General practice management of type 2 diabetes


Medication
×
☰ Table of contents


General medication


Recommendations

Reference

Grade*

Care should be taken to address the potential harmful effects of optimising blood glucose control when setting individual glycaemic targets

96

NHMRC, 2009

A

Interventions to achieve target glycated haemoglobin (HbA1c) should begin with lifestyle modification followed by pharmacological options selected on the basis of individual clinical circumstances, side effects and contraindications

96

NHMRC, 2009
A

Blood glucose control should be optimised because of its beneficial effects on the development and progression of microvascular complications

96

NHMRC, 2009
A

*Refer to Summary, explanation and source of recommendations for an explanation of the level of evidence and grade of evidence


Clinical context


In addition to lifestyle modification, people with type 2 diabetes may require pharmacotherapy to achieve long-term glycaemic control and to prevent complications of diabetes. There may be a need to commence medication without delay in patients who are symptomatic of hyperglycaemia or having accompanying metabolic dysfunction (eg ketosis), while providing ongoing lifestyle support.

The benefits of management of hyperglycaemia for the prevention of microvascular complications have been demonstrated in randomised clinical trials. BP and lipidlowering therapy have also been demonstrated in clinical trials to show clear benefits in preventing cardiovascular events and reducing premature mortality.

The choice, order and combination of medications used are based on evidence of improved clinical outcomes, risk of side effects and patient choice/capacity.


In practice


Use of these therapies is associated with risks and other negative effects. These should be taken into consideration when deciding the appropriateness of implementing the treatment recommendations contained in these guidelines. These therapies may be contraindicated in some situations and their use may result in troublesome side effects.


Glucose-lowering agents


Clinical context

Multiple glucose-lowering pharmacotherapies are available (Appendix E. Available glucose-lowering agents).

Algorithms have been designed to help navigate choice. However, applying the principles of patient-centred care may mean that choices made by algorithm are not always appropriate.

The Australian blood glucose treatment algorithm for type 2 diabetes (Figure 4) is an evidence-based algorithm developed by the Australian Diabetes Society (ADS) in consultation with all key stakeholders including the RACGP.

Additionally, when analysing combination therapies used in current suggested algorithms for the management of hyperglycaemia, high-quality trials of clinical outcomes may be lacking. The most studied agents include metformin and sulphonylureas. However, randomised controlled trials (RCTs) investigating the safety of newer agents such as the incretins and sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with high CVD risk are now being reported.106–108

Prescribing algorithms suggest multiple ways of combining agents. Always consult the PBS when combining therapy as restrictions and reimbursement may change. Table 6 provides a guide for clinical considerations when choosing diabetes medications.

Appendix F. Table of evidence and properties of glucose-lowering agents provides the evidence and properties of glucose-lowering agents for this algorithm.

What if medication is not working – The ‘Stop rule’

At each visit, ask about the patient’s understanding of their diabetes and the role of medication in management. Specific enquiry may help decisions on medication efficacy and choices.

Symptoms suggestive of hypoglycaemia or other side effects of medication should trigger a clinical examination and review. Symptoms of hyperglycaemia (eg polyuria, polydipsia), fatigue and visual changes may warn of poor adherence to medication by the patient, or indicate that the medication(s) is/are not effective in glycaemic management.

Confirmation with an assessment of HbA1c (usually every three months) in relation to the individual’s goals may be appropriate. Consideration of the effect of comorbidities (refer Chapter 12.

Diabetes multimorbidity and medication complications) or other medication affecting glycaemic control may need to be assessed and managed. Consideration of a home medicines review by the treating pharmacist may also assist assessment of clinical reasons for problems of persistence, side effects with medication or patient concerns.
 

Practice point


The ‘Stop rule’ emphasises that before advancing through additional glycaemiclowering combinations, after evaluating each patient’s HbA1c response after three to six months, support the patient to engage in healthy lifestyle choices, assess for comorbidities and complications (eg CVD risk or distress) and then evaluate the need for additional or altered medication/combination therapy.

