1. Alliance Meeting Portfolio Renal and hepatic considerations in type 2 diabetes
Boehringer Ingelheim and Lilly provided funding for this sponsored session, including speaker honoraria and agency support. Boehringer Ingelheim and Lilly have reviewed the presentation for medical accuracy and compliance with applicable laws and regulations.
Trajenta ® ▼ (linagliptin) and Jentadueto ® ▼ (linagliptin and metformin) prescribing information can be found at the end of this presentation
Adverse events should be reported. Reporting forms and information can be found at www. mhra.gov.uk/yellowcard.
Adverse events should also be reported to Boehringer Ingelheim Drug Safety on (freephone).

2. Overview and objectives
This module includes an overview of the renal and hepatic complications of T2D and how these factors may affect treatment decisions when prescribing OADs in patients with T2D
The main learning objectives are to:
Review the basic anatomy and functions of the kidney and liver
Understand the factors that contribute to the development of diabetic kidney disease and liver dysfunction
Understand the relationship between T2D, chronic kidney disease and cardiovascular risk
Review the implications of renal and hepatic disease on treatment decisions in T2D
Discuss the role of linagliptin in managing T2D patients with renal or hepatic complications
T2D: type 2 diabetes; OAD: oral anti-diabetic drug.

3. Management of T2D complexities becomes more challenging over time
At diagnosis
Treatment review
Older patients
Disease progression
Clear guidance1,2
At-risk screening
Diagnosis
Monitoring
Initial treatment
Complications may arise1,3,4
CVD
CKD
Liver disease
Adverse effects to treatment
Need for treatment optimisation
QoL becomes one of the most important considerations5
Diabetes can potentially affect almost every organ in the body.
Poor diabetes management can lead to damage of organs – including the heart kidneys and nervous system.1
The liver can also be affected.2
This module is going to focus on type 2 diabetes care in the context of liver and renal complications.
References:
How diabetes can affect the organs in your body. Diabetes UK. Available at Accessed August 2013.
Complications. Diabetes and fatty liver disease. Available at: Accessed August 2013.
T2D: type 2 diabetes; CVD: cardiovascular disease; CKD: chronic kidney disease. QoL: quality of life.
1. Adapted from National Institute for Health and Clinical Excellence. Clinical Guideline 87. Type 2 diabetes - newer agents (a partial update of CG66): quick reference guide. 2. Adapted from NICE (2012) PH38 Preventing type 2 diabetes - risk identification and interventions for individuals at high risk: guidance. Available at: (last accessed October 2013). 3. NICE clinical guideline 66: Type 2 Diabetes Management. Available at: (last accessed October 2013). 4. Diabetes and fatty liver disease. Available at (last accessed October 2013). 5. Morley JE. Diabet Med 1998;15 (Suppl. 4): S41–S46.

4. Diabetes is associated with many complications
Microvascular complications
Macrovascular complications
Stroke2
Brain and cerebral circulation1
Diabetic retinopathy2
Periodontal disease3
Heart disease2
Diabetic nephropathy2
Liver disease4
Erectile dysfunction2
Peripheral
vascular disease2
Diabetic neuropathy2
Kaplar M, et al. J Nucl Med 2009; 50:1993–1998.
Diabetes in the UK. Diabetes UK. Available at April Last accessed October 2013.
Mealey BL. JADA 2006; 137 (Suppl 10):26S–31S.
Tolman KG, et al. Diabetes Care 2007;30(3):734–43.

5. Anatomy and functions of the kidney
Calyces
Key functions of the kidney include:
Waste excretion
Osmolality regulation
Secretion of hormones including erythropoetin (EPO), renin and calcitriol
It is important to assess kidney function in patients with T2D as it may affect treatment options
Renal artery
Renal
pelvis
Renal vein
Medulla
Ureter
Cortex
T2D: type 2 diabetes.
The kidneys and how they work. National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC). Available at Accessed October 2013.

