Canadian Society of Internal MedicineAnnual Meeting 2016

Montreal, QC

Choosing the Right Agent for your Patient with

diabetes: Individualizing type 2 diabetes

management in light of the expanding therapies

availableKaberi Dasgupta, Associate Professor of Medicine, McGill

University

Canadian Society of Internal Medicine

Annual Meeting 2016

K Dasgupta: Choosing the right agent for your diabetes patient – 28 October 2016

The following presentation represents the views of the speaker

at the time of the presentation. This information is meant for

educational purposes, and should not replace other sources

of information or your medical judgment.

Canadian Society of Internal MedicineAnnual Meeting 2016

I sit on the CDA 2018 pharmacotherapy in type 2 diabetes

chapter. I have held and hold research grants from the CIHR,

FRQS, Heart and Stroke Foundation, Canadian Diabetes

Association, Lawson Foundation, Medavie Foundation, and

Diabete Quebec. None of these place me in conflict.

I study health behaviour change in type 2 diabetes, gestational

diabetes, and hypertension.

Conflict Disclosures

Some of the drugs, devices, or treatment modalities

mentioned

in this presentation are:

All current classes of antihyperglycemic medications

1. Identify therapeutic options for patients on maximal doses of / intolerant to biguanides, sulfonylureas, and insulin

1. Compare and contrast the effects of the expanding options for anti-diabetic agents in diabetic patients, considering the risks of hypoglycaemia, body weight and other their side effects.

2. Interpret the evidence for cardiovascular outcomes for various hypoglycaemic agents

3. Recognize the impact of eGFR on prescribing medications for type 2 diabetes.

guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca

Copyright © 2013 Canadian Diabetes Association

Add another class of agent best suited to the individual (agents listed in alphabetical order):

Class RelativeA1C Lowering

Hypo-glycemia

Weight Effect in Cardiovascular Outcome Trial

Other therapeutic considerations Cost

-glucosidase inhibitor (acarbose)

Rare neutral to Improved postprandial control, GI side-effects

$$

Incretin agents:DPP-4 InhibitorsGLP-1R agonists

to RareRare

Neutral to

Superior (Lira, )Neutral (alo, saxa, sita)Neutral (lixi)

Caution with saxagliptin in heart failureGI side-effects

$$$$$$$

Insulin Yes Neutral (glar) No dose ceiling, flexible regimens $-$$$$

Insulin secretagogue:Meglitinide

Sulfonylurea

Yes

Yes

Less hypoglycemia in context of missed meals but usually requires TID to QID dosingGliclazide and glimepiride associated with less hypoglycemia than glyburide

$$

$

SGLT2 inhibitors to Rare Superiority (empa in T2DM patients with clinical CVD)

Genital infections, UTI, hypotension, dose-related changes in LDL-C, caution with renal dysfunction and loop diuretics, dapagliflozin not to be used if bladder cancer, rare diabetic ketoacidosis (may occur with no hyperglycemia)

$$$

Thiazolidinediones Rare Neutral CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-12 weeks required for maximal effect

$$

Weight loss agent (orlistat)

None GI side effects $$$

alo=alogliptin; glar=glargine; saxa=saxagliptin; sita=sitagliptin; lixi=lixisenatide; empa=empagliflozin 2016

The ominous octet (3) depicting the mechanism and site of action of antidiabetes medications based upon the pathophysiologic disturbances present in T2DM.

View at: http://care.diabetesjournals.org/content/diacare/36/Supplement_2/S127/F1.large.jpg

Ralph A. DeFronzo et al. Dia Care 2013;36:S127-S138

©2013 by American Diabetes Association

67 year old woman with type 2 diabetes diagnosed 15 years ago and hypertension for the past 10 years. Her A1C is 8.7%, blood pressure is 140/90 mm Hg in your office, and her LDL is 2.2 mmol/l. Her GFR is 45. Her BMI is 34 kg/m2, her waist circumference is 93 cm, and she walks her dog 20 minutes each day. Her current medications include a statin, ASA, perindopril-indapamide combination, metformin, and maximal doses of gliclazide MR. She had an MI 1 year ago. How would you manage this patient?

