Stepwise Treatment of Type 2 Diabetes

(Recommendations from Diabetes Canada)

Information in algorithm/chart is from the Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada (reference 29) unless otherwise cited. The full guidelines are available at http://guidelines.diabetes.ca/docs/CPG-2018-full-EN.pdf.

Step 1: At diagnosisa of type 2 diabetes in nonpregnant adults

Lifestyle modification: healthy eating (e.g., DASH diet, Mediterranean style diet, etc), aerobic activity 150 min/week, resistance training two to three days/week, achievement of healthier weight.

Pharmacotherapy:

  • Prediabetes: metformin
  • A1C <1.5% above individualized targetb: lifestyle modification with or without metformin for two to three months, then start or increase metformin if goal A1C not reached.
  • A1C ≥1.5% above individualized targetb: start metformin with or without another agent (see chart below).
  • Symptomatic hyperglycemia or metabolic decompensation: insulin monotherapy OR insulin plus metformin
  • Overweight: consider adjunctive orlistat (Xenical).
  • Established cardiovascular disease; age ≥40 years; age >30 years with diabetes duration >15 years; or age <40 years with microvascular disease; or warrants statin per lipid guidelines: add a statin

Step 2: Add another agent. (See chart below.) For patients with clinical cardiovascular disease, use a drug with cardiovascular benefit. After giving priority to clinical cardiovascular disease, individualize choice based on degree of hyperglycemia, weight, comorbidities (e.g., heart failure, liver disease), medication side effects (e.g., hypoglycemia), patient preferences, and cost.

Step 3: Add an agent from a different class OR add or intensify insulin.

Goal: Reach target A1C (A1C ≤7% for most adults) in three to six monthsb

  1. A1C of ≥6.5% is diagnostic of diabetes in adults. An A1C 6% to 6.4% indicates prediabetes.
  2. Individualize. Aim for A1C ≤7% (fasting glucose 4 to 7 mmol/L) for most patients. Higher A1C goal (>7% to 8.5%) may be appropriate for some patients (e.g., limited life expectancy, functionally dependent, frailty, dementia, long-standing diabetes, advanced cardiovascular disease, severe hypoglycemic episodes, or hypoglycemic unawareness). Lower goal (≤6.5%) may be appropriate in some patients (e.g., newly diagnosed, long life expectancy, no advanced cardiovascular disease, low hypoglycemia risk, desire to reduce retinopathy or chronic kidney disease risk).

Drug or Drug Class

Expected A1C drop when added to metformin

Notable Adverse Effects

Comments

Acarbose (Glucobay)
(Alpha-glucosidase inhibitor)

0.7% to 0.8%

GI

Low risk of hypoglycemia when used as monotherapy

Weight neutral

Taken with meals1

Not for initial therapy if A1C ≥8.5%3

Reduces postprandial glucose1

 

Thiazolidinediones (TZD) (pioglitazone [e.g., Actos])
(Insulin sensitizer)

(November 2010: Health Canada announced the restricted use of rosiglitazone-containing products [Avandia, etc] due to an increased risk of cardiovascular events. Restricted to patients for whom all other oral agents, as monotherapy or in combination, are ineffective or inappropriate. Requires informed consent.)4


0.8% to 0.9%

Low risk of hypoglycemia when used as monotherapy

Edema, weight gain, heart failure (risk increased with insulin5,6), increased fracture risk, macular edema (rare), possibility of myocardial infarction with rosiglitazone (controversial)

Pioglitazone contraindicated in patients with history of bladder cancer or uninvestigated macroscopic haematuria. Assess risk factors for bladder cancer and counsel patients to report haematuria, dysuria, or urinary frequency.5

Glycemic control better sustained over diabetes course than metformin or sulfonylurea3

Pioglitazone increases HDL, reduces triglycerides, and increases LDL particle size.5

Contraindicated in heart failure (all stages [I to IV])5,6

Insulin

0.9% to 1.2%, or more

Highest risk of hypoglycemia (educate patient to prevent, recognize, and manage)

Highest risk of weight gain

 

Consider initial therapy with insulin plus metformin if blood glucose is ≥16.7 mmol/L and/or A1C is ≥10%.7

Usually start with basal insulin at bedtime.

Meglitinides
(repaglinide
[e.g., GlucoNorm])
(Insulin secretagogues)

0.7% to 1.1%

Hypoglycemia (educate patient to prevent, recognize, and manage)

Three- or four-times daily dosing

Can hold dose if skipping meal, to reduce risk of hypoglycemia.3

Consider over sulfonylureas (less hypoglycemia, better postprandial control).

Less weight gain than sulfonylureas

Relatively short-lived efficacy

Discontinue when more complex insulin regimens (e.g., basal plus prandial insulins) are started.