 

Figure 4. Australian diabetes algorithm and clinical medication table

Figure 4a. Australian diabetes algorithm and clinical medication table
 

Table 6. Clinical considerations when choosing diabetes medications
 

Clinical outcome Metformin Sulphonylurea (SU) Dipeptidyl peptidase-4 inhibitor (DPP-4i) Acarbose Thiazolidinedione (TZD) Sodium glucose co-transporter 2 inhibitor (SGLT2i) Glucagon-like peptide-1 receptor agonist (GLP-1 RA) Insulin
Patients with established or high isk cardiovascular disease (CVD) Neutral109 Increase risk when SU compared to metformin monotherapy (excluding gliclazide), but neutral when used in combination with etformin110 Neutral107,111–114 Refer to Note A Not yet known115 Contraindication if symptomatic heart failure*116 Selective benefit/not yet known117 Refer to Note B Selective benefit/118,119 not yet known Refer to Note C Neutral109,120,121
Patients with risk from hypoglycaemia Lower rates compared to SU110 Higher clinical risks as monotherapy and combination with other agents110 Gliclazide – 50% fewer hypoglycaemia episodes versus glimepiride122 Lower rates compared to SU110 Neutral Lower rates compared to SU110 Lower rates compared to SU110 Lower rates compared to SU110 Lower hypoglycaemia when metformin is added to basal versus premixed insulin (consider risks greater with prandial insulin)123
Patients at risk of gastrointestinal conditions (eg irritable bowel syndrome [IBS], inflammatory bowel disease [IBD] and gastroparesis) Known intolerance as monotherapy or combination therapy – diarrhoea110,124 Neutral effect Neutral effect Known Intolerance – bloating and flatulence† Neutral effect Neutral effect Known intolerance – nausea and vomiting, and diarrhoea ‡ 110 Neutral
Patients in whom stabilisation of body mass index [BMI] or weight loss is desired Neutral effect Neutral effect (gliclazide)125 Modest gain (other SUs) compared to metformin monotherapy110 Less weight gain (when added to metformin versus metformin and SU)110 Neutral effect Modest gain compared with other dual combination therapies110 Modest weight loss (in monotherapy, plus in combination with metformin versus metformin with alternate dual oral drug combinations)§ 110 Weight loss (in monotherapy, plus in combination with metformin versus metformin with alternate dual oral drug combinations)|| Modest gain – risk greater with prandial insulin110,123
Patients with renal dysfunction (eg lowered estimated glomerular filtration rate [eGFR]) Reduce dose eGFR 30–60
Contraindication with eGFR <30124
Hypoglycaemia risk increases Safe with dose reduction# Refer to Note D Contraindication in severe renal impairment** Neutral effect Efficacy decreases, thus contraindication with moderate renal impairment†† Contraindication eGFR<30‡ Hypoglycaemia risk increases
Unique/class-specific pharmacological effects Monotherapy or combination with other agents (DPP- 4i or SGLT2i) is available to reduce ‘pill burden’ The Australian algorithm (refer to Figure 4) suggests they may be used as monotherapy or combined with other agents Contraindication – do not use with a GLP–1 RA   Increased atypical fractures relative risk (RR) 1.57127 in women* Rare – Pioglitazone has been associated with an overall 63% increased risk of bladder cancer, with the risk increasing with increasing duration of use and dose128 Modest lowering of blood pressure (BP)110 Increased genitourinary (especially females) Refer to Note E Rare – euglycaemic ketoacidosis‡‡ Once weekly formulations are available‡ Contraindication – do not combine with a DPP-4i Dose required to be titrated to glycaemic goals


DPP-4i, dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon like peptide-1 receptor agonist; IBD, Inflammatory bowel disease; IBS, Irritable bowel syndrome; insulin, basal, basal analogue, NPH and rapid-acting or prandial insulins including mixed insulins; PI, product information; SGLT2i, sodium glucose co-transporter 2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedione

Important to note

Clinical considerations have been derived from the attached main references: Bennet W et al,127 Qaseem A et al 129 and Bolen T et al110

Careful interpretation of results is recommended due to medication in combination studies having variance from Australian prescribing algorithms Due consideration to each individual patient, diabetes and metabolic goals, disease and complication burden, medication side effects, and costs and psychosocial factors need to be incorporated in decision making, not just the medication factors (Table 6)

Notes

SU: Statements of evidence (SOEs) strengths110 are related to the common forms available in the US – but are not inclusive of gliclazide, the most commonly used SU agent in Australia

Note A. DPP-4i and heart failure: In the SAVOR-TIMI 53 trial107 – hospitalisations for heart failure (a secondary outcome) increased with saxagliptin. Despite this, a recent meta-analysis found difficulty in drawing firm negative conclusions on the comparative safety of this class of drugs in heart failure

Note B. SGLT2i: The EMPA-REG outcome trial117 found that patients with diabetes with existing CVD risk had reduced all-cause mortality and death from cardiovascular causes with empagliflozin. There have been no reported clinical trials for other drugs in this class