Glucose filtered, glucose resorbed (proximal tubule)

Glucosuria if maximal transporter capacity exceeded

SGLT2 inhibitors block reabsorption at higher glucose levels

Glucose

Glucose

View at: http://www.nature.com/nrd/journal/v9/n7/fig_tab/nrd3180_F1.html

Chao EC, Henry RR. SGLT2 inhibition: A novel strategy for diabetes

treatment. Nat Rev Drug Discov.2010;9:551–9

Both sodium and glucose are excreted when SGLT2 is blocked

Population- High risk CVD◦ Adults

◦ BMI < 45 kg/m2

◦ GFR > 30

◦ established CVD (MI, stroke, amputation, multivessel coronary artery disease, or CABG)

Intervention/comparison◦ Empagliflozin 10 mg vs. placebo

◦ Empagliflozin 20 mg vs. placebo

Outcomes: CVD morbidity and mortality

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes, Zinman and

colleagues, Nov 2015

Antihyperglycemics◦ Metformin 74%◦ Insulin 48%◦ Sulfonylureas 43%◦ DPP-4 inhibitor 11%◦ TZD 4%◦ GLP 1 agonist 3%

Other cardioprotective◦ ACE I/ARB 81%◦ Beta blocker 65%◦ Diuretic 44%◦ Statin 77%◦ ASA 83%◦ Plavix 11%

View at: http://www.nejm.org/doi/full/10.1056/NEJMoa1504720#t=article (fig 3)

Zinman B et al. N Engl J Med 2015;373:2117-2128

Some A1C lowering

View here: http://care.diabetesjournals.org/content/diacare/38/3/420.full.pdf

Fig 1

Ilkka Tikkanen et al. Dia Care 2015;38:420-428

©2015 by American Diabetes Association

Blood pressure lowering

Primary and Secondary Cardiovascular Outcomes.

Zinman B et al. N Engl J Med 2015;373:2117-2128

Adverse Events.

Zinman B et al. N Engl J Med 2015;373:2117-2128

Genital

infections

◦ Vulvovaginal

infections

◦ Balanitis

Candida

Canagliflozin (Invokana)

Dapagliflozin (Forxiga)

In Europe these and empagliflozin are available in

combination with metformin

From CDA website, 2016:

Rare but life threatening cases have occurred in type 2

diabetes patient taking SGLT2 inhibitors

Glucose levels may not be as high as expected for DKA

Context

◦ Low insulin production or increased need

Symptoms

◦ Nausea and vomiting

◦ Abdominal pain

◦ Thirst

◦ Tachypnea

◦ Confusion Medscape, Internal Medicine

European Medicines Agency, 2016

A. In whom should we use empagliflozin?

◦ All patients with type 2 diabetes?

◦ Those with established CVD?

◦ Those with creatinine clearance above 30?

◦ All patients with renal injury?

◦ What other antihyperglycemic agents should be used first?

A. Is this a class effect?

Secreted by intestinal mucosa (ileum, distal colon)

Half-life under two minutes

◦ enzyme dipeptidyl peptidase-IV (DPP-IV)

Stimulates insulin secretion

Slows gastric emptying

Short half-life in circulation

Liraglutide

◦ 97% structurally similar to GLP-1

◦ Longer half life because of a fatty chain for binding with

proteins

Manning and colleagues, Physiology, Published 5 January 2015 Vol. 30 no. 1, 50-62

View here: http://physiologyonline.physiology.org/content/30/1/50

Fig 2

EMPAreg eligibility LEADER eligibility

◦ Type 2 diabetes

◦ ≥ 18 years

◦ BMI < 45 kg/m2

◦ GFR > 30

◦ established CVD with 1 or more of: MI

Stroke

Amputation

Multivessel coronary artery disease

CABG

A1C ≥7% ≥ 50 years with ≥ 1◦ Coronary heart disease◦ Cerebrovascular disease◦ Peripheral vascular disease◦ Chronic kidney disease stage 3

or greater ≥ 60 years with ≥ 1◦ Microalbuminuria/Proteinuria◦ Hypertension with LVH◦ LV systolic or diastolic

dysfunction◦ Chronic kidney disease stage 3

or greater◦ Ankle-brachial index < 0.9

Intervention/comparison◦ 1.8 mg liraglutide injection once daily vs. placebo

following run-in period

◦ Stratified randomization by GFR (< 30 ≤)

Outcomes◦ Composite

Death from cardiovascular causes

Nonfatal MI

Nonfatal stroke

Coronary revascularization

Hospitalization for unstable angina

Hospitalization for heart failure

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes, Marso and colleagues, Aug 2016

Primary Composite Outcomes in Various Demographic and Clinical Subgroups.