6. How does diabetic kidney disease occur?
METABOLIC FACTORS
HAEMODYNAMIC CHANGES
Hyperglycaemia
Vasoactive system activation
Oxidative stress and inflammation
↑ Vascular permeability
Smooth muscle cell expansion
Cellular hypertrophy and ↑ collagen synthesis
Increased renal filtration
Glomerular sclerosis
Glomerular sclerosis and loss of nephrons
Glomerular hyperfiltration and hypertension
Albumin leakage → nephropathy
Adapted from: Dronavalli S, et al. Nat Clin Pract Endocrinol Metab 2008;4:444–452.

7. Prevalence of CKD (all stages) in T2D
Over a third of people with T2D have impaired kidney function (CKD stage 2–5) 40
Impaired kidney function (33.8%) 30
Prevalence in T2D population (%)
27.5
24.8 20
6.3
2.7
2.5
0.2
GFR ml/min/1.73m2
≥90
60-89
30-59
15-29
<15
Stage 1 2 3 4 5
Kidney Function
Kidney normal
Kidney damage with normal GFR
Kidney damage with mild ↓GFR
Moderate ↓GFR
Severe ↓GFR
Renal failure
Note: 36% of subjects with GFR ≥60 ml/min/1.73m2 without albuminuria data may have no kidney disease or stage 1–2 CKD
CKD: chronic kidney disease; T2D: type 2 diabetes; GFR: glomerular filtration rate.
Adapted from: Middleton RJ et al. Nephrol Dial Transplant 2006;21:88–92.

8. Diabetes is the most common cause of renal failure30
24.0 20
20.7
Diagnosis in patients with ESRD (%)
15.6
11.8 10
7.8
7.3
6.9
6.0
Diabetes
Uncertain aetiology*
Other
Glomerulo-nephritis
Pyelonephritis
Polycystic kidney
Renal vascular disease
Hypertension
Primary renal diagnosis†
*Includes presumed glomerulonephritis not biopsy proven.
† Figures shown are calculated excluding data not available. Data for primary renal diagnosis (PRD) missing in 10.8% of patients. In centres with >25% missing PRD data, percentages in the other diagnostic categories not calculated. Centres with very high rates of uncertain diagnosis also excluded.
ESRD: end stage renal disease.
Adapted from: The Renal Association. UK Renal Registry. Twelfth Annual Report (last accessed October 2013).

9. T2D and CKD drive a network of vascular risk
CVD
Mortality
Up to 75% of CVD in diabetes may be attributable to hypertension3
CKD is a major cause of cardiovascular morbidity
and mortality4
T2D
CKD
Hypertension
Coexistence of diabetes leads to elevated risk of
CVD1
Hypertension is a powerful and independent risk factor for CKD2
Microalbuminuria5
ESRD5
Macroalbuminuria5
CKD: chronic kidney disease; CVD: cardiovascular disease; ESRD : end stage renal disease.
Spoelstra-de Man AM, et al. Diabetes Care 2001;24:2097–2101; 2. Retnakaran R, et al. Diabetes 2006;55:1832–1839; 3. Sowers JR, et al. Hypertension 2001;37: ; 4. Dusing R. Business briefing: european endocrine review Available at: (last accessed October 2013); 5. Gansevoort RT, de Jong PE. J Am Soc Nephrol 2009;20:465–468.

10. CKD and CV risk As eGFR decreases, risk of CV events increases
Age-standardised rates of CV events
according to eGFR* 40
36.60 35 30
* Adults (1,120,295) within large US integrated healthcare system, with serum creatinine measured: 9.6% had been diagnosed with diabetes 25
21.80
Age-standardised rates of CV events
(per 100 person-yrs) 20 15
11.29 10 5
3.65
2.11
≥60
45–59
30–44
15–29
<15
Stage 1-2
Stage 3A
Stage 3A
Stage 4
Stage 5
Estimated GFR (ml/min/1.73m2)
No. of cardiovascular events
73,108
34,690
18,580
8,809
3,824
CKD: chronic kidney disease; CV: cardiovascular; eGFR: estimated glomerular filtration rate. A cardiovascular event was defined as hospitalization for coronary heart disease, heart failure, ischemic stroke, and peripheral arterial disease. Error bars represent 95 percent confidence intervals. The rate of events is listed above each bar.
Adapted from: Go AS, et al. N Engl J Med 2004; 351:1296–1305.

