Type 2 diabetes: Non-insulin pharmacotherapy

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This tool is designed to support primary care providers to prescribe and manage non-insulin pharmacotherapy for adult patients living with type 2 diabetes. This is an update of the original Achieving glycemic control in type 2 diabetes tool, released in 2012.

Diagnostic criteria for diabetes

Fasting plasma glucose (FPG) ≥7.0 mmol/L^*; OR
A1C ≥6.5%^†; OR
2-hour plasma glucose (2hPG) in a 75g oral glucose tolerance test (OGTT) ≥11.1 mmol/L; OR
Random^‡ plasma glucose (PG) ≥11.1 mmol/L

* = fasting – no caloric intake for at least 8 hours
† = using a standardized, validated assay in the absence of factors that affect the accuracy of the A1C
‡ = random – anytime of the day, without regard to the interval since the last meal

The decision of which test to use for diabetes diagnosis is left to clinical judgment. Each diagnostic test has advantages and disadvantages.

Diagnosis of diabetes is confirmed if:

Symptomatic hyperglycemia is present (therefore confirmatory tests are not required); OR
The results of two laboratory tests are in the diabetes range (in the absence of symptomatic hyperglycemia)
- The second confirmatory laboratory test must be done on another day, and it is preferable that the same test be repeated for confirmation (in a timely fashion, based on clinical judgment), with the exception of random PG.

Factors that can increase A1C: iron deficiency, B12 deficiency, $ erythropoiesis, alcoholism, chronic renal failure, splenectomy
Factors that can decrease A1C: use of erythropoietin, iron or B12, reticulocytosis, chronic liver disease, ingestion of acetylsalicylic acid, vitamin C/E, decreased
erythrocyte lifespan (e.g., chronic renal failure, hemoglobinopathies, splenomegaly, rheumatoid arthritis, antiretrovirals, ribavirin, dapsone)

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A1C targets and considerations for glycemic control

Individualize (and reassess) targets considering potential benefits and harms to the patient, and according to each patient’s:

Age and/or frailty
Comorbidities
Prognosis
Duration of diabetes

Risk of hypoglycemia
Patient preferences resources and support system number
Complexity and burden of medications

Note: A1C tends to rise over time, even for patients on stable treatments.

A1C target

if easy/safe to achieve, without hypoglycemia (e.g., with lifestyle modification and metformin).
In others, risks of an A1C of ≤6.5% may warrant deintensification of therapy.3,5

Guidelines differ on the target recommended for “most” adults, however they consistently note the need
to individualize treatment intensity and therapy based on patient factors.

To achieve A1C ≤ 7.0%, target:

FPG 4.0–7.0 mmol/L and/or
PPG 5.0–10.0 mmol/L or if A1C not at target, aim for PPG 5.0–8.0 mmol/L

HOWEVER, this must be balanced against the risk of hypoglycemia.

Functionally dependent adults (Clinical Frailty Scale11 score = 4-5, on a 9 point scale): deintensification (e.g., reducing dose, discontinuation) of therapy in older, frail adults is often appropriate to reduce potential harms
(e.g., hypoglycemia, risk of polypharmacy, lack of time-to-benefit).

Adults with cardiovascular disease/ risk: patients with A1Cs in the range of 7.3-7.9% have demonstrated
reductions in cardiovascular, renal, and/or mortality outcomes. However studies featured a specific drug (an
SGLT2i, GLP1-RA, or metformin) and demographic, rather than merely the intensity of glycemic control.6-10

Frail older adults (Clinical Frailty Scale11 score = 6-8, on a 9 point scale) and/or adults with dementia, limited life expectancy or a history of recurrent severe hypoglycemia and/or hypoglycemia unawareness.

Management of hyperglycemia in type 2 diabetes

At diagnosis of type 2 diabetes

Healthy lifestyle interventions

Start and support the ongoing maintenance of healthy lifestyle interventions (nutritional therapy, weight management, physical activity) +/- metformin

Lifestyle interventions have a greater potential for A1C lowering than any pharmacotherapy (nutrition A1C 1-2% and exercise A1C 0.5-0.7%)¹³

Select individualized A1C target

A1C < 1.5% above target

Add metformin if lifestyle changes not expected to reduce blood glucose levels by 3 months.

