5/22/2015

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New medicines for type 2 diabetes – when do you use them

1. Oral Secretagogues (e.g. sulfonylureas)

2. Metformin

3. Alpha glucosidase inhibitors

4. Thiazolidinediones

5. GLP-1 receptor agonists

6. DPP-4 inhibitors

7. Pramlintide

8. SGLT2 inhibitors

9. Insulin

10. (Bromocriptine; colesevelam)

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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 Inzucchi et al. Diabetes Care 2015;38:140–149

ADA/EASD algorithm 2015

6 classes of drugs: Metformin GLP1 receptor agonists/DPP 4 inhibitors Sulfonylureas (+other secretagogues) Pioglitazone SGLT2 inhibitors Insulin

metformin

Metformin

+ another

Metformin

+ 2 others

More complex

insulin regimens

In making therapeutic decision take into account efficacy; hypoglycemia risk; effect on weight; major side effects; cost

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Glycemic targets

• Younger patients with short duration of diabetes - aiming for an HbA1c of < 7% will reduce the risk of both microvascular and macrovascular complications (aim for 6% if it can be done safely)

• T2D patients who can easily achieve an HbA1c of < 7% with lifestyle +/- pharmacotherapy do not need to “raise” their HbA1c

• Patients with history of severe hypoglycemia & advanced atherosclerosis should not aim for < 7%

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• Children

ages 0-6 <8.5%

6-12 <8%

13-19 <7.5%

• Elderly with limited life expectancy <8%

• Pregnancy 6 % (NICE <6.1%)

GLP-1 receptor agonists

Exenatide (Byetta) (2005)

Pens – 5 & 10mcg

Inject SC twice daily. Do not use for GFR < 30

Exenatide LAR (Bydureon)

2mg powder Resuspend in diluent and inject SC weekly

Liraglutide (Victoza) (2010)

Pen – 0.6, 1.2 and 1.8 mg

Usually 1.2 mg SC daily

Albiglutide (Tanzeum) (2014)

Pen - 30 mg Inject SC weekly

Dulaglutide (Trulicity) (2014)

Pen – 0.75, 1.5 mg Usually inject 0.75 mg SC weekly

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DPP 4 inhibitors

Sitagliptin (Januvia) (2006)

25, 50, 100 mg 100 mg daily usual dose. Use 50 mg for GFR 30-50; 25 mg for < 30

Saxagliptin (Onglyza) (2009)

2.5, 5 mg 5 mg daily usual dose. Use 2.5 mg if GFR< 50 or if taking strong CYP/3A4 inhibitors

Linagliptin (Tradjenta) (2011)

5 mg 5 mg daily

Alogliptin (Nesina) (2013)

6.25,12.5,25 mg 25 mg daily usual dose. Use 12.5 mg for GFR 30-60; 6.25 mg for < 30

SGLT2 inhibitors

Canagliflozin (Invokana) (2013)

100 mg, 300 mg 100 mg daily usual dose. Can use 300 for additional glucose lowering

Dapagliflozin (Farxiga) (2014)

5, 10 mg 10 mg daily usual dose. Use 5 mg if liver disease

Empagliflozin (Jardiance) (2014)

10,25 mg 10 mg daily usual dose. Can use 25 for additional glucose lowering

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Insulins

U300 insulin glargine (Toujeo) (2015)

1.5 ml Pen Duration of action at least 24 hrs

Technosphere insulin (Afrezza) (2014)

4 and 8 unit cartridges

Peak levels in 12 to 15 minutes; duration 3 hours

GLP1 receptor agonists and DPP4 inhibitors

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-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

-3

-2.5

-2

-1.5

-1

-0.5

0

Placebo

5 mcg

10 mcg

% HbA1c lowering

Effect of exenatide therapy for 30 wks on glycemic control and

weight loss in metformin treated type 2 patients

DeFronzo et al. Diabetes 28:1092; 2005

Weight loss (kg)

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Exenatide promotes weight loss when added to

diet and exercise in obese nondiabetic subjects

-6

-5

-4

-3

-2

-1

0

Exenatide Placebo

Total (73)

Nausea (18)

No Nausea (55)

Rosenstock et al. Diabetes Care 33: 1173 (2010)

Kg

* Liraglutide 3 mg daily approved for weight loss

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GLP-1

receptor

agonists

DPP-4

inhibitors

HbA1c

lowering with

monotherapy

0.5 to 1.5 % 0.4 to 0.8%

Weight Decreased Neutral

These drugs have glucose dependent insulin release and have low risk

for hypoglycemia

GLP-1 receptor agonists : adverse events

Placebo Exenatide

(n= 483) (963)