11. Factors to be taken into consideration when selecting an appropriate drug
Age
Fracture
risk
Occupation
BMI / body weight
Hobbies
Person with type 2 diabetes
Liver
function
Gender
Driving
Past medical history (e.g. haematuria/ cancer)
Live alone/
nutrition
Renal
function
Fasting

12. T2D medication in patients with renal impairment
CKD can influence T2D management in several ways:1
Potential complications and cautions relating to OADs
Risk of increased frequency and severity of hypoglycaemic episodes with increasing renal impairment
The variable response to insulin therapy as renal function declines
The elimination of many drugs from the body is decreased by renal impairment, prolonging exposure to higher levels of the drug or its metabolites, and potentially leading to adverse effects1
In many patients with CKD, dose adjustment of medications should be considered2
CKD: chronic kidney disease, OAD: oral anti-diabetic drug; T2D: type 2 diabetes.
1. Cavanaugh KL. Clinical Diabetes. 2007; 25(3):90– American Diabetes Association. Diabetes Care 2013;36(Suppl. 1):S11–S66.

13. Cautions related to renal impairment for oral glucose-lowering therapies*
Metformin*
Sulphonylureas
Acarbose
Meglitinides
Pioglitazone
DPP-4 inhibitors
Dapagliflozin
Mild renal
impairment
Gliclazide
Nateglinide
Alogliptin
Linagliptin
Glimepiride
Saxagliptin*
Glipizide
Repaglinide
Sitagliptin*
Tolbutamide
Vildagliptin
Moderate renal
Severe renal
Not studied
End-stage renal
disease
All
Contraindicated/not recommended
Dose adjustment/caution required
No dose adjustment required
aAs described in the British National Formulary. No SPC available for glimbenclamide; SmPCs for Glucophage (metformin); Diamicron (gliclazide); Amaryl (glimepiride); Minodiab (glipizide); Tolbutamide; Glucobay (acarbose); Starlix (nateglinide); Prandin (repaglinide); Actos (pioglitazone); Vipidia (alogliptin); Trajenta (linagliptin); Onglyza (saxagliptin); Januvia (sitagliptin); Galvus (vildagliptin) ; Forxiga (dapagliflozin) all available at: Last accessed January 2014

14. DPP-4 inhibitors have different routes of excretion
*Including metabolites and unchanged drug; excretion after single dose administration of 14C labelled drug
All SmPCs available at (Accessed March 2014):
MSD. Januvia (sitagliptin). July 2013.
Novartis. Galvus (vildagliptin). July 2013.
Takeda. Vipidia (alogliptin). September 2013.
AstraZeneca. Onglyza (saxagliptin). July 2013.
Boehringer Ingelheim. Trajenta (linagliptin). August 2013.

