Treatment Intensification – Part 1

Question 1

Initial Pharmacologic Management

Answer 1

Set a treatment target
• Start healthy behaviour interventions
– Nutritional therapy
– Exercise
– Weight management
• Start metformin
• At follow-up…
– A1c target not achieved
– A1c target initially achieved, but no longer maintained

1. Why is initial therapy not working/ no longer working?
2. What is the next step?

Question 2

1. Why is initial therapy not working/ no longer working?

Answer 2

Progressive Loss of Beta Cell Function
from time before diagnosis to years after
A1c Level Over Time - UKPDS increases (even with intensive control)

Question 3

see slide 7 for trends with duration of diabetes

Answer 3

more people on insulin

most people on at least 1 oral drug 15+ years after

Question 4

Patient Education Points

Chronic, Progressive Nature of Diabetes

Answer 4

• Regular monitoring of A1c, even if it has been stable for some time
• Timely adjustments (dose increase, additional antihyperglycemic agents) will be needed
• Insulin is a common option for treatment intensification, but it has numerous negative images
– Punishment for not controlling blood glucose
– Stigma due to the perception that administering an injection means illicit drug use
– Fear of hypoglycemia
– Weight gain

Question 5

diabetes canada update 2020

Answer 5

5)Glycemic control, cardiovascular and renal status should be reviewed regularly (at least annually). Healthy behaviour interventions should be reinforced and supported. Efficacy, side effects and adherence to existing antihyperglycemic therapy should be assessed. [Grade D, Consensus]

6)Dose adjustments, substitutions and/or addition of
antihyperglycemic medications should be made in order to maintain A1c or attain target A1c within 3 to 6 months. [Grade D, Consensus]

7)If glycemic targets are not achieved or maintainedwith existing antihyperglycemic medication(s), or the individual’s clinical status changes, other classes of agents should be used (either by addition or replacement) to reduce cardiorenal outcomes and/or improve glycemic control; or glycemic targets should be reassessed. [Grade D, Consensus]

Question 6

name 7 aha drugs

Answer 6

1. Acarbose
2. Dipeptidyl peptidase-4 (DPP) inhibitors
3. Glucagon-like peptide-1 (GLP1) receptor agonists
4. Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors
5. Sulfonylureas & Meglitinides
6. Thiazolidinediones
7. Insulin

Question 7

Factors to Consider when Selecting a Second

(or Third) Antihyperglycemic Agent (AHA

Answer 7

High risk of cardiovascular or renal events
– Existing atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or
heart failure (HF)
– Age >60 years and ≥2 cardiovascular (CV) risk factors
• tobacco use, dyslipidemia, hypertension
• Renal function
• Degree of hyperglycemia
• Side effect profile
– Risk of hypoglycemia
– Weight gain
• Costs and coverage
• Patient preference
• Ability to adhere to the regimen

Question 8

how does kidney fxn affect choice of drugs?

Answer 8

Calculate GFR* and check product monograph
>60 mL/min ⟹ no adjustments
<60 mL/min ⟹ SGLT2i reassess use; SU & TZD use with caution;
GLP1ra depends on agent; DPP4i adjust dose
*GFR=Glomerular Filtration Rate
Product monographs use the GFR calculated by the Cockcroft-Gault equation

Question 9

degree of hyperglycemia

Answer 9

(pooled evidence from a meta-analysis1 & 2 network meta-analyses2,3)
• Majority of studies (81%) followed patients for ≤1 year
• All antihyperglycemic agents effectively reduce A1c when added to metformin
• A1c should reduce by 0.5% to 1.0%
• All antihyperglycemic agents (except insulin) will reach a plateau. Increasing the dose does not produce any further benefit in blood glucose reduction.
• Caution when comparing efficacy in head to head trials
• e.g., moderate dose sulfonylurea versus maximum

A1c reduction of 1%
Exception is acarbose (at best -.5% reducation)

