Individual with type 2 diabetes of long duration who ... with type 2 diabetes of long duration who ... Individual with type 2 diabetes of long duration who develops renal problems

Case study: Individual with type 2 diabetes of long duration who develops renal problems

Authored by Neil Munro and Clifford Bailey on behalf of the Global Partnership for Effective Diabetes Management.

The Global Partnership for Effective Diabetes Management is supported by an unrestricted educational grant from Bristol-Myers Squibb, AstraZeneca LP.

• This case study outlines the treatment of an adult with renal disease who has previously been diagnosed with type 2 diabetes

• The case reflects a full range of treatment and management tools available in the European/US context*

*The management of any patient is subject to social, economic, gender, age, co-morbidity and ethnic variables, and is dependent on the range of treatment options available in specific regions or countries.

Individual with type 2 diabetes of long duration who develops renal problems

• Sanjay, 56, lives with his wife

• Works as a furniture shop manager

• Diagnosed with type 2 diabetes 9 years ago

• Sanjay takes a range of medications to control his blood glucose, blood pressure and lipid levels

• Although now well controlled, Sanjay had poorly controlled hypertension for several years

• Background retinopathy diagnosed 3 years ago

• Two recent urine tests also indicated presence of microalbuminuria

• Sanjay has returned for further tests to assess his kidney function

– To determine presence and/or extent of CKD

Current medication

Ramipril: 10 mg/day

Chlorthalidone: 25 mg/day

Metformin: 2000 mg/day

Sitagliptin: 100 mg/day

Atorvastatin: 10 mg/day

CKD, chronic kidney disease

Diagnosis of CKD

Clinical chemistry ACR: 10 mg/mmol eGFR: 57 ml/min FPG: 7.0 mmol/l HbA1c: 6.5% LDL-cholesterol: 1.9 mmol/L HDL-cholesterol: 1.3 mmol/L Triglycerides: 2.1 mmol/L Systolic/diastolic BP:* 126/78 mmHg BMI: 28.5 kg/m2

The doctor explains that:

• Sanjay’s raised albumin:creatinine ratio (ACR) on three occasions confirms a diagnosis of microalbuminuria

• Sanjay’s estimated glomerular filtration rate (eGFR) indicates impaired kidney function

Click here to change units

Click here to show normal range

*With antihypertensive therapy. Confirmed on subsequent visits

ACR, albumin:creatinine ratio; BMI, body mass index; BP, blood pressure; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; HbA1c, glycosylated haemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

Question: What stage of kidney disease does Sanjay have?

Diagnosis of CKD

Clinical chemistry Normal range ACR: 10 mg/mmol <2.5 mg/mmol eGFR: 57 ml/min 90–120 ml/min FPG: 7.0 mmol/l 3.9–5.5 mmol/l HbA1c: 6.5% 4.0–6.0% LDL-cholesterol: 1.9 mmol/l <2.6 mmol/l HDL-cholesterol: 1.3 mmol/l >1.5 mmol/l Triglycerides: 2.1 mmol/l <1.7 mmol/l Systolic/diastolic BP:* 126/78 mmHg 120/80 mmHg BMI: 28.5 kg/m2 18.5–24.9 kg/m2


Click here to hide normal range Question: What stage of kidney disease

does Sanjay have? *With antihypertensive therapy. Confirmed on subsequent visits





Diagnosis of CKD

Clinical chemistry ACR: 88.4 mg/g eGFR: 57 ml/min FPG: 126 mg/dl HbA1c: 48 mmol/mol LDL-cholesterol: 73 mg/dl HDL-cholesterol: 50 mg/dl Triglycerides: 186 mg/dl Systolic/diastolic BP: 126/78 mmHg BMI: 28.5 kg/m2


