check ketones (urine or serum; breath?)

Daily vs. whenever feeling ill

Necrotizing genital fasciitis (a.k.a. Fournier’s gangrene)—Why does it happen?

↑ Glucose in urine

Decreased skin integrity (genital/perineal)

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Necrotizing genital fasciitis—How common is it?

https://www.medscape.com/viewarticle/912369?nlid=129783_4822&src=WNL_mdplsfeat_190514_mscpedit_phar&uac=78978BG&spon=30&impID=1963799&faf=1

Necrotizing genital fasciitis—What can we do about it?

Good hygiene

Daily genital inspections (just like feet )

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Lower limb amputations—Why does this happen?

??? WE DON’T KNOW!!!

HYPOTHESIS:

↓ volume ↑ PAD risk Supported by the fact that those with CKD are at the highest risk

https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2696730

Lower limb amputations—How common are they?

Another study showed a risk lower (2/million/year), but still “twice as high” as with GLP-1 analogs. (https://www.bmj.com/content/bmj/363/bmj.k4365.full.pdf

Drug class # of cases per 10,000 patient years

Interpretation

SGLT-2 inhibitors 10.53 1 in 100,000/year

DPP-4 inhibitors 8.52 0.8 in 100,000/year

GLP-1 analogs 7.10 0.7 in 100,000/year

“Other” (metformin, SUs,TZDs)*

4.90 0.5 in 100,000/year

https://jamanetwork.com/journals/jamainternalmedicine/article‐abstract/2696730

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Lower limb amputations—What can we do about it?

Teach and practice thorough foot care

Consider not using SGLT2i’s in those with highest risk of amputation/poor circulation PAD/PVD Peripheral neuropathyCKD(???)

GLP-1 analogs

The Good The Bad

Lower A1c (~1-2%)

Lower CVD Liraglutide (Victoza) >

semiglutide (Ozempic), dulglutide (Trulicity > exenatide XR (Bydureon)

Weight loss 7-15#

Low hypoglycemic risk

Pancreatitis (Gimme a minute )

Thyroid cancer (To be discussed)

Pancreatic cancer (Also to be discussed…)

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DPP-4 inhibitors

The Good The Bad(?)

Lower A1c (~0.5%)

Low hypoglycemic risk

HF risk Onglyza, Galvus, Nesina(?)

Pancreatitis (about to happen…I promise…)

Pancreatic cancer (Patience…)

↑ HF risk—Why does this happen?

??? HYPOTHESIS:

http://heartfailure.onlinejacc.org/content/early/2018/03/01/j.jchf.2017.12.016(modest)

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Drug Chances (active vs. comparator)

Statistics* What it really means

Overall 2.28% vs. 2.26% (n=54640)

RR 1.13 [1.01-1.25] Someone on a DPP-4 inhibitor is 13% more likely to develop HF OR be hospitalized for HF. (Statistically significant)

Alogliptin 2.22% vs. 2.60% (n=8454)

RR 1.15 [0.88, 1.51] No significant difference between alogliptinand comparators (but a “signal”).

Linagliptin 0.4% vs. 0.2% (n=2986)

RR 1.53 [0.46, 5.06] No significant difference between linagliptinand comparators (but a “signal”).

Saxagliptin 2.66% vs. 2.45%(n=20780)

RR 1.22 [1.03, 1.44] Someone on saxagliptin is 22% more likely to develop HF OR be hospitalized for HF. (Statistically significant.)

Sitagliptin 2.17% vs. 2.24% (n=21218)

RR 1.01 [0.85, 1.21] No difference between sitagliptin and comparators.

Vildagliptin

2.62% vs. 2.84% (n=994)

RR 1.17 [0.57, 2.43] No significant difference between vildagliptinand comparators (but a “signal”).

*The RR’s were calculated based upon the weights of individual trials included in the analysis, not simply the overall event rates reported here.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403656/pdf/cmajo.20160058.pdf

HF risk—What can we do about it? Modify other risk factors Educate on

signs/symptoms Fatigue/reduced exercise

tolerance Shortness of breath,

coughing, wheezing Edema or rapid weight gain

from fluid Irregular heartbeat

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Pancreatitis and incretins

Overall GLP-1 studies Event rate of

0.11% (# cases not reported)

OR 1.11 (95% CI 0.57-2.17)

Event rate 0.11% (16 cases)

OR 1.05 (95% CI 0.37-2.94)

https://www.bmj.com/content/348/bmj.g2366?ijkey=ff31fd4bab7bb08239ab45280b3d1b538aa4199c&keytype2=tf_ipsecsha

DPP-4 studies Event rate 0.12%

(23 cases)

OR 1.06 (95% CI 0.46-2.45)

2014 analysis 55 RCTs 33,350 subjects

Pancreatitis—What can we do about it?

Signs & symptoms—EDUCATE!

Risk factors—AVOID/MINIMIZE USE!

Abdominal pain and/or tendernessMay radiateMay worsen after

eating Fever Rapid pulse N/V

Heavy alcohol use

Gallstones

Smoking

CF

Family history

Hypercalcemia/hyperparathyroidism

Hypertriglyceridemia

Infection

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What about the “C” word?

