1. Diabetes – New Guidelines and Treatments
Anna Gibson, Pharm D.
Lead Pharmacist, Deaconess Specialty Clinics
September, 2015

2. Disclosures
I have no actual or potential conflicts of interest to disclose.

3. ADA position statement
Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach
Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes
Diabetes Care 2015;38:140–149 | DOI: /dc
Basically recommended patient centered care, rather than a “cookie cutter” approach for diabetes care management, including target A1C’s more or less aggressive depending on patient factors including disease duration, life expectancy, and patient attitude and resources.

4. Treatment Goals Individualize goals based on: Risks of hypoglycemia
Disease duration
Life Expectancy
Important Comorbidities
Vascular complications
Patient attitude and support system

5. Diabetes agents – site of action
This diagram was used with permission from Endotext.org. You can see it lays out where each class of drugs has activity – we’ll refer back to it as we discuss the new classes.
Accessed 10/14/

6. Incretins Potent insulin regulating hormones
Released in response to glucose or fat ingestion
Potentiate insulin secretion
Additive effects
Glucose-dependent insulinotropic Polypeptide (GIP)
Glucagon-like peptide (GLP-1)
Both metabolized rapidly by DPP-4
In Type 2 diabetes, GLP secretion is decreased and GIP-induced stimulation of postprandial insulin secretion is diminished.
DPP-4 = dipeptidyl peptidase-4
GIP – released in response to ingestion of food from cells in the jejunum. Causes insulin release in an effort to maintain euglycemia. GIP levels are usually normal to elevated in patients with type 2 diabetes, however, the effects are muted.
GLP-1 has multiple effects – enhances insulin secretion, suppressing postprandial glucagon secretion, slows gastric emptying, sends a satiety signal to the brain to suppress appetite.
Half life of naturally occurring incretins is only about 2 minutes
Studies with GLP-1 infusion showed most effect in those with highest fasting plasma glucose

7. GLP-1 agonists
Accessed 10/14/

8. GLP-1agonists Exenatide (Byetta®, Bydureon®) Liraglutide
Byetta: mcg sq BID before meals
Bydureon: 2 mg sq once weekly
Liraglutide
Victoza: 0.6 – 1.8 mg SQ daily
Saxenda (weight loss only): Start at 0.6 mg daily, increase weekly to 3 mg daily
Albiglutide (Tanzeum®)
Once weekly SQ injection – mg
Powder for injection – have to mix with provided diluent and wait 15 or 30 minutes before administration.
Dulaglutide (Trulicity®)
Once weekly SQ injection – mg
-GLP-1 agonists simulate the incretin effect (Increase insulin secretion and decrease Glucagon release and appetite in response to a meal) – all can decrease appetite and lead to weight loss
REMS for all drugs in this category to warn of risk of acute pancreatitis and medullary thyroid carcinoma – communication plan and a med guide – do not use in patients with personal or family history
All can cause nausea, all lead to weight loss
Start with lowest dose for at least a week to minimize nausea
all can cause renal toxicity, liraglutide requires renal dose adjustment
-Liraglutide (Saxenda) – new product for weight loss indication only - Average 8% weight reduction.
-Suicidal ideation has been reported with liraglutide – do not use in patients with a history of suicidal ideation and immediately discontinue use if changes in mood or behavior.
As you know, diabetes indications are mg daily – max of 1.8 mg daily
-All drugs in this class should not be used in patients with history of thyroid carcinoma or pancreatitis
Lixisenatide – Planning to resubmit to FDA this year
Semaglutide – Phase 3 trials
-Also Liraglutide/Insulin degludec combination product in phase 3

9. What is the Mechanism of action of a DPP-4 inhibitor?
Promote the release of endogenous incretins
Inhibit the breakdown of endogenous incretins
Act synergistically with exogenous GLP-1 agonists
Promote glucose excretion in the kidneys

10. What is the Mechanism of action of a DPP-4 inhibitor?
Promote the release of endogenous incretins
Inhibit the breakdown of endogenous incretins
Act synergistically with exogenous GLP-1 agonists
Promote glucose excretion in the kidneys

11. DPP-4 inhibitors
Accessed 10/14/

12. DPP-4 inhibitors Sitagliptin (Januvia®) Saxagliptin (Onglyza®)
100 mg daily
Saxagliptin (Onglyza®)
2.5-5 mg daily
Alogliptin (Nesina®)
25 mg daily
Linagliptin (Tradjenta®)
5 mg daily
DPP-4 inhibitors decrease the breakdown of naturally occurring GLP-1
More significant decrease in Hgb A1C when used as add-on therapy than when used as monotherapy
--sitagliptin (Janumet), saxagliptin (Kombiglyze), and alogliptin (Kazani) are Also in combination with metformin and alogliptin is also in a fixed combination with pioglitazone (Oseni)
-Dosed once a day, prices are comparable
Adverse effects: Hypoglycemia (reduce dose of insulin or sulfonylurea) – There have been reports of pancreatitis and Pancreatic cancer, but recent studies seem to disprove that association. Monitor renal function. Angioedema and Stephens Johnson syndrome have been reported.
Omarigliptin, Trelagliptin – both Phase 3 trials
Trials underway in children and adolescents

