Cardiac risk dominates in diabetes, but what about renal impairment?


The number of patients with type 2 diabetes dying from cardiovascular (CV) disease has significantly increased in the past 10 years – even though treatment advances have significantly reduced the number of Australians dying from CV disease over the past 30 years.1,2

Among the recent advances in favour of diabetes patients is the first oral anti-diabetic drug to receive a CV indication. Empagliflozin (Jardiance), a sodium glucose co-transporter 2 (SGLT2) inhibitor, has a new TGA indication and PBS listing to reduce the risk of CV death in patients with type 2 diabetes and established CV disease, in addition to its indication and PBS listing to improve glycaemic control in patients with type 2 diabetes.3,4

However, not all diabetes patients are suitable for treatment with an SGLT2 inhibitor. For example, the efficacy of SGLT2 inhibitors decreases in patients with renal impairment, so dapagliflozin is contraindicated with eGFR <60, and empagliflozin and canagliflozin are contraindicated with eGFR <45.5,6

So what are the options for renally impaired patients?

Worldwide, between 8 and 10% of adults have some form of kidney damage and one in 11 adults has diabetes, which is the single leading cause of end-stage kidney disease.7,8 In Australia, diabetes contributes to 36% of cases of chronic kidney disease; of those with type 2 diabetes, one in four women and one in five men has diabetic nephropathy.6,9

Diabetes guidelines recommend reducing the risk or slowing the progression of chronic kidney disease (CKD) by employing good glycaemic control.6

If glycaemic control is not achieved by first-line metformin, current treatment guidelines recommend three main second-line treatments: sulphonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors and SGLT2 inhibitors.5,6

Given that sulphonylureas increase the risk of hypoglycaemia in patients with renal impairment, this leaves DPP-4 inhibitors as key second-line treatment options for people with diabetes and renal impairment.5,6

Similar efficacy but dosage differs 5,6

Within the class of DPP-4 inhibitors, there is little difference in efficacy, but there are dosage considerations.5,6

In Australia, only one DPP-4 inhibitor – linagliptin (Trajenta) – does not require dose adjustment for type 2 diabetes patients with any degree of renal impairment.5,6,10

This is because other DPP-4 inhibitors are mainly renally excreted, while only about 5% of linagliptin is renally excreted.10,11

For the others, Australian guidelines recommend dose reduction of alogliptin (Nesina), saxagliptin (Onglyza), sitagliptin (Januvia) and vildagliptin (Galvus) in patients with eGFR <60 mL/min/1.73 m2.6,7

In patients with severe renal impairment*, linagliptin has been shown to provide a clinically meaningful reduction in HbA1c within 12 weeks that was sustained up to a year11. This improved glycaemic control with very low risk of severe hypoglycaemia, maintenance of stable body weight, and no cases of drug-related renal failure.11

Linagliptin has also been shown to be effective in another vulnerable group of patients – the elderly.12

Patients aged 65 years or more are largely overlooked in clinical trials, with only 0.6% of diabetes trials including patients in this age group.12

In a study specifically targeting type 2 diabetes patients aged 70 years or more, linagliptin added to their existing regimen reduced HbA1c in elderly patients who had long-standing diabetes, renal impairment and were uncontrolled on up to three other glucose-lowering drugs, including basal insulin – and with a tolerability profile similar to placebo.12

The studies suggest that linagliptin offers a good option, especially for those patients at risk for renal impairment, or who are elderly.

* Severe renal impairment: GFR <30 mL/min/1.73 m2.9

PBS Information: TRAJENTA®: Authority Required (STREAMLINED. Type 2 Diabetes.
Code 6346
– Add-on to metformin or SU. Code 6363 – Triple therapy (with metformin and SU).
Code 6376 – Add-on to insulin. Refer to PBS Schedule for full Authority Required Information.



TRAJENTA® (linagliptin) 5mg film-coated tablets. INDICATION: Trajenta is indicated in adult patients with type 2 diabetes mellitus to improve glycaemic control in conjunction with diet and exercise. Monotherapy when metformin and sulfonylureas are not tolerated, or are contraindicated. Add on to metformin, sulfonylureas or metformin plus sulfonylureas, or to insulin (with or without metformin). Add on to metformin plus SGLT2 inhibitors. CONTRAINDICATIONS: Hypersensitivity to linagliptin or to the excipients. PRECAUTIONS: Not for use in type 1 diabetes, diabetic ketoacidosis. Discontinue if pancreatitis or bullous pemphigoid is suspected. Risk of hypoglycaemia when used in combination with sulfonylureas and insulin; arthralgia, pregnancy; lactation; children <18 years. INTERACTIONS: Antagonised by strong P-gp or CYP3A4 inducers. Others, see full PI. ADVERSE REACTIONS:Very common: combination with metformin and a sulfonylurea and combination with insulin – hypoglycaemia; Common: increase in uric acid, increase in lipase; combination with metformin – arthralgia, back pain, headache; combination with a sulfonylurea – nasopharyngitis, hypertriglyceridaemia, urinary tract infections; combination with metformin and a sulfonylurea – cough. Others, see full PI. DOSAGE AND ADMINISTRATION: 5 mg once daily taken with or without food. No dose adjustment is necessary for the elderly, or patients with renal or hepatic impairment. Boehringer Ingelheim Pty Limited. ABN 52 000 452 308. 78 Waterloo Road North Ryde NSW 2113. July 2017.

References: 1.Australian Bureau of Statistics, 2014. Causes of Death Australia. Cat. No. 3303.0. Available at: Accessed August 2017. 2. AIHW 2014. Cardiovascular disease, diabetes and chronic kidney disease: Australian facts mortality. Cardiovascular disease, diabetes and chronic kidney disease series no. 1. Cat. No. CDK 1. Canberra AIHW.
3.Approved Product Information for Jardiance, 17 January 2017. 4. Pharmaceutical Benefits Scheme, August 2017. 5. Gunton JE et al. A new blood glucose management algorithm for type 2 diabetes: a position statement of the Australian Diabetes Society. December 2016. Available online: Accessed 27/6/17. 6. The Royal Australian College of General Practitioners and Diabetes Australia, General Practice Management of Type 2 Diabetes – 2016–18. Melbourne: 2016.7. Diabetes Australia. Diabetes Globally. Available online: Accessed 11/7/17. 8.World Kidney Day. Chronic Kidney Disease. Available online: Accessed 11/7/17. 9. Kidney Health Australia. Chronic Kidney Disease (CKD) Management in General Practice, 3rd edition, 2015. 10.Approved Product Information for Trajenta, 1 February 2017. 11.McGill JB et al. Diabetes Care 2013; 36: 237–44. 12. Barnett AH et al. Lancet 2013; 382: 1413–23.