15. DPP-4 exposure in varying degrees of renal impairment
Linagliptin
Two-fold increase in exposure relative to normal renal function in controls
Normal
n=6
Mild
Moderate
Severe
ESRD 1 2 3 4 5 6 7
Fold increase in exposure relative to normal renal function
Sitagliptin 7 6 5
Fold increase in exposure relative to normal renal function 4 3 2 1
Normal
(n=6)
Mild
(n=6)
Moderate
n=6
Severe
n=6
ESRD
n=6
Creatinine clearance* > >50 to ≤ >30 to ≤ ≤ ≤30 on HD
(ml/min)
Creatinine clearance* > >50 to ≤ >30 to ≤ ≤ ≤30 on HD
(ml/min)
Normal
n=8
Mild
Moderate
Severe
n=7
ESRD 1 2 3 4 5 6 7
Fold increase in exposure relative to normal renal function
Saxagliptin
(5-hydroxy saxagliptin metabolite)‡
Normal
Mild
Moderate
Severe
ESRD 1 2 3 4 5 6 7
Fold increase in exposure relative to normal renal function
Vildagliptin
(LAY151 metabolite)§
Creatinine clearance* > >50 to ≤ >30 to ≤ ≤ ≤30 on HD
(ml/min)
ESRD, end-stage renal disease; HD, haemodialysis.
*Estimated creatinine clearance values were calculated using the Cockcroft–Gault formula. ‡ 90% confidence intervals not available.
§n numbers, 90% confidence intervals and definitions of RI according to creatinine clearance not available for vildagliptin.
Adapted from Graefe-Mody U, et al. Diab, Obes & Metab 2011; 13:939–946.

16. Moderate renal impairment 1 Severe renal impairment 2
Linagliptin lowers HbA1c effectively in patients at different stages of renal impairment
Normal renal function 1
Mild renal impairment 1
Moderate renal impairment 1
Severe renal impairment 2
eGFR
≥80 ml/min
50–<80 ml/min
30–<50 ml/min
<30 ml/min
Linagliptin
Placebo
Linagliptin (placebo-corrected)
Adjusted mean change from baseline HbA1c (%) n
468
1216
104
314 12 27 66 62
Mean baseline HbA1c (%)
8.1
8.1
8.0
8.0
8.3
8.3
8.2
8.2
*p<0.001; †p<0.05; **p< A small proportion of patients in these studies were receiving treatment combinations that fall outside of the licensed indications for Trajenta® (linagliptin).
Note: eGFR was calculated using the Cockroft-Gault formula.
Subgroup analysis on pooled data from 3 pivotal Phase III randomised, placebo-controlled trials including treatment in monotherapy, as add-on to metformin, as add-on to metformin and a sulphonylurea.
eGFR: estimated glomerular filtration rate.
1. Adapted from Cooper M, et al. ADA 2011; Poster no P.
2. Adapted from McGill JB, et al. Diabetes Care 2013; 36:237–244.

17. DPP-4 inhibitors in practice

18. Dosing considerations with available DPP-4 inhibitors
Degree of renal impairment*
DPP-4 inhibitor
Normal function (CrCl ≥90 ml/min)
Mild impairment (CrCl 50 to <80 ml/min)
Moderate impairment (CrCl 30 to <50 ml/min)
Severe impairment /ESRD (CrCl <30 ml/min)
Linagliptin
5 mg OD
Sitagliptin
100 mg OD†
Vildagliptin
50 mg BD (50 mg OD with an SU)
Saxagliptin
5 mg OD†
Alogliptin
25 mg OD†
50 mg OD†
25 mg OD
ESRD only if no dialysis
50 mg OD
50 mg OD
use with caution
2.5 mg OD†
2.5 mg OD†
ESRD: not recommended
12.5 mg OD†
6.25 mg OD†
ESRD: use with caution
*As defined by respective Summaries of Product Characteristics. †Assessment of renal function is recommended prior to initiation and periodically thereafter. CrCl: creatinine clearance (based on Cockcroft-Gault formula); OD: once daily; BD: twice daily; SU: sulphonylurea. ESRD: end-stage renal disease.
All SmPCs available at (Accessed March 2014):
1. Boehringer Ingelheim. Trajenta (linagliptin). August MSD. Januvia (sitagliptin). July Novartis. Galvus (vildagliptin). July 2013.
4. AstraZeneca. Onglyza (saxagliptin). July Takeda. Vipidia (alogliptin). September 2013.