13. SGLT-2 inhibitors Sodium glucose type 2 transport inhibitors
Inhibit reabsorption of glucose in the proximal nephron, increasing excretion of glucose
Accessed 10/14/

14. SGLT-2 inhibitor Monotherapy or add-on.
Efficacy comparable to sulfonylurea
Weight loss
Not recommended in patients with history of bladder cancer
Increase glucose excretion in urine – increased risk for UTI/mycotic infections in genital area
Diuretic effect
Sodium Glucose Co-Transporter type 2 inhibitors
Decrease HgbA1C by 0.5-1% versus placebo
Modest weight loss of about 2 kg
Diuretic effect – osmotic diuresis – use caution in those already on diuretic whose intravascular volume status is unstable
Less effective when eGFR less than ml/min/1.73m2

15. SGLT-2 inhibitor Dapagliflozin (Farxiga®) Canagliflozin (Invokana®)
5-10 mg once daily
Not recommended in creatinine clearance less than 60 ml/min
Canagliflozin (Invokana®)
mg once daily
Dose adjustment required for creatinine clearance less than 60 ml/min, do not use in less than 45 ml/min.
Empagliflozin (Jardiance®)
10-25 mg once daily
Do not use in creatinine clearance less than 45 ml/min
All about the same price
Dapagliflozin/metformin (Xigduo)
Entrugliflozin – in phase 3 trials

16. Which patient is the best candidate for an SGLT-2 inhibitor?
48 year old woman, newly diagnosed type 2 diabetic with a history of chronic UTI
66 year old man, 10 year history of diabetes, Creatinine clearance 40 ml/min
52 year old woman, 5 year history of diabetes, previously well controlled on metformin, now with Hgb A1C 8.4.
67 year old man with uncontrolled diabetes who currently takes furosemide to control hypertension

17. Which patient is the best candidate for an SGLT-2 inhibitor?
48 year old woman, newly diagnosed type 2 diabetic with a history of chronic UTI
66 year old man, 10 year history of diabetes, Creatinine clearance 40 ml/min
52 year old woman, 5 year history of diabetes, previously well controlled on metformin, now with Hgb A1C 8.4.
67 year old man with uncontrolled diabetes who currently takes furosemide to control hypertension

18. New insulins in the pipeline
Insulin Glargine
Patent on U100 (Lantus®) expired in 2/2015
Biosimilar approved in Europe
Submitted to FDA as new drug in US (Basaglar®)
Tentative approval in 8/14
Insulin Glargine U-300
Toujeo®
Longer half-life and flatter activity curve
Less hypoglycemia
Insulin lispro
200 unit/ml
Humalog U-200 Kwikpen®
Not for IV use or for use in insulin pumps
Can not be mixed with any other insulins
-Lantus biosimilar – multiple companies are working on this – Eli Lilly, Boehringer Ingelheim, Merck. Already approved by European Medicines Agency.
U300 Insulin Glargine – when converting from BID insulin, decrease to 80% of daily insulin needs – from U-100 insulin glargine to U300, U300 dose requirements typically % higher than Lantus requirements – when changing back, decrease to 80%
U300 glargine is only available in pen form.
-Jumping on the concentrated insulin bandwagon, we have insulin lispro 200 unit/ml. Only comes in a pen, you dial the dose you want, and it works just like the U100 lispro pen, no dose conversion needed.
-Can not be used IV, in insulin pumps, or mixed with other insulins – unlike U100 lispro, which can be mixed with NPH.

19. New insulins in the pipeline
Insulin Peglispro
Basal insulin
Insulin Degludec (Tresiba®)
Ultra long acting
100 unit/ml, 200 unit/ml – pens only
42 hour half life may allow some patients to inject only 2-3 times per week.
-Insulin Peglispro – phase III trials - basal activity, “more hepato-preferential” activity, similar to endogenous insulin. Recently presented studies showed more patients obtained Hgb A1C less than 7 percent and less nocturnal hypoglycemia than with glargine, however, patients did experience more daytime hypoglycemia episodes (Imagine trials). Has not been submitted to the FDA yet, pending more safety studies.
-Insulin Degludec – 42 hours half life is about twice the half life of insulin glargine. Also being looked at in Europe in combination with liraglutide (IDegLira) – NDA still pending for this product. FDA requested more cardiovascular outcomes data.