A1C ≥ 1.5% above target

Start metformin plus a second antihyperglycemic agent, and:
- Check renal function before starting agent
- Monitor for hypoglycemia when on multiple agents of different classes

Symptomatic hyperglycemia and/or metabolic decompensation

(may include dehydration, diabetic
ketoacidosis, hyperosmolar hyperglycemic state)

Initiate insulin +/- metformin

If not at A1C target at 3 months

Start metformin (if not already started)
Adjust or advance therapy

If not at A1C target in 3-6 months and/or change in clinical status

(e.g., changes in cardiovascular or renal status, presence of diabetes complications, side effects, and ability to take current medications)

Does patient have:

Atherosclerotic cardiovascular disease; OR
Chronic kidney disease; OR
Heart failure; OR
Age > 60 years with at least 2 cardiovascular risk factors: smoking (tobacco use), hypertension (untreated BP ≥ 140/95 or current antihypertensive therapy), dyslipidemia (use of lipid-modifying therapy or a documented untreated LDL > 3.4 mmol/L, or HDL-C < 1.0 mmol/L for men and < 1.3 mmol/L for women, or triglycerides > 2.3 mmol/L), central obesity (waist circumference of ≥ 80cm for females, ≥ 90-94cm for males)

Add or substitute another antihyperglycemic agent based on shared decision-making factors

Proven cardiorenal benefit in high-risk populations

Glucagon-like peptide-1 receptor agonists (GLP1-RA) (dulaglutide, liraglutide, subcutaneous semaglutide)
Sodium-glucose co-transporter-2 inhibitors (SGLT2i) (canagliflozin, dapagliflozin, empagliflozin)
Note: benefit potential with GLP1-RA and SGLT2i is less in those with lower cardiovascular risk, so carefully weigh harms

Cardiovascular safety but no proven cardiorenal benefit

GLP1-RA receptor agonists (exenatide, lixisenatide, oral semaglutide)
Dipeptidyl peptidase-4 inhibitors (DPP4i) (sitagliptin, linagliptin)
Alpha-glucosidase inhibitor (acarbose)
Insulin secretagogues (sulfonylureas and meglitinides)
Insulin
Note: AVOID (due to risk of heart failure) saxagliptin (and possibly alogliptin), thiazolidinediones (TZD)

Minimizing risk of hypoglycemia

Note: caution use of insulin secretagogues (sulfonylureas and meglitinides), insulin
Other agents have negligible risk as monotherapy

Weight considerations

Agents that decrease weight: GLP1-RA, SGLT2i, metformin
Agents that increase weight: TZD, insulin secretagogues (sulfonylureas and meglitinides), insulin

Add or substitute another antihyperglycemic agent with demonstrated cardiorenal benefits

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Non-insulin pharmacotherapy

Shared decision-making

Shared decision-making is an approach to clinical decision-making in which patients and providers jointly consider clinical factors and patient preferences to arrive at a mutually agreeable decision.¹⁴ Shared decision-making aims to bridge the information gap between patients and providers while prioritizing patient autonomy.¹⁴

Engage patients in a discussion regarding which of the following factors are most important to them:^15,16

Use this information and a shared decision-making approach to support patients in deciding which diabetes therapy they would prefer.

cost

Affordability of therapy for 100 day supply

= < $100

Yellow = $100-$400
Red = > $400

Therapy that fits with daily routine

= twice daily or less administration

Yellow = ranges from once daily to 3+ daily
Red = 3+ administration per day, inconvenient

Avoiding therapy that requires injections

Yellow = weekly injection
Red = daily injection

Avoiding therapy that has gastrointestinal side effects

= gastrointestinal side effects are common

Glucose

Avoiding therapy that increases risk of hypoglycemia

Red = risk of hypoglycemia

weight

Therapy that impacts weight change

Green = decreases weight
Red = increases weight

Heart

Therapy that also provides cardiovascular benefits

= cardiovascular benefit

Red = cardiovascular risk (e.g., worsening myocardial infarction or heart failure)

Lung

Therapy that also provides kidney protection

Green = provides kidney protection
Red = may cause acute renal injury

First line options

Scroll (left-right) for details

Biguanides
Metformin HCL / Glucophage®

Agent with evidence-based outcome benefits

Generic available

Formulations: 500mg tab and 850mg tab

Coverage: 500mg tab covered by ODB and/or NIHB; 850mg covered by NIHB

A1C reduction (%)^12,18: 1.0

Other benefits, CVD outcomes, weight^12,18: Reduced MI in overweight (>120% IBW) patients; reduced all-cause mortality;reduced insulin requirements; reduced risk of lactic acidosis; weight loss of up to 2.9kg in 5 years²⁰

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise): GI intolerance; Vitamin B12 deficiency

Drug cost for usual dose* ($/100 days)¹⁷: Generic: $20 (1g bid) to $80 (850mg tid); Trade: $140
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Dose¹⁸: Initial: 250–500mg po daily cc; Usual: 1000mg po bid cc OR 1700mg cc am and 850mg cc pm; Max: 2550mg daily OR 850mg tid