19. Clinical Practice Research Datalink (CPRD)
Background
The aim was to investigate glucose control therapies prescribed to Type 2 diabetes mellitus patients with and without renal impairment
Objective
To calculate the number of patients in the Type 2 diabetes mellitus cohort extracted from CPRD with a prescription for a DDP-4i in 2012 by month and dosage
To calculate the percentage of patients at each dosage level with a diagnosis or test result confirming renal impairment
Comorbidities
Renal impairment (CKD stage 3–5) was defined as having a diagnosis of renal impairment prior to the index date or a latest eGFR test result of less than 60 ml/min/1.73m2
Observational data analysis: DPP-4i prescriptions in patients with and without renal impairment carried out prior to the availability of alogliptin
Scowcroft A and Thomas A D. Diabetes UK Professional Conference Poster Number P499.

20. Patients with renal impairment(%)2
DPP-4 inhibitor prescriptions in patients with and without renal impairment
Product1
Product strength1
Number of patients
Patients with renal impairment(%)2
Sitagliptin
100 mg
50 mg
25 mg
6,266 34 7
20%
88%
57%
Linagliptin
5 mg
159
70%
Vildagliptin
50 mg bd
50 mg od
181 76
21%
37%
Saxagliptin
2.5 mg
676
265
25%
74%
1Where a patient was prescribed multiple products or doses in 2012, the patient was included in multiple groups.
2Renal impairment defined as diagnosis of moderate/severe/failure or chronic kidney disease stages 3/4/5 prior to period, or a latest estimated glomerular filtration rate test result <60 ml/min/1.73m2 prior to the period.
Scowcroft A and Thomas A D. Diabetes UK Professional Conference Poster Number P499.

21. DPP-4 inhibitor prescriptions in patients with and without renal impairment – conclusions
UK GP prescribing data reveals that 20-25% of patients treated with saxagliptin, sitagliptin and vildagliptin had renal impairment and, as a result, were receiving higher than recommended doses.
Patients receiving linagliptin did not require dose adjustment in renal impairment so they were all treated with the 5 mg od recommended dose.
NB. Study carried out prior to the availability of alogliptin
OD: once daily
Scowcroft A and Thomas A D. Diabetes UK Professional Conference Poster Number P499.

22. Implications for clinical governance
The term ‘unlicensed medicine‘ is used to describe
medicines that are used outside the terms of their
UK licence or which have no licence for use in the UK
When prescribing an unlicensed medicine you must:
Be satisfied that there is sufficient evidence or experience of using the medicine to demonstrate its safety and efficacy
Take responsibility for prescribing the medicine and for overseeing the patient’s care, monitoring, and any follow up treatment, or ensure that arrangements are made for another suitable doctor to do so
Make a clear, accurate and legible record of all medicines prescribed and, where you are not following common practice, your reasons for prescribing an unlicensed medicine.
General Medical Council. January Available at: (Accessed March 2014).

23. DPP-4 inhibitor prescriptions in patients with and without renal impairment – implications
Choosing a DPP-4 inhibitor that does not require dose adjustment as renal function declines can help simplify management
This could help avoid:
Using a medicine outside of the approved licence
Having to spend time counselling patients on dose reduction
Causing confusion for the patient as a result of a dose change
Affecting the patient’s perception of how their disease is progressing

24. Case study: Liz
What are the considerations for a patient that has a declining eGFR / creatinine clearance?
49-year-old female
T2D for 2 years
BP: 140/80 mmHg
BMI = 31 kg/m2
Last eGFR:
70 ml/min/1.73 m2, which has dropped by 10ml/min/1.73 m2 in the last three months
Evidence of microalbuminuria (protein in urine)
Metformin 1000 mg bd
Gliclazide 80 mg bd
Bendroflumethiazide 2.5 mg od
Ramipril 10 mg od
HbA1c = 7.4%
T2D: type 2 diabetes; BP: blood pressure; BMI: body mass index; eGFR: estimated glomerular filtration rate; bd: twice daily; od: once daily.