Nausea 18 % 44 %

Vomiting 4 13

Diarrhea 6 13

Feeling jittery 4 9

Dizziness 6 9

Headache 6 9

Dyspepsia 3 6

Hypoglycemia risk increased if on sulfonylurea

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Caution using GLP-1 receptor agonists in patients with renal impairment

FDA: 16 cases of renal kidney impairment and 62 cases of acute kidney injury in patients taking exenatide

- preexisting kidney disease

- one or more risk factors for kidney disease.

- nausea, vomiting, and diarrhea - possible that these side effects caused volume depletion and renal injury.

DPP4 inhibitors: adverse events

• Nasopharyngitis; upper respiratory infections

• Allergic reactions – angioedema, anaphylaxis,

exfoliative dermatologic reactions

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Cases of pancreatitis during clinical trials with GLP-1

receptor agonists

Experimental drug

Comparator group (placebo; other meds; insulin)

Exenatide 8 2

Liraglutide 13 1

Albiglutide 6 2

Dulaglutide 5 1

1.4-2.2 vs 0.6-0.9 cases of pancreatitis per 1000 patient years

FDA reporting mechanism 30 cases of acute pancreatitis with exenatide

No cases of pancreatitis reported during clinical trials with sitagliptin and saxagliptin. FDA adverse reporting mechanism 2009 – 88 cases of acute pancreatitis in patients on sitagliptin In one study with linagliptin, 8 cases of pancreatitis in 4687 patients exposed to drug (4311 patient yrs) & no cases in 1183 patients on placebo (433 patient yrs). With alogliptin there were 11 cases in 5902 patients exposed to drug (0.2%) and 5 cases in 5183 on comparator drugs (<0.1%)

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Used 10ug of exenatide in rats ~ 70 times the

clinical dose for 75 days *

Pancreatic acinar inflammation and pyknosis

The rats had 30% reduction in weight

In human islet amyloid polypeptide transgenic

rats, sitagliptin (200 mg/kg ~ 140 times clinical

dose) increased pancreatic ductal turnover,

metaplasia and induced pancreatitis in one rat

**

*Nachnani et al. Diabetologia 53: 153 (2010)

**Matveyenko et al. Diabetes 58: 1604 (2009)

Acinar

cells Dedifferentiated

cells

Pancreatic

adenocarcinoma

Endocrine cells

Cellular plasticity within the pancreas – the potential for fully

differentiated cells to change fate

Puri & Hebrok Dev Cell 18:342 (2010)

Acinar

injury

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Rats given GLP1 receptor agonists developed C- cell tumors Avoid if family or personal history of MTC; MEN 2

Differences between the GLP1 receptor agonists

• GI symptoms less with weekly treatment

• Weight loss slightly greater with liraglutide

• ~ 6% of patients on exenatide develop antibodies that attenuate glycemic response

• Albiglutide has less weight loss than exenatide and liraglutide

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Differences between the DPP4 Inhibitors

• Linagliptin- no dose adjustment for renal or liver disease

• Sitagliptin/saxagliptin/alogliptin adjust dose if renal disease

• Adjust saxgliptin dose if a strong CYP3A4/5 inhibitor is prescribed

Postmarketing study with Saxagliptin – 16, 492 T2D randomized to Saxagliptin or Placebo. Mean followup 2.1 years 289, 3.5% on Saxagliptin vs 228, 2.8% on placebo admitted to hospital for heart failure (P=0.007)

Scirica et al Circ. 130:1579 (2014)

Alogliptin 106 admission for heart failu (3.1%) vs Placebo 89 (2.9%) NS

(5380 patients, median followup 18 months)

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SGLT2 inhibitors

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SGLT 2 inhibitors lower threshold for glycosuria to 70 to 90 mg/dl

100 mg canagliflozin lowers fasting and postprandial glucose

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Reduces threshold for glycosuria to 70 to 90 mg/dl Improves fasting and postprandial glucose levels Lowers HbA1c by 0.6 to 1 % Give 100 mg daily and if necessary 300 mg daily Weight lost ~ 5 to 10lbs; decreases systolic BP; raises HDL and LDL chol Side effects – Vaginal yeast infection (~10.4%); UTI (~ 6%); dehydration Do not use if GFR < 45 mL/min; lower dose if < 60 mL/min