Renal dose^12,18: eGFR 30-45mL/min (≤1000mg daily); eGFR <30mL/min (avoid*)

Comments^12,18 (titration, administration, monitoring, notes)

Titrate up every 1–2 weeks to avoid GI AE

Take with largest meal to minimize GI AE

85% of max glucose lowering seen at 1500 mg daily

Fewer GI side effects with ER formulation

Monitor: hemoglobin and vitamin B12 deficiency (annually), SCr (baseline and periodically)

On SADMANS list²¹

*Sometimes used at low dose when eGFR between 15-30 mL/min in renally stable patients
Biguanides
Metformin HCL / Glumetza®

Agent with evidence-based outcome benefits

Generic available

Formulations: 500mg extended release tab and 1000mg extended release tab

Coverage: NOT covered by ODB and/or NIHB

A1C reduction (%)^12,18: 1.0

Other benefits, CVD outcomes, weight^12,18: Reduced MI in overweight (>120% IBW) patients; reduced all-cause mortality;reduced insulin requirements; reduced risk of lactic acidosis; weight loss of up to 2.9kg in 5 years²⁰

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise): GI intolerance; Vitamin B12 deficiency

Drug cost for usual dose* ($/100 days)¹⁷: Generic: $120 (1g/d) to $235 (2g/d); Trade: $300 (2g/d)

*Sometimes used at low dose when eGFR between 15-30 mL/min in renally stable patients
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Dose¹⁸: Initial: 250–500mg po daily cc; Usual: 11000–2000mg po cc pm; Max: 2550mg daily

Renal dose^12,18: eGFR 30-45mL/min (≤1000mg daily); eGFR <30mL/min (avoid*)

Comments^12,18 (titration, administration, monitoring, notes)

Titrate up every 1–2 weeks to avoid GI AE

Take with largest meal to minimize GI AE

85% of max glucose lowering seen at 1500 mg daily

fewer GI side effects with ER formulation

Monitor: hemoglobin and vitamin B12 deficiency (annually), SCr (baseline and periodically)

On SADMANS list²¹

*Sometimes used at low dose when eGFR between 15-30 mL/min in renally stable patients

Second line options

Avoid combining Dipeptidyl peptidase-4 inhibitor (DPP4i) with Glucagon-like peptide-1 receptor agonists (GLP1-RA).

Scroll (left-right) for details

Alpha-glucosidase inhibitor
Acarbose / Glucobay®

Generic available

Formulations: 50mg tab and 100mg tab

Coverage: Covered by ODB (LU 175, 176) and/or NIHB

A1C reduction (%)^12,18: 0.7-0.8

Other benefits, CVD outcomes, weight^12,18: Improved postprandial control; neutral affect on weight

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise): GI intolerance, flatulence, diarrhea

Drug cost for usual dose* ($/100 days)¹⁷: Generic: $74 to $100
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Dose¹⁸: Initial: 25mg po daily cc; Usual: 50–100mg po tid cc; Max: 100mg po tid cc

Renal dose^12,18: eGFR<25-30mL/min (contraindication)

Comments^12,18 (titration, administration, monitoring, notes)

Titrate up every 1–2 weeks until 50 mg tid to avoid GI AE; then every 4–8 weeks

Max effect may take weeks

Take with first bite of meal

Monitor: SCr and LFTs (baseline and periodically)
Dipeptidyl peptidase-4 inhibitor (DPP4i)
Alogliptin / Nesina®

NOT on Ontario drug formulary

Formulations²³: 6.25mg tab, 12.5mg tab, 25mg tab

Coverage: NOT covered by ODB and/or NIHB

A1C reduction (%)^12,18: 0.5–0.7

Other benefits, CVD outcomes, weight^12,18: Improved postprandial control; well tolerated option in older adults; neutral effect on CVD outcomes; neutral affect on weight

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise): Pancreatitis (rare); severe joint pain (rare); possible worsening of HF in patients with acute
coronary syndrome without a history of HF

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $265
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Dose¹⁸: 25mg po daily

Renal dose^12,18: eGFR 30-50mL/min (12.5mg po daily); eGFR <30mL/min (6.25mg po daily)

Comments^12,18 (titration, administration, monitoring, notes)

Monitor: SCr (baseline and periodically), LFTs (baseline)

May elevate LFTs
Dipeptidyl peptidase-4 inhibitor (DPP4i)
Linagliptin / Trajenta®

Avoid combining with GLP1-RA

Formulations: 5mg tab

Coverage: Covered by ODB and/or NIHB

A1C reduction (%)^12,18: 0.5–0.7

Other benefits, CVD outcomes^12,18: Improved postprandial control; Well tolerated option in older adults; Neutral effect on CVD outcomes

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise): Pancreatitis (rare); severe joint pain (rare)

Dose¹⁸: 5mg po daily

Renal dose^12,18: eGFR <15mL/min (use with caution). No dosage adjustment.