Will reach a plateau at 2/3 of dose
At this pt stop and add 2nnd agent

Question 10

what is the risk of increasing metformin dose

Answer 10

as dose increases, A1C reduction increases but so does stopping the drug due to GI distress

Question 11

rank drug classes based on risk of hypoglycemia

Answer 11

Insulin&raquo_space; Sulfonylureas > Meglitinides > DPP4i ≈ GLP1ra ≈ SLGT2i

Question 12

rank drug classes based on risk of weight gain

Answer 12

insulin&raquo_space; Sulfonylureas ≈ Meglitinides ≈ TZD
Weight Neutral: DPP4i ≈ Acarbose
Weight Loss: GLP1ra ≈ SLGT2i

Other side effects:
Genital Mycotic Infections: SGLT2i
Fracture Risk: SGLT2i, TZD
Pancreatitis(??): DPP4i, GLP1ra

Question 13

rank drug classes based on cost

Answer 13

Insulin&raquo_space; GLP1ra > DPP4i ≈ SLGT2i ≈ TZD > Acarbose ≈ Meglitinides > Sulfonylureas

Question 14

pt preference

which drugs are injected?

Answer 14

Injection: Insulin & GLP1ra
Oral: DPP4i, SLGT2i, TZD, Acarbose, Meglitinides, Sulfonylureas

Question 15

What is the evidence
to support intensive glycemic control
in T2DM on Clinical Outcomes?

Global Comments on Evidence
for Microvascular Outcomes

Answer 15

18 RCTs and 2 Meta analyses

Both meta-analyses had the same clinical question, searched the same literature, were
published within 4 months of each other in the same journal, yet…
– Do not include the same randomized controlled trials
– Do not use the same definition for each microvascular outcome
• Does intensive glycemic control significantly reduce the risk of…
– Any microvascular event? Yes
– Retinopathy? Probably (depends on the meta-analysis)
– Nephropathy? Probably (depends on the outcome used)
– Neuropathy? No
• Does intensive glycemic control significantly increase the risk of hypoglycemia? YES!!
• Bottom Line: despite weak clinical trial evidence, intensive glycemic control makes sense
from a pathophysiologic perspective.

Question 16

Evidence to Support Intensive Glycemic Control

Reduces the Risk of Macrovascular Outcomes

Answer 16

18 RCTs, 5 Meta analyses

• All meta-analyses had the same clinical question, searched the same literature, yet…
– Do not include the same randomized controlled trials
– Have substantive heterogeneity for most outcomes (I2 40-60%)
• Does intensive glycemic control significantly reduce the risk of…
– Major Adverse Cardiovascular Event Yes
– All-Cause Mortality? No (ACCORD reported significant increased risk)
– Cardiovascular Mortality? No (ACCORD reported significant increased risk)
– Fatal or non-Fatal Myocardial Infarction? Maybe (depends on the meta-analysis used)
– Fatal or non-Fatal Stroke? No
– Heart Failure? No
• Bottom Line: despite weak clinical trial evidence, intensive glycemic control makes sense
from a pathophysiologic perspectiv

Wanna lower bg, avod hyperglemic events
Don’t lower it too much

Question 17

ORIGIN (Insulin Therapy)
– To determine whether insulin glargine-mediated normoglycemia can reduce
cardiovascular morbidity and/or mortality in people at high risk for vascular
disease with either IFG, IGT or early type 2 diabetes

Answer 17

no diff with insulin glargine and standard care
• No effect on MACE endpoints
– HR: 1.02 (0.94-1.11)

Question 18

Look AHEAD (weight loss)
– to examine, in overweight volunteers with type 2 diabetes, the long-term effects
of an intensive lifestyle intervention program designed to achieve and maintain
weight loss by decreased caloric intake and increased physical activity

Answer 18

Stopped due to futility – no effect on CV endpoints

– HR: 0.95 (0.83-1.09)