Canagliflozin (Invokana)

Differences between the SGLT2 inhibitors

• Inducers of UDP-glucuronosyltransferase enzymes (e.g. rifampin, phenytoin, phenobarbital, ritonavir) increase metabolism of canagliflozin

• Dapagliflozin- higher rates of breast cancer and bladder cancer in clinical trials

• Canaglifozin & empagliflozin – do not use if eGFR < 45

• Dapagliflozin- do no use if eGFR < 60

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Insulins

36 hr euglycemic clamp in T1D patients after 8 days of daily injections

of insulin glargine – U100 or U300

Becker et al. Diabetes Care 38: 637 (2015)

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T1D – 0.2 units/Kg

(from FDA.gov)

Results from open label clinical trials with U300 insulin glargine

In the two type 1 studies – control was the same and no difference in overall hypoglycemia rates In the six type 2 studies – control was the same; 2 of 6 studies had less hypoglycemia (glucose 70 or less; or needed help to treat low) Higher doses of U300 were required compared to U100 to achieve glycemic targets (~ 11 to 18% more insulin units)

Rosselli et al J Pharm Tech 2015

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Fumaryl diketopiperazine is an excipient that forms 2-2.5µm crystal (technosphere

particle) that provide a large surface area for adsorption of regular insulin

Angelo et al J Diab Sci Tech 3:545 (2009)

Insulin levels after inhaled insulin vs SC insulin analog

Time to maximal glucose infusion rate : 53 mins inhaled insulin; 108 mins SC analog

(back to baseline 3 hr with inhaled insulin; 4 hr with SC analog)

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Technosphere insulin - Afrezza

From: Sanofi Afrezza prescribing insert

4 unit cartridge – 0.35 mg insulin

~ 39% of dose distributed to lungs;

t ½ clearance from lung epithelium

~ 1hr

[1 unit SC insulin ~0.04 mg insulin]

In clinical trials, inhaled insulin boluses + SC basal insulin

as effective as SC insulin analogs + SC basal insulin (or a little worse)

Inhaled insulin use was associated with less symptomatic &

severe hypoglycemia (e.g. severe events 8.05 vs 14.45 per 100

subject-months in T1D)

FDA briefing document

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~ 40 mL decline in FEV1 in first 3 months which persisted for 2 years of

follow-up

FDA briefing document

Spirometry before prescribing, at 6 months and then annually

Cough most common side effect (~27%)

Bronchospasm in patients with asthma, COPD

Not recommended for active smokers or recent ex-smokers

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Inhaled insulin Comparator

Exubera clinical trial data *

6/4740 patients 1/4292 patients

FUSE (followup study of exubera trial subjects ) 2536 subjects (34%) **

18 primary lung cancers (6 deaths)

5 primary lung cancers (2 deaths)

Technosphere insulin ***

2/2750 patient yrs 0/2169 patient yrs

* All in previous cigarette smokers

** Primary lung cancer rates with Exubera 1.07/1000 patient years;

Comparator 0.29/1000 patient years

*** both ex smokers; and 2 cases of squamous cell lung cancers

in nonsmokers after completion of trials

Lung cancer and inhaled insulin

Clinical cases

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ADA/EASD algorithm 2015

6 classes of drugs:

Metformin

GLP1 receptor agonists/DPP 4 inhibitors

Sulfonylureas (+other secretagogues)

Pioglitazone

SGLT2 inhibitors

Insulin

metformin

Metformin

+ another

Metformin

+ 2 others

More complex

insulin regimens

In making therapeutic decision take into account efficacy; hypoglycemia risk;

effect on weight; major side effects; cost

Decisions based on

Efficacy – DPP4 moderate; others high

Hypoglycemia risk – oral secretagogues and insulin have high risk

Effect on weight – metformin, DPP4 neutral; GLP1 receptor agonists, SGLT2

inhibitors promote weight loss; oral secretagogues, insulin,

pioglitazone cause weight gain

Major side effects – metformin lactic acidosis

pioglitazone fractures; fluid retention, possib. bladder CA

GLP1 receptor agonists nausea, vomiting, possibly pancreatitis

DPP4 may cause pancreatitis

SGLT inhibitors – UTI; genital mycotic infections; dehydration

Cost – all except metformin and oral secretagogues are expensive

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Randomized controlled study of gastric banding vs lifestyle weight loss

in 60 obese patients (BMI 30 to 40) with DM < 2 years

Dixon et al. JAMA 299: 316 (2008)

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Case 1

UCSF 2013 – 66 yr old Caucasian man with DM 10 yrs. BMI 39.5 (290lb). On

metformin for 5yrs. Stopped and on insulin. 50 units of glargine; 20 to 30

units insulin aspart premeals (total insulin ~ 125 units daily).