Note C. GLP-1 RA – The LEADER trial, a prospective cardiovascular safety outcomes trial for liraglutide, found a 13% reduction in major adverse cardiac events and a 22% reduction in cardiovascular death in high-risk cardiovascular patients.130 This effect has not been replicated in similar trials for lixisenatide and no trials on exenatide have yet been reported

Note D. DPP-4i: All except linagliptin (no dose reduction) as this is hepatically metablised

Note E. All classes: The recent Agency for Healthcare Research and Quality (AHRQ) US review110 determined no moderate to high levels of evidence for the following adverse events (this does not mean no risk):

  • Lactic acidosis (metformin)
  • Urinary tract infections/fractures/volume depletion (SGLT2i)
  • pancreatitis (DPP-4i and GLP-1 RA)
  • bladder cancer risks (pioglitazones)
  • thyroid cancer (GLP-1 RA)

*Pioglitazone product information
 †Acarbose product information 
‡Exenatide product information
§Dapagliflozin product information (–2.14 kg) as an add-on to metformin versus placebo at 104 weeks; empagliflozin (–1.63 kg) and (–2.03 kg) at doses 10 mg and 25 mg respectively as an add-on to metformin at 24 weeks\

||Exenatide –1 kg to 3.9 kg in comparative trials with combinations including metformin and SU and TZD

#All except linigliptin (no dose reduction)

**Exenatide (Bydureon) product information

††Dapagliflozin contraindicated of eGFR <60; empagliflozin/canagliflozin contraindicated of eGFR <45

‡‡Safety advisory – risk of diabetic ketoacidosis 


In practice


Beginning glucose-lowering therapy

Healthy eating, physical activity and education remain the foundation of all type 2 diabetes treatment programs.

If lifestyle modification is not effective in controlling hyperglycaemia, metformin is the first choice unless contraindicated or not tolerated. Second-line agents (added to existing metformin) may be necessary and should be chosen using an individualised approach, noting that agents work in different ways and are chosen to work synergistically.

While these guidelines recommend a stepwise approach to the management of type 2 diabetes, glycaemic management has become more complex with an increasing range of medications now available. There are a number of trials exploring the effects of various therapies on major cardiovascular events such as myocardial infarction (MI) and stroke.These trials include short-term trials of dipeptidyl peptidase-4 inhibitors (DPP-4i; oral: saxagliptin, alogliptin and sitagliptin) and glucagon like peptide-1 receptor agonists (GLP-1 RA; injectables: lixisenatide and liraglutide) and a sodium glucose co-transporter 2 inhibitor (SGLT2i; empagliflozin). However, there is a lack of data regarding long-term outcomes as well as potentially serious adverse outcomes associated with some of the newer agents. Unfortunately, a simple stepwise algorithm cannot match all individual patient’s needs.

The Australian Diabetes Society position statement131 provides patient options based on consideration of efficacy, side effects, and costs.

Start with the correct dose of each medication and review on an individual basis at least every three to six months, keeping in mind the patient’s individual HbA1c target.132

Safety

Each different class of glycaemic medications may have common and uncommon side effects that impact quality of life and require careful clinical re-assessment. Examples include some weight gain with sulphonylureas,110 or mycotic infections and the rare euglycaemic diabetic ketoacidosis with SGLT2i.

Some patient groups (eg elderly and those with multiple comorbidities) may not be represented in the published clinical outcome trials of newer diabetes agents, so caution should be exercised when considering choice of agents for these patients.

When used as monotherapy, metformin, acarbose, glitazones, GLP-1 RA, DPP-4i and SGLT2i should not cause hypoglycaemia.

Long-acting sulphonylureas (eg glimepiride) or sulphonylureas with renally excreted active metabolites (eg glibenclamide) are more likely to cause hypoglycaemia than shorter-acting sulphonylureas (eg gliclazide).133,134

Special care needs to be taken with those at increased risk of hypoglycaemia, especially the elderly. People taking sulphonylureas or insulin may need to notify motor vehicle licensing authorities as these medications can affect driving performance, as well as increase the patient’s burden by requiring glucose self monitoring, especially on initiation or dose titrations. It is important that patients inform their insurance agents or companies (also refer to Chapter 14. Management of other impacts of diabetes).