25. Case study: Liz (three years later)
How could you optimise the treatment for this patient?
52-year-old female
T2D for 5 years
BP: 150/80 mmHg
BMI = 31 kg/m2
eGFR has now reduced to
59 ml/min/1.73 m2
Metformin 1000 mg bd
Gliclazide 80 mg bd
Bendroflumethiazide 2.5 mg od
Ramipril 10 mg od
HbA1c = 7.4%
T2D: type 2 diabetes; BP: blood pressure; BMI: body mass index; eGFR: estimated glomerular filtration rate; bd: twice daily; od: once daily.

26. Summary: renal considerations in T2D
T2D progression can be associated with the development and progression of renal impairment
Where necessary, treatment choice and/or dose of T2D medication may need to be optimised according to kidney function
Irrespective of kidney function, linagliptin does not require dose adjustment in patients with T2D
T2D: type 2 diabetes.

27. Anatomy and function of the liver
The liver has many functions including:
Bile synthesis
Conversion of glucose to glycogen for storage
Production of cholesterol
Regulation blood clotting
It is important to assess liver function in patients with T2D as it may affect treatment options
T2D: type 2 diabetes.
Adapted from The liver. British Liver Trust. Available at Last updated Accessed October 2013.

28. T2D and liver dysfunction
↑Liver enzymes2
Poorly controlled diabetes3
70%1
Liver disorders in T2D
Fatty liver disease2
Severe insulin resistance3
Cirrhosis2
High insulin requirements3
T2D is associated with several liver disorders including1:
Elevated liver enzymes
Fatty liver disease
Cirrhosis
Approximately 70% of T2D patients have fatty liver disease2
Elevated liver aminotransferases are a strong indicator of future T2D3
Pre-diabetes or T2D is commonly diagnosed when a routine OGTT (oral glucose tolerance test) is performed in patients with non-alcoholic fatty liver disease3
Fatty liver disease may not be detected until end-stage liver disease develops2
The presence of a fatty liver in T2D is associated with more difficult to control diabetes, severe insulin resistance and high insulin requirements3
References:
Tolman KG, et al. Diabetes Care 2007;30(3):734–43.
Cusi K. Curr Opin Endocrinol Diabetes Obes. 2009; 16:141–149.
Lomonaco R, et al. Ther Adv Endocrinol Metab. 2011; 2(5) 211–225.
T2D: type 2 diabetes.
Adapted from Cusi K. Curr Opin Endocrinol Diabetes Obes 2009; 16:141–149.
Adapted from Tolman KG, et al. Diabetes Care 2007;30(3):734–43.
Adapted from Lomonaco R, et al. Ther Adv Endocrinol Metab 2011; 2(5) 211–225.

29. Factors to be taken into consideration when selecting an appropriate drug
Age
Fracture
risk
Occupation
BMI / body weight
Hobbies
Person with type 2 diabetes
Liver
function
Gender
Driving
Past medical history (e.g. haematuria/ cancer)
Live alone/
nutrition
Renal
function
Fasting

30. T2D medication in patients with hepatic impairment
The management of diabetes in patients with liver impairment may be complicated by:
Liver-related alterations in drug metabolism
Considerations around drug-drug metabolism
Possible hepatotoxicity
Patients with evidence of liver failure (e.g. ascites, coagulopathy, or encephalopathy) are at risk of altered drug metabolism
Altered drug metabolism may have an impact on treatment decisions
In addition, patients with decompensated (unstable) liver disease may have increased susceptibility to hypoglycaemia and require careful monitoring
The choice of T2D medication and/or dosing may require optimisation with respect to liver function
T2D: type 2 diabetes.
Tolman KG, et al. Diabetes Care. 2007; 30(3):734–743.

