Stepwise Treatment of Type 2 Diabetes

Full update June 2018

(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: empagliflozin, liraglutide, or canagliflozin [except in patients with amputation]). 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 glucose2

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 size5

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 hypoglycemia3

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 gain3

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 alogliptin11-13

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 impairment28

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 reported with canagliflozin or dapagliflozin (may require dialysis).15

Urinary tract infection (may be severe)16-18,30

Genital fungal infections (male and 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

Dapagliflozin may increase risk of bladder cancer. Use with pioglitazone is not recommended.17

Association with ketoacidosis (rare)

May be associated with acute pancreatitis (rare).31,33

Rare cases of Fournier’s gangrene in men and women, with onset early (days) and late in therapy (~2 years).32

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

Amputations may occur in about 6 of every 1,000 patients treated with canagliflozin over one year, compared to about 3 in every 1,000 patients on other diabetes meds.19,20

Canagliflozin use in patients at high CV risk for about 3.5 years may increase risk of amputations, NNH ~77 [Evidence level A-1].19,21

Weight loss 2 to 3 kg16-18,30

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

Low risk of hypoglycemia with monotherapy

Canagliflozin and ertugliflozin are contraindicated if eGFR <45 mL/min/1.73m2; do not start if eGFR <60 mL/min/1.73m2.16,30

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 <60 mL/min/1.73m2.17

Empagliflozin contraindicated if eGFR <30 mL/min/1.73m2.25

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

Not recommended in severe hepatic impairment16-18,30

When used as an add-on, consider insulin/sulfonylurea/meglitinide dose reduction16-18,30

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

Empagliflozin reduces cardiovascular mortality (NNT = 45 for three years), overall mortality (NNT = 39 for three years), and hospitalization due to heart failure (NNT = 71 for three years) in type 2 diabetes patients with cardiovascular disease.24 [Evidence level A-1].22

CANVAS (CANagliflozin cardioVascular Assessment Study) [Evidence level A-1] found canagliflozin use for about 3.5 years when added to standard glucose-lowering therapy in patients with type 2 diabetes and very high CV risk (>70% of patients had atherosclerotic CV disease), may reduce the combined endpoint of CV mortality, nonfatal MI, or nonfatal stroke (NNT=224). However, when evaluated individually, these endpoints were no longer significantly reduced.19

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

Liraglutide may reduce cardiovascular death (NNT = 77 for four years) and overall mortality (NNT = 71 for four years) in patients with high cardiovascular risk or cardiovascular disease [Evidence level A-1].26

Semaglutide use in patients with CV disease, chronic kidney disease, or CV risk factors for about two years may reduce the combined endpoint of CV death, nonfatal MI, or nonfatal stroke (NNT=44) [Evidence level A-1].27 When evaluated individually, only nonfatal stroke was significant.27

Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.

Level

Definition

Study Quality

A

Good-quality patient-oriented evidence.*

  1. High-quality RCT
  2. SR/Meta-analysis of RCTs with consistent findings
  3. All-or-none study

B

Inconsistent or limited-quality patient-oriented evidence.*

  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study

C

Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

RCT = randomized controlled trial; SR = systematic review [Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. http://www.aafp.org/afp/2004/0201/p548.pdf.]

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

References

  1. Product monograph for Glucobay. Bayer. Mississauga, Ontario L4W 5R6. November 2014.
  2. Diabetes Canada. Blood glucose-lowering therapies. For healthcare providers. Updated November 2016. http://guidelines.diabetes.ca/bloodglucoselowering/therapiesrefguide. (Accessed May 12, 2018).
  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 May 12, 2018).
  5. e-CPS [Internet]. Ottawa (ON): Canadian Pharmacists Association; c2018. Actos monograph. January 2018. http://www.e-therapeutics.ca. (Accessed May 12, 2018).
  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. 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 May 12, 2018).
  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 May 12, 2018).
  11. Product monograph for Nesina. Takeda Canada. Oakville, ON L6M 4X8. April 2018.
  12. Product monograph for Onglyza. AstraZeneca Canada. Mississauga, ON L4Y 1M4. March 2018.
  13. Product monograph for Januvia. Merck Canada. Kirkland, QC H9H 4M7. March 2017.
  14. Product monograph for Trajenta. Boehringer Ingelheim. Burlington, ON L7L 5H4. December 2016.
  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 16, 2016). https://www.fda.gov/drugs/drugsafety/ucm505860.htm. (Accessed May 12, 2018).
  16. Product monograph for Invokana. Janssen. Toronto, ON M3C 1L9. November 2017.
  17. Product monograph for Forxiga. AstraZeneca Canada. Mississauga, ON L4Y 1M4. March 2018.
  18. Product monograph for Jardiance. Boehringer Ingelheim Canada. Burlington, ON L7L 5H4. April 2018.
  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. FDA. FDA drug safety communication. FDA confirms increased risk of leg and foot amputations with the diabetes medication canagliflozin (Invokana, Invokamet, Invokamet XR). May 16, 2017. Last updated July 25, 2017. https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm. (Accessed May 13, 2018).
  21. Personal communication (written). Titi. Medical Information and Services. Janssen Pharmaceuticals. Titusville, NJ 08560. July 18, 2017.
  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. February 2018.
  24. Faillie J, 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. January 2018.
  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. 2018. http://clinicalkey.com. (Accessed May 21, 2018).
  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 19, 2018. https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?lang=en&linkID=SSR00204. (Accessed October 1, 2018).
  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 October 1, 2018).
  33. 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 October 4, 2018).

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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