20. New insulins in the pipeline
Inhaled insulin
Afrezza®
4 units per inhalation
Contraindicated in patients with chronic lung disease
Administer at the beginning of each meal
Round up to nearest 4 units
Cough, throat pain or irritation
Teach on proper inhalation technique
Oral insulin (Oral-Lyn®)
Phase 3 trials
Insulin spray
Absorbed through oral mucosa
Onset 5 minutes, peak 30 minutes, duration 2 hours
Approved in other countries, In US on Treatment IND only.

21. Implementation of drug therapy
3 months
3 months
Non-pharmacologic treatment, of course, is still first line.
Metformin still first line – low cost, safe, weight neutral, Use now deemed appropriate in patients with mild-moderate but stable CKD (Clcr ml/min/1.73m2), consider dose adjustments to account for reduced clearance. Still contraindicated if eGFR less than 30 ml/min/1.73m2
Renal dysfunction, which therapy to use? Sulfonylureas not the best, nor are SGLT-2’s – probably DPP-4’s are the best choice, with dose adjustments for all but linagliptin.
Combination therapy may allow patients to get to goal quicker than sequential therapy – consider if A1C much above goal (i.e. >9). Prompt sequential therapy with frequent follow up is also a reasonable alternative
The combo of GLP-1 receptor agonist plus basal insulin has shown equal or slightly superior efficacy over mealtime insulin with less hypoglycemia and weight loss.
Not DPP-4 with GLP-1 – similar mechanism

22. Implementation of drug therapy
Add from any class with differing mechanism of action
May reach goal faster if initiate double therapy at onset
Consider especially if Hgb A1C > 9
DPP-4 and GLP-1 have similar mechanisms
SGLT-2’s have not been tested with GLP-1’s

23. Basal Insulin Peglispro Studies Demonstrate Superiority to Insulin Glargine Across Multiple Measures in People with Type 1 Diabetes. releases/basal-insulin-peglispro-studies-demonstrate-superiority-to-insulin-glargine-across-multiple-measures-in-people-with-type-1-diabetes html. Accessed 8/13/
Buffery, MA, ABD. Specialty Drugs Top the Trends in the 2014 Pipeline. American Health & Drug Benefits. April 17, volume-7-special-feature-fifth-annual-payers-guide-to-new-fda-approvals/1704-specialty-drugs-top-the-trends-in-the-2014-pipeline. Accessed 8/12/
Busco, M. FDA Approves Weekly Injectable Diabetes Drug: Albiglutide. Accessed 10/15/
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Evans, J and Rushakoff, R. Oral Agents, Incretins, and other “Non-Insulin” Pharmacologic Interventions for Diabetes. Accessed 10/14/
Fennel, D. Oral Insulin Conditionally Approved by FDA. Accessed 10/15/
Fiore, C. Sanofi submits U300 to FDA. Accessed 10/3/
Fennell, D. Oral Insuline Conditionally Approved by FDA. Accessed 9/8/
Foster, M. Basal Insulin Peglispro vs. Insulin Glargine in Type 1 Diabetes. glargine-type-1-diabetes/article/419161/. Accessed 9/8/
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Garde, D. Merck takes aim at Sanofi with a Lantus biosimilar of its own. Accessed 10/3/
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Accessed 9/8/
The Incretin Effect. Accessed 8/12/
Inzucchi, S. et al. Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a Position Statement of the American Diabetes Associaton and the European Association for the Study of Diabetes. DiabetesCare. January : ;doi: /dc
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Lowes, R. Diabetes Drug Empagliflozin (Jardiance) wins FDA OK on second try. Accessed 10/15/
Nainggolan, Lisa. First Biosimilar Insulin, Glargine, Approved in EU. Medscape Multispecialty. Accessed 8/12/
Palmer, Eric. Novo’s Tresiba news injects uncertainty in insulin market, particularly for Sanofi. insulin-market-particularly-sanofi/ Accessed 8/13/
Accessed 9/8/
VQ15-1t1-VQ16-c&moc=TJOCO23027WB. Accessed 9/8/
Tucker, M. FDA Approves Once-Weekly Dulaglutide for Type 2 diabetes. Accessed 10/15/
Tucker, M. FDA Approves Dapagliflozin (Farxiga) for Type 2 Diabetes Treatment. Accessed 10/15/
Tucker, M. FDA Rejects Novo Nordisk’s Insulin Degludec. Accessed 9/8/
Diabetes and Heart Research Center. Accessed 10/15/