Click here to show normal range Question: What stage of kidney disease

does Sanjay have? *With antihypertensive therapy. Confirmed on subsequent visits





Diagnosis of CKD

Clinical chemistry Normal range ACR: 88.4 mg/g <30 mg/g eGFR: 57 ml/min 90–120 ml/min FPG: 126 mg/dl 70–100 mg/dl HbA1c: 48 mmol/mol 20–42 mmol/mol LDL-cholesterol: 73 mg/dl <100 mg/dl HDL-cholesterol: 50 mg/dl >60 mg/dl Triglycerides: 186 mg/dl <150 mg/dl Systolic/diastolic BP: 126/78 mmHg 120/80 mmHg BMI: 28.5 kg/m2 18.5–24.9 kg/m2


Click here to hide normal range

Question: What stage of kidney disease does Sanjay have? *With antihypertensive therapy. Confirmed

on subsequent visits





Staging of CKD1

eGFR (ml/min/1.73m2 ) Stage of kidney disease Severity

≥90 + other signs of damage of kidney damage

1 Function not compromised but other findings indicate kidney disease

60‒89 ml + other signs of kidney damage

2 Mild

45‒59 3a Mild-to-moderate

30‒44 3b Moderate-to-severe

15‒29 4 Severe

<15 5 Renal failure (or dialysis)

1. Levy AS & Coresh J. Lancet 2012;379:165‒180.

eGFR, estimated glomerular filtration rate.

Glycaemic target* • The doctor explains to Sanjay that CKD is associated with increased risk of

CV events and hypoglycaemia

• Disease progression can be slowed and CV risk reduced through excellent glycaemic control

• Sanjay’s current glycaemic (HbA1c) target is 6.5–7.0%

Question In light of his CKD, what is the most appropriate glycaemic target for Sanjay?

6.0–6.5%: as kidney function is impaired, glycaemic control must be tightened to reduce CV risk

6.5–7.0%: glycaemic control must be optimized to reduce CV risk while also minimizing the risk of hypoglycaemia

7.0–7.5%: glycaemic control should be relaxed due to decline in kidney function

*Equivalent values: 6.0%/42 mmol/mol; 6.5%/48 mmol/mol; 7.0%/53 mmol/mol; 7.5%/58 mmol/mol

CKD, chronic kidney disease; CV, cardiovascular; HbA1c, glycosylated haemoglobin

Glycaemic target

• Patients with CKD are at increased risk for CV events and good glycaemic control can slow disease progression and reduce this risk

– Renal insufficiency can also increase risk of hypoglycaemia if individuals are prescribed agents associated with hypoglycaemia, such as insulin or sulphonylureas

• Thus, the benefits of strict glycaemic control to reduce progression of microvascular complications must be balanced against the risk of hypoglycaemia in this patient group1

• In patients with early stage CKD, and where goals can be achieved safely, the glycaemic target should be as close to normal as possible (6.5‒7.0%*)1

• Less stringent targets may be favoured in circumstances where disease progression limits treatment (impeding achievement of glycaemic targets)1

Question What is the most appropriate glycaemic target for Sanjay?

6.5–7.0%:* glycaemic control must be optimized to reduce CV risk while also minimizing the risk of hypoglycaemia

1. Bailey CJ et al. Diab Vasc Dis Res 2013;10:397–409.

*48–53 mmol/mol. CKD, chronic kidney disease; CV, cardiovascular.

Glycaemic control in CKD • Sanjay maintains good glycaemic control on a regimen of metformin plus

the dipeptidyl peptidase-4 inhibitor sitagliptin

• Individualization of antihyperglycaemic therapy is paramount in CKD patients as some medications are contraindicated

Question Should Sanjay’s antihyperglycaemic medication be altered?

No, continue with metformin and sitagliptin

Yes, continue with metformin and replace sitagliptin

Yes, sitagliptin and metformin are inappropriate in people with CKD

Yes, continue with sitagliptin and replace metformin

CKD, chronic kidney disease; DPP-4, dipeptidyl peptidase-4.