View herehttp://www.nejm.org/doi/full/10.1056/NEJMoa1603827#t=articleFig 2

Marso SP et al. N Engl J Med 2016;375:311-322

View herehttp://www.nejm.org/doi/full/10.1056/NEJMoa1603827#t=articleTable 1

Marso SP et al. N Engl J Med 2016;375:311-322

View herehttp://www.nejm.org/doi/full/10.1056/NEJMoa1603827#t=articleTable 2

Marso SP et al. N Engl J Med 2016;375:311-322

Exenatide

Lixisenatide

Dulaglutide

Albiglutide

Semaglutide

Once/week GLP-1 agonist

In whom would you use a GLP-1 agonist? Which one? Why?

DPP 4 saxagliptin and heart failure

Population◦ Type 2 diabetes 35 to 75 years of age with A1C >

6.5%

◦ MI, stroke, PTCA, CABG, PVD,

Intervention vs. Control◦ Pioglitazone vs. placebo

Population◦ No type 2 diabetes

◦ HOMA-IR > 3

◦ Ischemic stroke or TIA

Intervention vs Control◦ Pioglitazone vs. Placebo

Outcome◦ Fatal or nonfatal stroke or MI

Many agents lower A1C to similar extent

DeFronzo provides evidence that durability of glycemic control differs across agents

Studying the impact of combo therapy

The effect of sulfonylurea (glibenclamide = glyburide) and metformin therapy on the plasma

HbA1c concentration in newly diagnosed T2DM subjects in UKPDS. Conventionally treated

diabetic subjects received diet plus exercise therapy (113,114).

View here:

http://care.diabetesjournals.org/content/36/Supplement_2/S127.figures-only

Fig 3

Ralph A. DeFronzo et al. Dia Care 2013;36:S127-S138

©2013 by American Diabetes Association

Durability of glycemic control with sulfonylureas.

©2013 by American Diabetes Association

View here:

http://care.diabetesjournals.org/content/36/Supplement_2/S127.figures-only

Fig 4

Ralph A. DeFronzo et al. Dia Care 2013;36:S127-S138

Durability of glycemic control with TZDs. Summary of studies examining the effect of TZDs

versus placebo or versus active comparator on HbA1c in T2DM subjects.

©2013 by American Diabetes Association

View here:

http://care.diabetesjournals.org/content/36/Supplement_2/S127.figures-only

Fig 5

Ralph A. DeFronzo et al. Dia Care 2013;36:S127-S138

Population◦ Newly diagnosed type 2 diabetes patients

Intervention◦ Combination: Pioglitazone, metformin, exenatide

Comparison◦ Sequential: metformin, then sulfonylurea, then

insulin

Outcome◦ A1C

◦ 134 patients (preliminary): 2.7% vs. 2.2% reduction at 2 years with 1.5 vs 4 kg loss and less hypos

The ominous octet (3) depicting the mechanism and site of action of antidiabetes medications based upon the pathophysiologic disturbances present in T2DM.

©2013 by American Diabetes Association

View at: http://care.diabetesjournals.org/content/diacare/36/Supplement_2/S127/F1.large.jpg

Ralph A. DeFronzo et al. Dia Care 2013;36:S127-S138

guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca

Copyright © 2013 Canadian Diabetes Association

Add another class of agent best suited to the individual (agents listed in alphabetical order):

Class RelativeA1C Lowering

Hypo-glycemia

Weight Effect in Cardiovascular Outcome Trial

Other therapeutic considerations Cost

-glucosidase inhibitor (acarbose)

Rare neutral to Improved postprandial control, GI side-effects

$$

Incretin agents:DPP-4 InhibitorsGLP-1R agonists

to RareRare

Neutral to

Superior (Lira, )Neutral (alo, saxa, sita)Neutral (lixi)

Caution with saxagliptin in heart failureGI side-effects

$$$$$$$

Insulin Yes Neutral (glar) No dose ceiling, flexible regimens $-$$$$

Insulin secretagogue:Meglitinide

Sulfonylurea

Yes

Yes

Less hypoglycemia in context of missed meals but usually requires TID to QID dosingGliclazide and glimepiride associated with less hypoglycemia than glyburide

$$

$

SGLT2 inhibitors to Rare Superiority (empa in T2DM patients with clinical CVD)

Genital infections, UTI, hypotension, dose-related changes in LDL-C, caution with renal dysfunction and loop diuretics, dapagliflozin not to be used if bladder cancer, rare diabetic ketoacidosis (may occur with no hyperglycemia)

$$$

Thiazolidinediones Rare Neutral CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-12 weeks required for maximal effect

$$

Weight loss agent (orlistat)

None GI side effects $$$

alo=alogliptin; glar=glargine; saxa=saxagliptin; sita=sitagliptin; lixi=lixisenatide; empa=empagliflozin 2016

If you were diagnosed with type 2 diabetes, what would you do?