New Medications for Diabetes Cynthia Way, BScPharm, ACPR June 9, 2015

Learning objectives At the end of the presentation the learner will be able to: Compare and contrast the newest DPP-4 inhibitor, alogliptin, with the older agents Describe the mechanism of action of the SGLT-2 inhibitors Describe usual monitoring of patients on SGLT-2 inhibitors Discuss the place in therapy of the SGLT-s inhibitors

DPP-4 inhibitors Four available in Canada, alone and in combination with metformin. Sitagliptin (Januvia®; Janumet®, Janumet XR®) Saxagliptin (Onglyza®; Komboglyze®) Linagliptin (Trajenta®; Jentadueto®) Alogliptin (Nesina®; Kazano®) All cost approx $3/day and all except Nesina® & Kazano® are general benefit under Ontario Drug Benefit (ODB).

DPP-4 inhibitors Mechanism of Action

Alogliptin (Nessina®; Kazano®) Indication as monotherapy if cannot take metformin; in combo w/ metformin, pioglitazone, SU, met+pio, insulin +/- met. Not with met +SU. Usual dose 25mg/day Dose reduced to 12.5mg/d if CrCl <50mL/min and to 6.25mg/d if <30mL/min Use w/ caution if dialysis due to little experience in this population

Alogliptin (Nessina®; Kazano®) Can be taken with or without food No known drug interactions Did have slightly higher incidence of hypoglycemia when combined with metformin & pioglitazone as triple therapy Manufacturer suggests using with caution if CHF

DPP-4 Inhibitors How are they the same? All given once daily (unless combined with regular-release metformin; exception Janumet XR®) Roughly the same effectiveness at lowering the A1C (about 0.7%) All generally well-tolerated All have same low risk of inducing hypoglycemia

DPP-4 Inhibitors How do they differ from one another? Saxagliptin More significant drug interactions (metabolized by CYP3A4/5)? Would only be significant with longer-term combinations. Signal for increased risk of heart failure Linagliptin: Not renally eliminated so dose not adjusted for renal function (caution in ESRD/HD) The only one that should not be combined with insulin Different official indications for combination therapies. All indicated in combination with metformin. For all other combinations, check the product monograph in the CPS. Linagliptin not licensed for use w/ insulin “b/c of a CV risk that cannot be excluded”. TRAJENTA is not indicated in combination with insulin due to an increase in cardiovascular risk, which cannot be excluded. In a Phase III randomized, double-blind, placebo-controlled, parallel group efficacy and safety study of TRAJENTA 5 mg, administered orally once daily for at least 52 weeks in 1255 type 2 diabetic patients in combination with basal insulin therapy, a composite endpoint of cardiovascular and cerebrovascular death, myocardial infarction, and stroke occurred in 0.80% (5 of 627) of patients in the placebo group and in 1.59% (10 of 628) of subjects in the linagliptin group (Hazard Ratio 1.93 [0.66, 5.66]). The incidence of cardiovascular death was 0.16% (1 of 627) in the placebo group and 0.80% (5 of 628) in the linagliptin group (Hazard Ratio 4.79 [0.56, 40.98]). These findings were not statistically significant. In a pooled analysis of 4 studies with insulin background consisting of 1613 patients on linagliptin and placebo, the difference between the linagliptin and placebo group for cardiovascular risk was not statistically significant. A composite endpoint of cardiovascular and cerebrovascular death, myocardial infarction, and stroke occurred in 1.12% (9 of 802) of patients in the placebo group and in 1.97 (16 of 811) of subjects in the linagliptin group (Hazard Ratio 1.73 [ 0.77, 3.92]). No dose adjustment of linagliptin for renal dysfunction. PM says should be used w/ caution in pts w/ ESRD or on dialysis. Don’t use if severe hepatic insufficiency. About 90% excreted unchanged, mostly in the feces. Sitagliptin: decrease dose for 30-50mL/min (50mg) & <30mL/min or ESRD/HD/PD (25mg)

DPP-4 Inhibitors Cardiovascular Safety Both EXAMINE and SAVOR showed that the DPP-4 inhibitors tested (alogliptin & saxagliptin) do NOT increase risk of MI, stroke. CAROLINA and CARMELINA (both linagliptin) due to report in 2018 and TECOS (sitagliptin) due to report 2015

DPP-4 Inhibitors CV Safety SAVOR-TIMI found an increase in hospitalizations due to heart failure in patients who received saxagliptin in the first year of treatment (e.g. NNH 142 for 2 yrs) Risk factors included chronic kidney disease and previous heart failure.