Option chosen: Continue with metformin and sitagliptin

• No therapy adjustment is required at present

• The safety of metformin (potential risk of lactic acidosis) in patients with renal insufficiency remains a subject of debate

• However, owing to the possible CV benefit of metformin, both NICE1 and the ADA/EASD2

position statements suggest:

• Avoid metformin if eGFR <30 mL/min

• Reduce dosage if eGFR 30‒45 mL/min

• In the current circumstances Sanjay is able to continue with his existing dose of metformin

• Sitagliptin can also be used without the need for dose reduction until eGFR is <50 mL/min

1. National Institute for Health and Clinical Excellence. 2009;CG87. 2. Nathan DM et al. Diabetes Care 2009;32:193‒203. 3. Bailey CJ et al. Diab Vasc Dis Res 2013;10:397–409. 4. Inzucchi SE et al. Diabetes Care 2012;35:13641379.

Metformin3,4

HbA1c efficacy: High

Hypoglycaemia risk: Low

Weight effect: Neutral/loss

Major side effects: GI Lactic acidosis

Cost: Low

DPP-4 inhibitor3,4

HbA1c efficacy: Intermediate


Weight effect: Neutral

Major side effects: Rare

Cost: High

CV, Cardiovascular; DPP-4, dipeptidyl peptidase-4; eGFR, estimated glomerular filtration rate; GI, gastrointestinal; HbA1c, glycosylated haemoglobin.

Option chosen: Continue metformin, replace sitagliptin

• Sitagliptin can be used without the need for dose reduction until eGFR <50 mL/min

• The safety of metformin (potential risk of lactic acidosis) in patients with renal insufficiency remains the subject of debate






Metformin3,4





Cost: Low

DPP-4 inhibitor3,4





Cost: High



Option chosen: Continue sitagliptin, replace metformin

• Sitagliptin can be used without the need for dose reduction until eGFR <50 mL/min







Metformin3,4





Cost: Low

DPP-4 inhibitor3,4





Cost: High



Option chosen: Replace both metformin and sitagliptin







• Sitagliptin can also be used without the need for dose reduction until eGFR <50 mL/min

Metformin3,4





Cost: Low

DPP-4 inhibitor3,4





Cost: High



Controlling CV risk factors • Sanjay’s BP is controlled using an ACE inhibitor and a thiazide diuretic1,2

– ACE inhibitors and ARBs reduce albuminuria and delay progression of nephropathy in patients with type 2 diabetes: these are recommended in patients with diabetes and CKD whether or not hypertension is present1,2

– CCBs may reduce CV risk compared with thiazide diuretics in high-risk individuals:3 the doctor replaces the thiazide diuretic with a CCB (amlodipine 5 mg/day)

• Lowering LDL-cholesterol with statin-based therapies reduces the risk of major atherosclerotic events in patients with CKD:1

– Sanjay’s LDL-cholesterol is controlled using a statin and is below target levels

• The doctor reinforces the importance of weight loss to reduce CV risk

• Sanjay is referred to a diabetes nurse (for further dietary and lifestyle advice) who specializes in the management of people with renal disease

1. National Kidney Foundation. Am J Kidney Dis 2007;49:S1–S180. 2. ESC and ESH Guidelines. Eur Heart J 2007;28:1462–1536. 3. Jamerson KA et al. N Engl J Med 2008;359:2417–2428.

ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; BP, blood pressure; CCB, calcium channel blocker; CKD, chronic kidney disease; CV, cardiovascular; LDL, low density lipoprotein.

3-month follow up appointment

• Sanjay returns for a 3-month follow up appointment

• Renal dysfunction has not progressed substantially and Sanjay’s BG levels are under control

• Sanjay’s weight has remained unchanged despite efforts to change his diet and exercise more

• The doctor tells Sanjay to come back in 3 months

FPG: 7.0 mmol/l (126 mg/dl)

HbA1c: 6.5% (48 mmol/mol)

eGFR: 57 ml/min

ACR: 12 mg/mmol

BP: 124/76 mmHg

BMI: 28 kg/m2

Current medication

Ramipril: 10 mg/day

Amlodipine: 5 mg/day

Metformin: 2000 mg/day

Sitagliptin: 100 mg/day

Atorvastatin: 10 mg/day

ACR, albumin:creatinine ratio; BMI, body mass index; BP, blood pressure; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; HbA1c, glycosylated haemoglobin.