Peripheral neuropathy; nephropathy with urine albumin 3.1 g/g creatinine .

Normal creatinine. HbA1c 8.1 %

Started metformin + 40 insulin glargine; 15 to 20 insulin aspart premeals.

HbA1c ~ 6.7%. Weight loss ~ 4 lbs.

Exenatide initiated 6 months ago

I month ago – taking 60 units of insulin a day; exenatide 10 mcg twice a day;

Metformin XR 1000 daily. HbA1c 6.2 %. Weight 280 lbs. Urine albumin

1.4 g/g creatinine

Suggested stop insulin and start glimepiride

Case 2

UCSF 2013. 63 yr old Caucasian man with DM since his late 40s. Oral

agents until age 60 when placed on insulin pump. Has proliferative retinopathy;

peripheral neuropathy with toe amputation; PVD with fem-pop bypass; MI history;

left nephrectomy for renal CA – creatinine 2.0. Admitted to UCSF with MRSA

bacteremia with septic shock; epidural abscess. Patient before acute illness

weighed 220 lbs – after hospitalization weighed 175 lbs. Excellent control

on insulin – HbA1c 7.1%

Oct. 2014 -- regained weight – 218 lbs; quite sedentary. HbA1c 10%. Creat 1.78

Negative antibodies for type 1 diabetes. Quite insulin resistant.

Started sitagliptin 25 mg daily

Jan 2015 – HbA1c 8.9%. Add glipizide 5 mg BID

April 2015 – HbA1c 8 %

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Case 3

54 yr old Caucasian man with DM for 10 years. No complications. BMI 27.5

On metformin, glimepiride, insulin detemir (40 Units). Intolerant of GLP-1 receptor

agonists. HbA1c 7.7%

Started on Canagliflozin 300 mg daily

2 months later – BG low 100’s; HbA1c 6.7 %; insulin detemir dose reduced.

No polyuria. No infections

Case 4

84 year old woman with DM for 12 yrs. BMI 41

On metformin 1000 bid, glimepiride 4 mg/day

HbA1c 8.5 %. Fingerstix glucose high 100’s to low 200’s

Would prefer pills to injections

Canagliflozin 100 mg daily

1 week later called complain of vulvar itching and rash

Canagliflozin stopped; yeast infection treated

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A cautionary case: SGLT2 inhibitor use in type 1 diabetes

23 year old Caucasian woman with T1D since age 8 – on injections

HbA1c around 8 %

Started on Canagliflozin Sept 2014

Glucose levels dropped and so insulin doses were gradually decreased

Insulin glargine dose reduced 30 to 10 to 8 to 2; also significant decrease

in bolus insulin doses

Admitted to hospital with nausea, vomiting, dehydration and ketoacidosis

A case of needle phobia

Diabetes clinic 2012. 53 yr old Vietnamese woman with diabetes

since age 37. BMI 18. Initially treated as type 2 diabetes. HbA1c 8-12

GAD antibody +ve

Refused to inject insulin even though she agreed that the needles

were almost painless (refused to use syringes or pens)

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Given Novofine autocover needles

Now on basal bolus insulin regimen (4 injections a day)

HbA1c 6.9 to 7.4 %

Dulaglutide pen – you cannot see

the needle

Wolpert Diab Care 2008

Stacking can be an issue for T1D patients who are on pumps and sensors

and inhaled insulin would reduce the risk of hypoglycemia

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Costs for 1 month supply (standard doses; Walgreens, Costco)

Metformin (4 ); glipizide (5); repaglinide (50)

Pioglitazone (12)

Acarbose (48)

DPP4 inhibitors ( ~ 330 )

SGLT2 inhibitors ( ~ 370)

GLP1 receptor agonists (~500)

Analog insulins ( ~ 400)

Old insulins ( ~ 150)

Make your own toolkit

Metformin

Oral secretagogues – glipizide,

glimepiride, nateglinide, repaglinide

DPP4 inhibitors – sitagliptin

GLP-1 receptor agonists – exenatide,

liraglutide

Insulins – glargine U100, aspart, lispro,

some premixed; NPH, Regular

( an SGLT2 inhibitor in the future?)