 

Metformin
(e.g., Glucophage)
(Biguanide)

1%
(as monotherapy)

GI

Low risk of hypoglycemia as monotherapy

Lactic acidosis (rare) in patients with cardiovascular, renal, or hepatic dysfunction

Weight neutral

Ameliorates insulin-associated weight gain.3

A first-line agent after diet and exercise

Metformin can be initiated if eGFR is >45 mL/min/1.73 m2.8 Discontinue if eGFR later falls below 30 mL/min/1.73 m2.8,29

Inexpensive

 

Alogliptin (Nesina),
Linagliptin (Trajenta),
Sitagliptin (Januvia),
Saxagliptin (Onglyza)
(Dipeptidyl peptidase-4 [DPP-4] inhibitors)

0.5% to 0.7%

Low risk of hypoglycemia as monotherapy

May be associated with pancreatitis (rare)

New or worsening heart failure (saxagliptin, alogliptin)9

May cause severe joint pain10


Weight neutral

Postprandial efficacy3

Dosage modification with renal impairment needed with sitagliptin, saxagliptin, and alogliptin.11-13

CYP3A4 interactions with saxagliptin and linagliptin12,14

Expensive

Sulfonylurea (e.g.,
glimepiride [e.g., Amaryl], glyburide [e.g., Diabeta], gliclazide [e.g., Diamicron])
(Insulin secretagogues)

0.7% to 1.3%

Hypoglycemia (educate patient to prevent, recognize, and manage)

Weight gain (highest with glyburide3)

Less hypoglycemia with glimepiride or gliclazide vs glyburide

Tolbutamide rarely used

Relatively short-lived efficacy

Discontinue when more complex insulin regimens (e.g., basal plus prandial insulins) are started.

Inexpensive

Avoid chlorpropamide in elderly or renal impairment.28

 

Canagliflozin
(Invokana)
Dapagliflozin
(Forxiga)
Empagliflozin
(Jardiance)
Ertugliflozin
(Steglatro)

(Sodium glucose co-transporter 2 [SGLT2] inhibitor)

0.4% to 0.7%

Increased serum creatinine.16-18,30 Acute kidney injury, may require dialysis.15,28

UTI (may be severe)16-18,30

Genital fungal (yeast) infections (male/female)16-18,30

Increased urination

Hypotension

Hyperkalemia (canagliflozin)11

Small LDL increase (0.1 to 0.2 mmol/L, or about 3%)16-18,30

Ketoacidosis (rare)

May be associated with acute pancreatitis (rare).2,31

Fournier’s gangrene (rare; in men and women). Onset: days to years into therapy.32

Fractures and decrease in BMD (canagliflozin).16 Dapagliflozin is also linked to fractures in patients with moderate renal impairment.17

May be associated with rare amputations (canagliflozin).21

 

Weight loss 2 to 3 kg16-18,30

Systolic blood pressure reduction 3 to 5 mmHg16-18,30

Low risk of hypoglycemia with monotherapy

Ertugliflozin is contraindicated if eGFR <45 mL/min/1.73m2; do not start if eGFR <60 mL/min/1.73m2.30

Canagliflozin max dose is only for patients with eGFR ≥60 mL/min/1.73 m2 and a low risk of harm due to volume depletion.16

Dapagliflozin contraindicated if eGFR <30 mL/min/1.73m2.17

Canagliflozin and empagliflozin should be used with caution if eGFR <30 mL/min/1.73m2, and use is not recommended in end-stage renal disease.16,25

Canagliflozin may increase digoxin levels. May require dose increase with enzyme inducers.16

Not recommended in severe hepatic impairment.16-18,30

When used as an add-on, consider insulin/sulfonylurea/meglitinide dose reduction.16-18,30

Risk factors for acute kidney injury include use of NSAIDs, ACEIs, ARBS, or diuretics, or reduced blood volume, chronic kidney disease, and heart failure.15

CV benefit (canagliflozin, dapagliflozin, empagliflozin)19,20,22,24,33,36-39

Renal benefit (canagliflozin, dapagliflozin, empagliflozin)20,33-35

Dulaglutide (Trulicity),
Liraglutide (Victoza),
Lixisenatide (Adlyxine),
Exenatide (Byetta, Bydureon),
Semaglutide (Ozempic)
(Glucagon-like peptide-1 [GLP-1] agonists)

Also see our chart, Comparison of GLP-1 Agonists.

1%

(See GLP-1 agonist chart for individual agents)

GI

Low risk of hypoglycemia as monotherapy

Reports of pancreatitis (rare)23

Associated with renal insufficiency23

May be associated with gallbladder disease (liraglutide, exenatide)24

May lead to retinopathy complications (semaglutide)25

 

Weight loss

Postprandial efficacy3

More weight loss and efficacy than DPP-4 inhibitors

Expensive

Injectable

CV benefit (dulaglutide, liraglutide, semaglutide)26,27,40,41

Renal benefit (liraglutide, semaglutide)26,27,42

Abbreviations: BMD = bone mineral density; CV = cardiovascular; eGFR = estimated glomerular filtration rate; GI = gastrointestinal; HDL = high-density lipoprotein; LDL = low-density lipoprotein; UTI = urinary tract infection

Project Leader in preparation of this clinical resource (340630): Melanie Cupp, Pharm.D., BCPS, last modified November 2020.

