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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?