DPP-4 Inhibitors CV Safety Meta-analyses have varying conclusions. At least two have found a signal that hospitalizations for heart failure are increased, while one (performed by the manufacturer of saxagliptin) has not. Bottom line: need more data but for now, avoid in those with pre-existing heart-failure and consider stopping if new onset CHF, esp in the first year of tx. Officially: Sitagliptin & linagliptin: use not recommended - saxagliptin & alogliptin: use with caution

DPP-4 Inhibitors Summary Pros Cons Once daily administration (unless in combo pill w/ metformin) Low risk of hypoglycemia Weight neutral Well-tolerated Maybe less effective than sulfonylurea at lowering A1C Not shown to reduce complications (yet?) Expensive Possible concerns re pancreatic adverse effects and heart failure In relatively short-term trials (SAVOR & EXAMINE) there was no reduction in microvascular complications SAVOR looked at nephropathy. No difference in b/t groups in terms of composite endpt of doubling of Cr+ initiation dialysis + transplant + creatinine >530micromol/L, median f/up 2 years. EXAMINE: changes in eGFR and initiation dialysis same in both groups, median f/up 18 months

DPP-4 Inhibitors What to watch for Arrival of vildagliptin Results of TECOS, CAROLINA, CARMELINA Results of VERIFY, a 5-yr trial comparing early combination treatment with vildagliptin + metformin with metformin monotherapy and second agent added based on threshold criteria

SGLT-2 Inhibitors

SGLT-2 Inhibitors Mechanism of Action

SGLT-2 Inhibitors Canagliflozin (Invokana®) Dapagliflozin (Forxiga®) Both cost approximately $3/day, similar to DPP-4 inhibitors. Neither are currently covered by ODB.

SGLT-2 Inhibitors Effectiveness: lower A1C by 0.5-0.7%, roughly comparable to DPP-4 inhibitors. No evidence that they reduce complications of diabetes (yet?) Do not work as well in chronic kidney disease, including reduced renal function related to age Low risk hypoglycemia unless combined w/ SU or insulin.

SGLT-2 Inhibitors Both given once daily, canagliflozin preferably before breakfast Canagliflozin: 100mg/day, increase to 300mg if needed Dapagliflozin: 5mg/day, increase to 10mg/d if needed Don’t use dapagliflozin if CrCl<60mL/min Don’t start canagliflozin if CrCl<60mL/min and stop if <45mL/min

Associated with weight loss of SGLT-2 Inhibitors Associated with weight loss of 2-4kg on average

SGLT-2 Inhibitors Lower BP SBP ↓ 4-5mmHg DBP ↓ 2-3mmHg

SGLT-2 Inhibitors Theoretically could be combined with any other class of anti-diabetic agent but only some combinations approved by Health Canada. Can be used with insulin Because mechanism is insulin-independent, being studied for use in DM1

SGLT-2 inhibitors Combinations Met SU Pio Met + Met + pio Insulin +/- met Cana + Dapa

SGLT-2 Inhibitors Adverse effects Few GI adverse effects Risk of orthostasis and dehydration due to increased u/o; not recommended in combination with loop diuretics (e.g. furosemide) Dose-dependent ↑ creatinine Higher risk of UTI and genital mycotic infections (i.e. vulvovaginitis, balanitis), tend to be mild to moderate in severity and respond to usual treatment. (NNH 30-40) Large CV safety trials underway for both CANVAS (cana; n=4000; report in 2018; no longer recruiting) DECLARE-TIMI 58 (dapa; n=17000, report in 2019; no local trial sites)

SGLT-2 Inhibitors Seem very similar to each other but… Canagliflozin can increase K+; careful if combined with ACE inhibitor, ARB or K+-sparing diuretic Dapagliflozin: signal for slight increase risk of bladder CA. Do not combine w/ pioglitazone or use if previous hx of bladder CA.

SGLT-2 Inhibitors Monitoring Orthostasis, hypotension, dehydration Creatinine +/- K+ (timing?) SMBG, A1C Educate patients re symptoms UTI and candida infections

SGLT-2 Inhibitors FDA Warning FDA has received >20 reports of DKA in DM2 patients treated w/ SGLT-2 inhibitors. Presentation atypical since glucose was <10mmol/L in some pts. Only ½ of cases identified a triggering event Onset ranged from 1-175d after beginning tx w/ SGLT-2 inhibitor Watch for symptoms, check for acidosis & stop SGLT-2 inhibitor if acidotic Usual signs DKA = difficulty breathing, N/V/ abdo pain, confusion, unusual fatigue or sleepiness.

SGLT-2 Inhibitors Pros Cons Low risk hypoglycemia unless added to SU or insulin Generally well-tolerated in selected groups of pts Likely low risk of secondary failure Weight loss No evidence they ↓ risk DM complications Don’t work as well in those w/ ↓ renal fxn Expensive Long-term safety unknown b/c so new

SGLT-2 Inhibitors Place in therapy? Role in the elderly population unknown reduced efficacy with reduced renal function risk of orthostasis low risk hypoglycemia attractive Option for those who want to lose weight or avoid insulin and can afford the $3/day