31. Overview of cautions and contraindications related to hepatic function for commonly prescribeda oral antidiabetic therapies
Metformin
Sulphonylureas
Acarbose
Meglitinides
Pioglitazone*
DPP-4 inhibitors
Dapagliflozin
Mild hepatic
impairment
Nateglinide
Alogliptin
Linagliptin
Glimepiride*
Saxagliptin
Glipizide
Repaglinide
(not studied)
Sitagliptin
Tolbutamide
Vildagliptin*
Moderate
hepatic
Severe
Gliclazide
Gliclazide
Gliclazide
Sitagliptin
(not studied)
Dose adjustment/caution/monitoring required
Contraindicated/not recommended
No dose adjustment required
aAs described in the British National Formulary; * Periodic monitoring of hepatic function required. No SPC available for glibenclamide.
DPP-4: dipeptidyl peptidase 4.
SmPCs for Glucophage (metformin); Diamicron (gliclazide); Amaryl (glimepiride); Minodiab (glipizide); Tolbutamide; Glucobay (acarbose); Starlix (nateglinide); Prandin (repaglinide); Actos (pioglitazone); Vipidia (alogliptin); Trajenta (linagliptin); Onglyza (saxagliptin); Januvia (sitagliptin); Galvus (vildagliptin); Forxiga (dapagliflozin) all available at: (last accessed October 2013).

32. Influence of hepatic impairment on linagliptin pharmacokinetics
24 hours
Single dose 5 mg
Steady state#
Steady
state kinetics
This study aimed to investigate whether hepatic impairment affected linagliptin pharmacokinetics, pharmacodynamics and tolerability.
This open label, parallel group, single centre study enrolled patients with mild (n= 8), moderate (n= 9) or severe (n= 8) hepatic impairment and healthy subjects (n= 8).
In mild hepatic impairment, steady-state linagliptin exposure was slightly lower than in healthy subjects. Exposure also tended to be lower in moderate hepatic impairment.
After a single dose of linagliptin, AUC in patients with severe hepatic impairment was similar to that in healthy subjects.
Mild, moderate or severe hepatic impairment did not result in an increase in linagliptin exposure after single and multiple dosing compared with normal hepatic function.
Therefore no dose adjustment is necessary.
Reference:
Graefe-Mody U, et al. Br J Clin Pharmacol 2012 Jul;74(1):75–85.
Linagliptin dose does not require adjustment in patients with mild, moderate, and severe hepatic impairment**
**Following Child-Pugh Classification. #Application of 6 oral doses of 5 mg linagliptin at 24-hour intervals.
AUC: area under the curve.
Adapted from Graefe-Mody U, et al. Br J Clin Pharmacol 2012; 74(1):75–85.

33. Case study: Doug 50-year-old male T2D for 5 years
BP = 160/80 mmHg
BMI = 30 kg/m2
HbA1c = 8.0%
Child-Pugh Score: 8
Moderate hepatic impairment
Which of the patient’s glucose-lowering agents may need reviewing?
Metformin only
Metformin and gliclazide
Linagliptin and gliclazide
None. All three treatments can continue as before
Metformin 1000 mg bd
Gliclazide 80 mg bd
Linagliptin 5 mg od
T2D: type 2 diabetes; BP: blood pressure; BMI: body mass index.

34. Summary and learning points
The management of T2D is challenging and becomes increasingly complex as the disease progresses
T2D progression can be associated with the development and progression of both renal and hepatic impairment
Where necessary, treatment choice and/or doses of T2D medication may need to be optimised according to kidney and liver function
Irrespective of kidney or liver function, linagliptin does not require dose adjustment in patients with T2D
T2D: type 2 diabetes.

35. Summary of linagliptin: key clinical information
Linagliptin is:
Indicated for patients on MET, on MET+SU, on insulin±MET, or as monotherapy*
Suitable for any adult age group, including elderly patients†
Suitable for patients with renal or hepatic impairment, without dose adjustment
Not associated with increased CV risk versus comparators
*When each of these regimens, plus diet and exercise, does not provide adequate glycaemic control. †Clinical experience is limited.
MET, metformin; SU, sulphonylurea.
Boehringer Ingelheim and Eli Lilly and Company Limited. Trajenta (linagliptin) Summary of Product Characteristics. Apr 2013 (Last accessed October 2013).

36. Prescribing information

37. Prescribing information