New Medications for DiabetesCynthia Way, BScPharm, ACPRJune 9, 2015

Learning objectivesAt 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 inhibitorsFour 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 inhibitorsMechanism 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/dayDose 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 foodNo known drug interactionsDid have slightly higher incidence

of hypoglycemia when combined with metformin & pioglitazone as triple therapy

Manufacturer suggests using with caution if CHF

DPP-4 InhibitorsHow 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-toleratedAll have same low risk of inducing

hypoglycemia

DPP-4 InhibitorsHow 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.

DPP-4 InhibitorsCardiovascular 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 InhibitorsCV 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 InhibitorsCV 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.

DPP-4 InhibitorsSummary

Pros

Once daily administration (unless in combo pill w/ metformin)

Low risk of hypoglycemia

Weight neutral Well-tolerated

Cons

Maybe less effective than sulfonylurea at lowering A1C

Not shown to reduce complications (yet?)

Expensive Possible concerns re

pancreatic adverse effects and heart failure

DPP-4 InhibitorsWhat 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 InhibitorsMechanism of Action

SGLT-2 InhibitorsCanagliflozin (Invokana®)Dapagliflozin (Forxiga®)

Both cost approximately $3/day, similar to DPP-4 inhibitors.

Neither are currently covered by ODB.

SGLT-2 InhibitorsEffectiveness: 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 InhibitorsBoth given once daily, canagliflozin

preferably before breakfastCanagliflozin: 100mg/day, increase to

300mg if neededDapagliflozin: 5mg/day, increase to

10mg/d if neededDon’t use dapagliflozin if

CrCl<60mL/minDon’t start canagliflozin if

CrCl<60mL/min and stop if <45mL/min

SGLT-2 Inhibitors

Associated with weight

loss of 2-4kg on average

SGLT-2 InhibitorsLower BPSBP ↓ 4-

5mmHgDBP ↓ 2-

3mmHg

SGLT-2 InhibitorsTheoretically could be combined with

any other class of anti-diabetic agent but only some combinations approved by Health Canada.

Can be used with insulinBecause mechanism is insulin-

independent, being studied for use in DM1

SGLT-2 inhibitorsCombinations

Met SU Pio Met +SU

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

SGLT-2 InhibitorsSeem 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 InhibitorsMonitoring

Orthostasis, hypotension, dehydration Creatinine +/- K+ (timing?) SMBG, A1C Educate patients re symptoms UTI and

candida infections

SGLT-2 InhibitorsFDA 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

SGLT-2 Inhibitors

Pros 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

Cons 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 InhibitorsPlace 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