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $297
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Comments^12,18 (titration, administration, monitoring, notes)

Monitor: SCr (baseline and periodically), LFTs (baseline)

no dosage adjustment in renal impairment
Dipeptidyl peptidase-4 inhibitor (DPP4i)
Saxagliptin / Onglyza®

Formulations: 2.5mg tab and 5mg tab

Coverage: Covered by ODB and/or NIHB

A1C reduction (%)^12,18: 0.5–0.7

Other benefits, CVD outcomes, weight^12,18: Improved postprandial control; well tolerated option in older adults; neutral effect on CVD outcomes; neutral affect on weight

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise): Pancreatitis (rare); severe joint pain (rare); HF

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $297
View dosage, titration, administration, monitoring, notes
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Dose¹⁸: 5mg po daily

Renal dose^12,18: eGFR <15mL/min (use with caution). No dosage adjustment.

Comments^12,18 (titration, administration, monitoring, notes)

Monitor: SCr (baseline and periodically), LFTs (baseline)

avoid in HF
Dipeptidyl peptidase-4 inhibitor (DPP4i)
Sitagliptin / Januvia®

Formulations: 25mg tab, 50mg tab, 100mg tab

Coverage: Covered by ODB and/or NIHB (LU – for patients who did not achieve glycemic control or who demonstrated intolerance to an adequate trial of
metformin and a sulfonylurea)

A1C reduction (%)^12,18: 0.5–0.7

Other benefits, CVD outcomes, weight^12,18: Improved postprandial control; well tolerated option in older adults; neutral effect on CVD outcomes; neutral affect on weight

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise): Pancreatitis (rare); severe joint pain (rare)

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $354
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Dose¹⁸: 100mg po daily

Renal dose^12,18: eGFR 30-49mL/min (50mg podaily); eGFR <30mL/min, hemodialysis, peritoneal dialysis, chronic kidney disease (25mg po daily)

Comments^12,18 (titration, administration, monitoring, notes)

Monitor: SCr (baseline and periodically), LFTs (baseline)

no dosage adjustment in renal impairment
Glucagon-like peptide-1 receptor agonists (GLP1-RA) – short acting
Exenatide / Byetta®

NOT on Ontario drug formulary

Formulations²⁴: Pre-filled pen (multiuse) 250μg/mL, 1.2mL, 2.4mL Pk

Coverage: NOT covered by ODB and/or NIHB

A1C reduction (%)^12,18: 0.6-1.4

Other benefits, CVD outcomes, weight^12,18: Weight loss of 1.6-3kg¹; other benefits unknown; CVD outcomes unknown

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise): SC injection; GI side effects; acute pancreatitis/gallstone disease (rare); contraindicated with personal/family hx of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $510
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Dose¹⁸: Initial/Usual: 5μg SC bid ac, prior to main meals ≥6 hour apart; Max: 10μg SC bid ac

Renal dose^12,18: eGFR <50mL/ min (caution), <30mL/min (contraindicated)

Comments^12,18 (titration, administration, monitoring, notes)

Administer within 60 minutes before meal

Injection daily or once weekly

Initiate 5ug SC bid within 60 mins ac x 1 month, then 10ug bid

If no improvement in blood glucose control after 3-4 months, consider alternatives

Monitor: SCr (baseline and periodically)

Less A1C lowering with short-acting agents than long-acting agents
Glucagon-like peptide-1 receptor agonists (GLP1-RA) – short acting
Lixisenatide / Adlyxine®

Formulations²⁴: Pre-filled pen (multiuse) 0.05mg/mL, 0.1mg/mL; 3mL Pk

Coverage: Covered by ODB and/or NIHB

A1C reduction (%)^12,18: 0.6-1.4

Other benefits, CVD outcomes, weight^12,18: Weight loss of 1.6-3kg¹; neutral effect on CVD outcomes

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise): SC injection; GI side effects; acute pancreatitis/gallstone disease (rare); contraindicated with personal/family hx of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $419
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Dose¹⁸: Initial: 10mcg SC daily ac x 2 weeks; Usual/Max: 20mcg SC daily ac

Renal dose^12,18: eGFR <15-20mL/min (contraindicated)