Long-term follow up: 5 years later

• Sanjay returns to see his doctor and undergoes a series of tests as part of routine monitoring

• He reports good adherence to medication and lifestyle interventions

• On the regimen of medications prescribed, Sanjay has maintained good control of BG levels, BP and lipids

• However, Sanjay’s renal disease has progressed, albeit slowly (eGFR decrease of 2 ml/min/year)

Current status

HbA1c: 6.6% (49 mmol/mol)

FPG: 6.3 mmol/l (114 mg/dl)

LDL-cholesterol: 1.7 mmol/l (66 mg/dl)

HDL-cholesterol: 1.5 mmol/l (58 mg/dl)

Triglycerides: 2.0 mmol/l (177 mg/dl)

eGFR: 47 ml/min

ACR: 20 mg/mmol

BP: 122/76 mmHg

BMI: 26.1 kg/m2

Question: What stage of kidney disease does Sanjay have? Click to reveal

ACR, albumin:creatinine ratio; BMI, body mass index; BP, blood pressure; BG, blood glucose; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; HbA1c, glycosylated haemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

Staging of CKD1

1. Levy AS & Coresh J. Lancet 2012;379:165‒180.

eGFR (ml/min/1.73m2 ) Stage of kidney disease Severity

≥90 + other signs of damage of kidney damage

1 Function not compromised but other findings indicate kidney disease

60‒89 ml + other signs of kidney damage

2 Mild

45‒59 3a Mild-to-moderate

30‒44 3b Moderate-to-severe

15‒29 4 Severe

<15 5 Renal failure (or dialysis) eGFR, estimated glomerular filtration rate.

Optimizing glycaemic control • The doctor explains to Sanjay that his kidney function has declined over the past

few years (although slowly) and they discuss his antihyperglycaemic medication

Question What is the most appropriate course of action for Sanjay

Continue metformin and switch to a different DPP-4 inhibitor

Begin insulin therapy

Do not adjust therapy

Continue metformin and reduce sitagliptin dosage

Continue metformin and switch to an alternative oral antihyperglycaemic

DPP-4, dipeptidyl peptidase-4.

Option chosen: Do not adjust therapy

• According to the ADA/EASD position statement:1

– Metformin can be used at the current dosage until eGFR reaches 45 ml/min

• However, most DPP-4 inhibitors, including sitagliptin, require dosage reductions at eGFR <50 ml/min2

– An exception to this is linagliptin, which is eliminated enterohepatically2

• The doctor and Sanjay decide to switch to linagliptin as this will avoid further dose reductions in the future

• Insulin therapy may become necessary if Sanjay’s hyperglycaemia becomes difficult to manage and/or as his CKD progresses

1. Nathan DM et al. Diabetes Care 2009;32:193‒203. 2. National Kidney Foundation. Am J Kidney Dis 2012;60:850‒886.

Dose adjustments for DPP-4 inhibitors in CKD1,2

DPP-4 inhibitor eGFR mL/min Dose

Alogliptin* ≥60 25 mg daily

≥30 to <60 12.5 mg daily

≥15 to <30/ESRD / haemodialysis

6.25 mg daily

Linagliptin No dose adjustment

Saxagliptin >50 5 mg daily

≤50 2.5 mg daily

Sitagliptin >50 100 mg daily

30‒50 50 mg daily

<30 25 mg daily

Vildagliptin ≥50 50 mg twice daily

<50 50 mg daily *Approved by: • Japanese Ministry of Health, Labour and Welfare, April 2010. • US Food and Drug Administration, January 2013. CKD, chronic kidney disease; DPP-4, dipeptidyl

peptidase-4; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease.

