Case study: when it’s time to turn to a DPP-4 inhibitor

The case

Jimmy is a 76-year-old retired teacher who lives alone and was diagnosed with type 2 diabetes (T2D) five years ago, and has been maintained on metformin 850 mg twice daily.

Presenting condition and symptoms

He presents for a routine visit and, as part of pathology testing, the HbA1c was noted to be 7.7%. Just six months ago, the HbA1c was only 7.1%, which was close to his designated HbA1c target of 7.0%. On questioning, he has no symptoms of hyperglycaemia.

Medical history

As well as his five-year history of T2D, he is also overweight with a BMI of 28 kg/m2. His current dose of metformin was the maximum tolerated dose – higher doses caused gastrointestinal side effects.

Jimmy had well-controlled hypertension (BP 130/78 mmHg) and dyslipidaemia (LDL 2.1 mmol/L).

He is known to have some microalbuminuria (urine albumin-to-creatinine ratio [uACR] 12.6 mg/mmol) and stable renal impairment (eGFR 42 ml/min/1.73m2.

While he has minimal retinopathy, he is free of any other diabetes complications such as overt cardiovascular disease or peripheral neuropathy.

Medication history

  • Metformin 850 mg bd
  • Telmisartan 80 mg daily
  • Atorvastatin 20 mg daily

Outcome

The implications of chronic high blood-glucose levels were discussed with Jimmy. Despite the fact that he was asymptomatic, he accepted the need to improve his glycaemic control to help slow the progression of his known kidney and eye disease.

Given his age, home situation and BMI, it was decided that a sulfonylurea would not be the best option as it may put him at risk of hypoglycaemia and weight gain. He expressed a preference for oral medication and this ruled out the use of insulin or a glucagon-like peptide 1 receptor agonist (GLP-1RA).

While a sodium glucose co-transporter 2 inhibitor (SGLT-2i) may have been a good option, especially in light of his weight, his eGFR was 42 and currently there are no SGLT-2is that are licensed for use below 45 ml/min/1.73m2.1,2

A dipeptidyl peptidase 4 inhibitor (DPP-4i) was decided as the best choice as this class of oral agents has relatively minimal impact on hypoglycaemia risk or weight when used in dual therapy with metformin and can be used in renal impairment/failure.2

One of the agents in the DPP-4i class, linagliptin, can be used without dose adjustment in any degree of renal dysfunction.3 Because Jimmy already had a low eGFR, it was felt best for him to start on linagliptin 5mg daily in addition to his unchanged dose of metformin.

Three months later, Jimmy is reviewed and a repeat set of pathology was requested. His HbA1c had decreased to 7.0% and his eGFR remained essentially unchanged at 43 ml/min/1.73m2. uACR had improved slightly to 8.6 mg/mmol. His BMI stayed at 28 kg/m2 and he reported no adverse effects from his linagliptin.

Practice points/discussion

There are many choices for second-line therapy in T2D. Sulfonylureas have historically been the default choice after metformin, but issues around hypoglycaemia and weight gain have seen a recent decline in their use in Australia.>

At the same time, there has been a commensurate rise in DPP-4i and SGLT-2i prescriptions. The SGLT-2is, in particular, have received much attention of late as there have been some large clinical trials showing excellent cardiovascular mortality, heart failure and renal outcomes in patients treated with empagliflozin and canagliflozin.4,5

However, SGLT-2i cannot be used in all patients with T2D, with the most notable restriction being that patients need good renal function for these agents to be effective.

Dapagliflozin requires the eGFR to be above 60 ml/min/1.73m2 while empagliflozin and canagliflozin need the eGFR to be above 45 ml/min/1.73m2, as detailed in Table 1.1,2

DPP-4is, on the other hand, can be very safely used in any degree of renal impairment, even when the eGFR is <15 ml/min/1.73m2.

However, four of the agents in this class require detailed dose adjustment and Table 1 depicts the dose considerations for DPP-4is at various stages of kidney disease.1

The clear exception is linagliptin, which can be used at the full 5 mg dose at any stage of renal disease.3 This gives linagliptin the advantage of being easy to prescribe at initiation, as the same dose can be used irrespective of the baseline eGFR.

Additionally, there is no need to adjust the dose should the patient’s eGFR decline over time, potentially reducing the need for close monitoring of DPP-4i dose to match the eGFR trajectory.

Conclusion

DPP-4is and SGLT-2is are both increasingly used in T2D as second-line therapy after metformin as they have lower risks of hypoglycaemia and weight gain in comparison to sulfonylureas.1,2

SGLT-2is are not approved for use if the eGFR is below 45 ml/min, but DPP-4is can be used in even end-stage kidney disease.1,2

While most DPP-4is require dose adjustment for use in renal impairment, linagliptin can be given at the same 5 mg daily dose in all patients, regardless of eGFR.3

Thus, for our patient Jimmy, who has a low baseline eGFR, linagliptin is the preferable second-line agent for both initiation and maintenance.

Table 1: Recommendations for DPP-4i and SGLT-2i dosing in chronic kidney disease (CKD)

table

Adapted from Gunton et al, 2016.1

 

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.

 

BEFORE PRESCRIBING, PLEASE REVIEW THE FULL PRODUCT INFORMATION WHICH IS AVAILABLE ON REQUEST FROM BOEHRINGER INGELHEIM OR FROM WWW.BOEHRINGER-INGELHEIM.COM.AU/PI

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.

References: 1. 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: https://diabetessociety.com.au/documents/ADS_POSITIONSTATEMENT_v2.4.pdf Accessed 11/8/17. 2. The Royal Australian College of General Practitioners and Diabetes Australia, General Practice Management of Type 2 Diabetes – 2016–18. Melbourne: 2016. 3. Approved Product Information for Trajenta, July 2017. 4. Neal B et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med 2017. 5. Zinman B et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117–28.

Dr Wu has received research funds, participated in educational/advisory panels and been a speaker for various companies including: Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk, MSD, AstraZeneca, Bristol-Myers Squibb, Novartis, Sanofi, Takeda, Janssen Cilag, Roche, and Abbott.

Boehringer Ingelheim Pty Limited. ABN 52 000 452 308. 78 Waterloo Road North Ryde NSW 2113. AU/TRJ/00270. Date of Preparation: August 2017.

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