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

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)

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)
Yes
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

 

No
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

IV

Avoiding therapy that requires injections
  • Yellow = weekly injection
  • Red = daily injection

GI

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, weight12,18: 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 risk12,18 (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

    View dosage, titration, administration, monitoring, notes
  • 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, weight12,18: 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 risk12,18 (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

    View dosage, titration, administration, monitoring, notes

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®
    A

    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, weight12,18: Improved postprandial control; neutral affect on weight

    Harms, hypoglycemic risk12,18 (negligible risk as monotherapy unless stated otherwise): GI intolerance, flatulence, diarrhea

    Drug cost for usual dose* ($/100 days)17: Generic: $74 to $100

    View dosage, titration, administration, monitoring, notes
  • Dipeptidyl peptidase-4 inhibitor (DPP4i)
    Alogliptin / Nesina®
    A

    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, weight12,18: Improved postprandial control; well tolerated option in older adults; neutral effect on CVD outcomes; neutral affect on weight

    Harms, hypoglycemic risk12,18 (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

    View dosage, titration, administration, monitoring, notes
  • Dipeptidyl peptidase-4 inhibitor (DPP4i)
    Linagliptin / Trajenta®
    A

    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 outcomes12,18: Improved postprandial control; Well tolerated option in older adults; Neutral effect on CVD outcomes

    Harms, hypoglycemic risk12,18 (negligible risk as monotherapy unless stated otherwise): Pancreatitis (rare); severe joint pain (rare)

    Dose18: 5mg po daily

    Renal dose12,18:  eGFR <15mL/min (use with caution). No dosage adjustment.

    Drug cost for usual dose* ($/100 days)17: Trade: $297

    View comments (titration, administration, monitoring, notes)
  • Dipeptidyl peptidase-4 inhibitor (DPP4i)
    Saxagliptin / Onglyza®
    A

    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, weight12,18: Improved postprandial control; well tolerated option in older adults; neutral effect on CVD outcomes; neutral affect on weight

    Harms, hypoglycemic risk12,18 (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
  • Dipeptidyl peptidase-4 inhibitor (DPP4i)
    Sitagliptin / Januvia®
    A

    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, weight12,18: Improved postprandial control; well tolerated option in older adults; neutral effect on CVD outcomes; neutral affect on weight

    Harms, hypoglycemic risk12,18 (negligible risk as monotherapy unless stated otherwise): Pancreatitis (rare); severe joint pain (rare)

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

    View dosage, titration, administration, monitoring, notes
  • Glucagon-like peptide-1 receptor agonists (GLP1-RA) – short acting
    Exenatide / Byetta®
    A

    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, weight12,18: Weight loss of 1.6-3kg1; other benefits unknown; CVD outcomes unknown

    Harms, hypoglycemic risk12,18 (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

    View dosage, titration, administration, monitoring, notes
  • Glucagon-like peptide-1 receptor agonists (GLP1-RA) – short acting
    Lixisenatide / Adlyxine®
    A

    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, weight12,18: Weight loss of 1.6-3kg1; neutral effect on CVD outcomes

    Harms, hypoglycemic risk12,18 (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

    View comments (titration, administration, monitoring, notes)
  • Glucagon-like peptide-1 receptor agonists (GLP1-RA) – longer acting
    Dulaglutide / Trulicity®
    A

    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, weight12,18: decreased MACE in patients with clinical CVD ; weight loss of 1.6-3kg1

    Harms, hypoglycemic risk12,18 (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)

    View dosage, titration, administration, monitoring, notes
  • Glucagon-like peptide-1 receptor agonists (GLP1-RA) – longer acting
    Exenatide / Bydureon®
    A

    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, weight12,18: Neutral effect  on CVD outcomes; weight loss of 1.6-3kg1

    Harms, hypoglycemic risk12,18 (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)

    View dosage, titration, administration, monitoring, notes
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