Diabetes and cancer risk Increased incidence of:Overall (19-27% increase) Stomach LungKidney EsophagusColorectal Pancreatic Bladder Thyroid Liver

https://link.springer.com/article/10.1007/s00125-018-4664-5#SupplementaryMaterial

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Why??? Hypothesis (simplified)…

Cancer cell(s)

Type 1 diabetes mellitus

Damage to normal cells

Hyperglycemia

Type 2 diabetes mellitus

Treat with insulin

Hypersecreteinsulin

Hyperinsulinemia & increased IGF-1

Increased cell growth and metabolism

Dysplasia

Diabetes drugs and cancer (overall)

Decreased risk

Insulin: 21% higher risk (CI 1.08-1.36; p<0.05)

Sulfonylureas: 20% higher risk (CI 1.13-1.27; p<0.05)

Metformin: 14% lower risk (CI 0.83-0.90; p,0.05)

TZDs: 6% lower risk (CI 0.91-0.96; p<0.05)

Increased risk No difference GLP-1 analogs

DPP4 inhibitors

Glinides

Dapagliflozin

https://www.nature.com/articles/srep10147

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Insulin and cancer

Increased incidence of:Overall ratePancreaticRespiratoryColorectalLiverKidney

https://link.springer.com/article/10.1007/s12672-012-0112-zhttps://www.ingentaconnect.com/contentone/ben/cds/2013/00000008/00000005/art00004?crawler=true

TZDs and…wait, NOT bladder cancer?

Bladder cancer HR: 1.06 (95% CI, 0.89-1.26); OR 1.13 (95% CI, 0.96-1.33) (i.e. NO DIFFERENCE! But…)

Prostate cancer HR: 1.13 (95% CI, 1.02-1.26)

Pancreatic cancer HR: 1.41(; 95% CI, 1.16-1.7)

JAMA. 2015;314(3):265-277. doi:10.1001/jama.2015.7996Diabetes Ther. 2017 Aug; 8(4): 705–726. doi: 10.1007/s13300-0273-4

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GLP-1 analogs and thyroid cancer Significant increase seen… in RODENTS taking exenatide

and liraglutide.

DEFINITELY don’t give to those with a personal family history of C-cell medullary thyroid carcinoma!

Mouse cell Human cell

Pancreatic cancer and incretins

WHOA! DPP4 inhibitors: 1.66% Controls: 0.50%

GLP1 agonists: 0.55% Controls: 0.23%

BUT… Metformin 14.68% Controls: 6.09%

Insulin: 9.39% Controls: 2.61%

OR 3.9

OR 2.7

OR 2.7

OR 3.6

Presented at 2015 EASD meeting. Available at: http://www.easdvirtualmeeting.org/resources/risk-of-pancreatic-cancer-associated-with-use-of-incretin-based-therapy-and-other-glucose-lowering-agents-a-nationwide-case-control-study-in-denmark--2

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Cancer risk and diabetes meds… CONCLUSION?

DIABETES (insulin?) is a RISK FACTOR for many types of cancer

Do research to determine if better glucose control lower incidence of various cancers!!!

My patient says “no way”… Now what?

Review of the 2019 ADA Standards of Medical Care

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Therapeutic Decision Making **METFORMIN IS FIRST LINE THERAPY** Questions to ask (in this order!):

1. Does the patient has ASCVD?2. Does the patient have CKD?3. Is the patient at high risk from hypoglycemia?4. Does the patient need to lose weight (or not gain

any more)?5. Is cost a big consideration?

Does the patient have ASCVD?

GLP-1 RA Liraglutide (Victoza) Semiglutide (Ozempic) Exenatide ER (Bydureon) Dulaglutide (Trulicity)*

SGLT-2i Empagliflozin (Jardiance) Canagliflozin (Invokana) Dapaglifloxin (Farxiga)*

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Does the patient have CKD?

SGLT2i Empagliflozin (Jardiance) Canagliflozin (Invokana) Dapagliflozin (Farxiga)*

Is hypoglycemia risk a big concern?

DPP4i

GLP1 RA SGLT2i

TZD

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Does the patient need to lose weight?

GLP1 RA Semiglutide (Ozempic) Liraglutide (Victoza)

SGLT2i

Is cost a major concern?

SU

TZD Pioglitazone (Actos)

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Other questions to ask…What is their A1c at diagnosis?≥9%Start 2 drugs

≥ 10%Consider basal insulin as one of your drugs

Other questions to ask…Are glucose elevations pre- or post-prandial?

Class ⇩FPG ⇩PPGMetformin Mod Low

Thiazolidinediones Mod LowSulfonylureas Mod ModMeglitinides Low ModGLP-1 RAs Mild to Mod Mod to Hi

DPP-4 inhibitors Low ModSGLT-2 inhibitors Mod LowAmylin agonist Low Mod to Hi

a-glucosidase inh. Low ModInsulin Mod to Hi

(basal)Mod to Hi

(bolus)

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Questions?

Thank you!

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