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

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

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: 10.2337/dc14- 2441 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.

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

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. http://diabetesmanager.pbworks.com/w/page/17680289/Oral%20Pharmacological%20Agents%20for%20Type%202%20Diabetes. Accessed 10/14/2014 1624.

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

GLP-1 agonists http://diabetesmanager.pbworks.com/w/page/17680289/Oral%20Pharmacological%20Agents%20for%20Type%202%20Diabetes. Accessed 10/14/2014 1624.

GLP-1agonists Exenatide (Byetta®, Bydureon®) Liraglutide Byetta: 5-10 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 – 30-50 mg Powder for injection – have to mix with provided diluent and wait 15 or 30 minutes before administration. Dulaglutide (Trulicity®) Once weekly SQ injection – 0.75-1.5 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 0.5-1.2 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

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

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

DPP-4 inhibitors http://diabetesmanager.pbworks.com/w/page/17680289/Oral%20Pharmacological%20Agents%20for%20Type%202%20Diabetes. Accessed 10/14/2014 1624.

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

SGLT-2 inhibitors Sodium glucose type 2 transport inhibitors Inhibit reabsorption of glucose in the proximal nephron, increasing excretion of glucose http://diabetesmanager.pbworks.com/w/page/17680289/Oral%20Pharmacological%20Agents%20for%20Type%202%20Diabetes. Accessed 10/14/2014 1624.

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 45-60 ml/min/1.73m2

SGLT-2 inhibitor Dapagliflozin (Farxiga®) Canagliflozin (Invokana®) 5-10 mg once daily Not recommended in creatinine clearance less than 60 ml/min Canagliflozin (Invokana®) 100-300 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

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

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

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 11-17.5% 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.

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.

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.

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 45-60 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

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

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