 


Diabetes Australian and RACGP logo's
 
  1. Toth PP. Overview of saxagliptin efficacy and safety in patients with type 2 diabetes and cardiovascular disease or risk factors for cardiovascular disease. Vasc Health Risk Manag 2015;11:9–23.
  2. Scirica BM, Braunwald E, Raz I, et al. Heart failure, saxagliptin, and diabetes mellitus: Observations from the SAVOR-TIMI 53 randomized trial. Circulation 2014;130(18):1579–88.
  3. Paneni F. DPP-4 inhibitors, heart failure and type 2 diabetes: All eyes on safety. Cardiovasc Diagn Ther 2015;5(6):471–78.
  4. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352(9131):854–65.
  5. Bolen S, Tseng E, Hutfless S, et al. AHRQ comparative effectiveness reviews: Diabetes medications for adults with type 2 diabetes: an update. Rockville, MD: Agency for Healthcare Research and Quality, 2016.
  6. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373(3):232–42.
  7. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369(14):1327–35.
  8. Zannad F, Cannon CP, Cushman WC, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: A multicentre, randomised, double-blind trial. Lancet 2015;385(9982):2067–76.
  9. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369(14):1317–26.
  10. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: The STOP-NIDDM trial. JAMA 2003;290(4):486–94.
  11. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A randomised controlled trial. Lancet 2005;366(9493):1279–89.
  12. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373(22):2117–28.
  13. Bentley-Lewis R, Aguilar D, Riddle MC, et al. Rationale, design, and baseline characteristics in evaluation of LIXisenatide in acute coronary syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo. Am Heart J 2015;169(5):631–38.e7.
  14. Pfeffer M, et al. The evaluation of lixisenatide in acute coronary syndrome—The results of the ELIXA trial. Symposium at the 75th Scientific Sessions of the American Diabetes Association; Boston, MA; June 8, 2015.
  15. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352(9131):837–53.
  16. Gerstein HC, Bosch J, Dagenais GR, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012;367(4):319–28.
  17. Schernthaner G, Grimaldi A, Di Mario U, et al. GUIDE study: Double-blind comparison of oncedaily gliclazide MR and glimepiride in type 2 diabetic patients. Eur J Clin Invest 2004;34(8):535–42.
  18. Mosenzon O, Raz I. Intensification of insulin therapy for type 2 diabetic patients in primary care: basal-bolus regimen versus premix insulin analogs: when and for whom? Diabetes Care 2013;36 Suppl 2:S212–18.
  19. Davoren P. Safe prescribing of metformin in diabetes. Aust Prescr 2014;37:2–5.
  20. Zoungas S, Chalmers J, Kengne AP, et al. The efficacy of lowering glycated haemoglobin with a gliclazide modified release-based intensive glucose lowering regimen in the ADVANCE trial. Diabetes Res Clin Pract 201;89(2):126–33.
  21. Trujillo JM, Nuffer W, Ellis SL. GLP-1 receptor agonists: A review of head-to-head clinical studies. Ther Adv Endocrinol Metab 2015;6(1):19–28.
  22. Bennett WL, Wilson LM, Bolen S, et al. AHRQ comparative effectiveness reviews. Oral diabetes medications for adults with type 2 diabetes: an update. Rockville MD: Agency for Healthcare Research and Quality, 2011.
  23. Tuccori M, Filion KB, Yin H, Yu OH, Platt AW, Azoulay L. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ 2016;352:i1541.
  24. Qaseem A, Humphrey LL, Sweet DE, Starkey M, Shekelle P. Oral pharmacologic treatment of type 2 diabetes mellitus: A clinical practice guideline from the American College of Physicians. Ann Intern Med 012;156(3):218–31.
  25. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 201; 375(4):311–22.
  26. Gunton JE, Cheung NW, Davis TM, Zoungas S, Colagiuri S. A new blood glucose management algorithm for type 2 diabetes: a position statement of the Australian Diabetes Society. Med J Aust 2014;201(11):650–53.
  27. Cheung NW, Conn JJ, d’Emden MC, et al. Position statement of the Australian Diabetes Society: Individualisation of glycated haemoglobin targets for adults with diabetes mellitus. Med J Aust 2009;191(6):339–44.
  28. Ahren B. Avoiding hypoglycemia: A key to success for glucose-lowering therapy in type 2 diabetes. Vasc Health Risk Manag 2013;9:155–63.
  29. Stahl M, Berger W. Higher incidence of severe hypoglycaemia leading to hospital admission in Type 2 diabetic patients treated with long–acting versus short-acting sulphonylureas. Diabet Med 1999;16(7):586–90.