Comments^12,18 (titration, administration, monitoring, notes)

Start 10ug SC daily within the hour prior to any meal of the day x 2 weeks then 20ug SC daily

If not tolerated, the dose can be temporarily reduced to 10ug SC daily and consider increasing the dose to 20ug SC once daily within 4 weeks

Monitor: SCr (baseline and periodically)
Glucagon-like peptide-1 receptor agonists (GLP1-RA) – longer acting
Dulaglutide / Trulicity®

Agent with evidence-based outcome benefits

NOT on Ontario drug formulary

Formulations²⁵: Pre-filled pen(single use) 0.75mg/0.5ml; 1.5mg/0.5ml

Coverage: NOT covered by ODB and/or NIHB

A1C reduction (%)^12,18: 0.6-1.4

Other benefits, CVD outcomes, weight^12,18: decreased MACE in patients with clinical CVD ; weight loss of 1.6-3kg¹

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise): SC injection; GI side effects (less GI side effects with weekly GLP1-RA vs daily); acute pancreatitis/gallstone disease (rare); contraindicated in patients with personal/family hx of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $720 (12 weeks)
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Dose¹⁸: Initial: 0.75mg SC once weekly; Usual/Max: 1.5mg SC once weekly

Renal dose^12,18: eGFR <15mL/min (caution)

Comments^12,18 (titration, administration, monitoring, notes)

With or without meals

Monitor: SCr (baseline and periodically)

Single use disposable (environmental impact)
Glucagon-like peptide-1 receptor agonists (GLP1-RA) – longer acting
Exenatide / Bydureon®

NOT on Ontario drug formulary

Formulations²⁵⁶: ER pen (powder, single use) 2mg

Coverage: NOT covered by ODB and/or NIHB

A1C reduction (%)^12,18: 0.6-1.4

Other benefits, CVD outcomes, weight^12,18: Neutral effect on CVD outcomes; weight loss of 1.6-3kg¹

Harms, hypoglycemic risk^12,18(negligible risk as monotherapy unless stated otherwise): SC injection; GI side effects (less GI side effects with weekly GLP1-RA vs daily); acute pancreatitis/gallstone disease (rare); contraindicated in patients with personal/family hx of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2

Drug cost for usual dose* ($/100 days)¹⁷: Trade: $775 (12 weeks)
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Dose¹⁸: 2mg SC once weekly (must reconstitute)

Renal dose^12,18: eGFR <50mL/min (caution), <30mL/min (contraindicated)

Comments^12,18 (titration, administration, monitoring, notes)

With or without meals

Monitor: SCr (baseline and periodically)

Supplied as a powder suspension to be reconstituted into a solution

Type 2 diabetes: Non-insulin pharmacotherapy

Diagnostic criteria for diabetes

Diagnosis of diabetes is confirmed if:

A1C targets and considerations for glycemic control

A1C target

≤ 6.5% (some adults)

≤ 7.0% (most adults)

7.1-8.0% (functionally dependent adults)

7.3-7.9% (adults with cardiovascular disease/risk)

7.1-8.5% (frail older adults)

Management of hyperglycemia in type 2 diabetes

At diagnosis of type 2 diabetes

Healthy lifestyle interventions

Select individualized A1C target

A1C < 1.5% above target

A1C ≥ 1.5% above target

Symptomatic hyperglycemia and/or metabolic decompensation

If not at A1C target at 3 months

If not at A1C target in 3-6 months and/or change in clinical status

Does patient have:

Add or substitute another antihyperglycemic agent based on shared decision-making factors

Add or substitute another antihyperglycemic agent with demonstrated cardiorenal benefits

Non-insulin pharmacotherapy

Shared decision-making

Affordability of therapy for 100 day supply

Therapy that fits with daily routine

Avoiding therapy that requires injections

Avoiding therapy that has gastrointestinal side effects

Avoiding therapy that increases risk of hypoglycemia

Therapy that impacts weight change

Therapy that also provides cardiovascular benefits

Therapy that also provides kidney protection

First line options

Scroll (left-right) for details

Metformin HCL / Glucophage®

Metformin HCL / Glumetza®

Second line options

Scroll (left-right) for details

Acarbose / Glucobay®

Alogliptin / Nesina®

Linagliptin / Trajenta®

Comments12,18 (titration, administration, monitoring, notes)

Saxagliptin / Onglyza®

Sitagliptin / Januvia®

Exenatide / Byetta®

Lixisenatide / Adlyxine®

Dulaglutide / Trulicity®

Exenatide / Bydureon®

Comments^12,18 (titration, administration, monitoring, notes)