References

  1. Product monograph for Glucobay. Bayer. Mississauga, Ontario L4W 5R6. November 2014.
  2. American College of Cardiology Foundation. Cohort study of serious adverse events with sodium-glucose cotransporter 2 inhibitors. 2018. https://www.acc.org/~/media/Clinical/PDF-Files/Approved-PDFs/2018/08/21/ESC-2018-Slides/Aug25-Sat/5amET_Serious-Adverse-Events-SGLT2-Inhibitors.pdf. (Accessed November 12, 2020).
  3. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee, Harper W, Clement M, et al. Pharmacologic management of type 2 diabetes. Can J Diabetes 2013;37 Suppl 1:S61-8.
  4. Health Canada. Avandia, Avandamet and Avandaryl—important new restrictions on the use of rosiglitazone products due to information on cardiovascular related events—for health professionals. November 18, 2010. http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2010/14591a-eng.php. (Accessed November 12, 2020).
  5. Product monograph for pioglitazone. Teva Canada. Novopharm Court. Toronto, ON M1B 2K9. February 2020.
  6. Product monograph for Avandia. GlaxoSmithKline. Mississauga, ON. L5N 6L4. October 2017.
  7. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38:140-9.
  8. Clinical Resource, Clinical Use of Metformin in Special Populations. Pharmacist’s Letter/Prescriber’s Letter. March 2015. (Last modified May 2016).
  9. FDA. FDA drug safety communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin. Last updated March 7, 2018. http://www.fda.gov/Drugs/DrugSafety/ucm486096.htm. (Accessed November 12, 2020).
  10. FDA. FDA drug safety communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain. August 28, 2015. Last modified June 23, 2016. http://www.fda.gov/Drugs/DrugSafety/ucm459579.htm. (Accessed November 12, 2020).
  11. Product monograph for Nesina. Takeda Canada. Oakville, ON L6M 4X8. October 2018.
  12. Product monograph for Onglyza. AstraZeneca Canada. Mississauga, ON L4Y 1M4. December 2018.
  13. Product monograph for Januvia. Merck Canada. Kirkland, QC H9H 4M7. November 2018.
  14. Product monograph for Trajenta. Boehringer Ingelheim. Burlington, ON L7L 5H4. May 2020.
  15. FDA. FDA drug safety communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). June 14, 2016. Last updated June 17, 2016. https://www.fda.gov/drugs/drugsafety/ucm505860.htm. (Accessed November 12, 2020).
  16. Product monograph for Invokana. Janssen. Toronto, ON M3C 1L9. May 2020.
  17. Product monograph for Forxiga. AstraZeneca Canada. Mississauga, ON L4Y 1M4. June 2020.
  18. Product monograph for Jardiance. Boehringer Ingelheim Canada. Burlington, ON L7L 5H4. April 2020.
  19. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-57.
  20. Heerspink HJL, Stefansson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-46.
  21. FDA. FDA removes boxed warning about risk of leg and foot amputations for the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). September 2, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-removes-boxed-warning-about-risk-leg-and-foot-amputations-diabetes-medicine-canagliflozin. (Accessed November 6, 2020).
  22. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.
  23. Clinical Resource, Comparison of GLP-1 Agonists. Pharmacist’s Letter/Prescriber’s Letter. August 2019.
  24. Faillie JL, Yu OH, Yin H, et al. Association of bile duct and gallbladder diseases with use of incretin-based drugs in patients with type 2 diabetes mellitus. JAMA Intern Med 2016;176:1474-81.
  25. Product monograph for Ozempic. Novo Nordisk Canada. Mississauga, ON L5N 6M1. August 2020.
  26. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22.
  27. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834-44.
  28. Clinical Pharmacology powered by ClinicalKey. Tampa, FL: Elsevier. 2020. http://clinicalkey.com. (Accessed November 12, 2020).
  29. Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2018;42(Suppl 1):S1-S325.
  30. Product monograph for Steglatro. Merck Canada. Kirkland, QC H9H 4M7. May 2018.
  31. Health Canada. Summary safety review-SGLT2 inhibitors (canagliflozin, dapagliflozin and empagliflozin)-Health Canada. July 20, 2018. Updated September 17, 2020. https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?lang=en&linkID=SSR00204. (Accessed November 12, 2020).
  32. FDA. FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes. August 29, 2018. https://www.fda.gov/Drugs/DrugSafety/ucm617360.htm. (Accessed November 12, 2020).
  33. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295-306.
  34. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323-34.
  35. Perkovic V, Heerspink HL, Chalmers J, et al. Intensive glucose control improves kidney outcomes in patients with type 2 diabetes. Kidney Int 2013;83:517-23.
  36. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-57.
  37. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381;1995-2008.
  38. ClinicalTrials.gov. Empagliflozin outcome trial in patients with chronic heart failure with preserved ejection fraction (EMPEROR-preserved). Updated November 5, 2020. https://clinicaltrials.gov/ct2/show/NCT03057951. (Accessed November 4, 2020).
  39. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383;1413-24.
  40. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394:121-30.
  41. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019;381:841-51.
  42. Mann JFE, Orsted DD, Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med 2017;377:839-48.

Cite this document as follows: Clinical Resource, Stepwise Treatment of Type 2 Diabetes. Pharmacist’s Letter/Prescriber’s Letter. June 2018.

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