Option chosen: Begin insulin therapy

• Insulin clearance is reduced in those with more severe renal dysfunction, increasing the risk of hypoglycaemia

– However, insulin doses can be adjusted as necessary with close SMBG

• As the options for oral glycaemic control become more limited as CKD progresses, insulin is often the preferred option

Please select another option

Insulin1,2


Hypoglycaemia risk: High

Weight effect: Gain

Major side effects: Hypoglycaemia

Cost: Variable

CKD, chronic kidney disease; HbA1c, glycosylated haemoglobin; SMBG, self-monitoring of blood glucose.

• Sanjay is not keen on switching to injectable therapy, and requests that he stick with oral medication if possible

• The doctor explains that insulin therapy may become necessary in the future if his hyperglycaemia becomes difficult to manage and/or as his CKD progresses

1. Bailey CJ et al. Diab Vasc Dis Res 2013;10:397–409. 2. Inzucchi SE et al. Diabetes Care 2012;35:13641379

Option chosen: Continue metformin and reduce sitagliptin dosage











≥30 to <60 12.5 mg daily


6.25 mg daily



≤50 2.5 mg daily


30‒50 50 mg daily

<30 25 mg daily




Option selected: Continue metformin; switch to different DPP-4 inhibitor











≥30 to <60 12.5 mg daily


6.25 mg daily



≤50 2.5 mg daily


30‒50 50 mg daily

<30 25 mg daily




Option selected: Metformin and alternative oral antihyperglycaemic

1. National Kidney Foundation. Am J Kidney Dis 2012;60:850‒886.

• Sanjay’s DPP-4 inhibitor medication requires dose adjustment, but does not need to be replaced1

• Other oral antihyperglycaemics are available, but should be chosen cautiously: – Sulphonylureas are not appropriate for

those with CKD, due to risk of hypoglycaemia

– TZDs can be used in CKD; however, fluid retention is a major limiting factor

• The doctor and Sanjay decide to stick with DPP-4 inhibitors, but switch to linagliptin as this will avoid further dose reductions in the future




≥30 to <60 12.5 mg daily


6.25 mg daily



≤50 2.5 mg daily


30‒50 50 mg daily

<30 25 mg daily


<50 50 mg daily

*Approved by: • Japanese Ministry of Health, Labour and Welfare, April 2010. • US Food and Drug Administration, January 2013.

CKD, chronic kidney disease; DPP-4, dipeptidyl peptidase-4; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; TZDs, thiazolidinediones.

Additional risk factor control

• Reducing CV risk becomes increasingly important as CKD progresses

• Sanjay’s blood pressure and LDL-c are below the recommended targets

• Sanjay’s HDL-c and triglyceride levels are also within the normal ranges

• However, while Sanjay has lost weight, his BMI currently places him in the overweight category

• The doctor praises Sanjay for his weight loss but encourages stringent adherence to diet and exercise interventions to achieve further reductions

• The doctor explains that as kidney function deteriorates, it is all the more important to reduce CV risk and weight loss contributes to this

Current status and additional medications

LDL-c: 1.7 mmol/l (66 mg/dl)

HDL-c: 1.5 mmol/l (58 mg/dl)

Triglycerides: 2.0 mmol/l (177 mg/dl)

BP: 122/76 mmHg

BMI 26.1 kg/m2

Medication: ramipril; amlodipine;

atorvastatin

BMI, body mass index; BP, blood pressure; CV, cardiovascular; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol.

Long-term management • Sanjay’s CKD is progressing slowly; with optimal

management the progression should remain slow

• As part of ongoing management, Sanjay should:

– Be monitored carefully for comorbidities related to progressive renal disease

– Have his eGFR measured at least every 6 months

– Continue to attend check-ups every 3 months to ensure optimal BG , BP and lipid management

– Be considered for referral to a nephrologist when he approaches stage 4 CKD

• Preparations for treatment of end stage kidney disease (transplant or dialysis) can be made at a sufficiently early stage1

1. Seaquist ER & Ibrahim HN. J Clin Endocrinol Metab 2010;95:3103‒3110.

10 Steps to get more type 2 diabetes patients

to goal

10 Steps to get more people with type 2 diabetes to goal: • Aim for an appropriate individualized glycaemic target, e.g. HbA1c 6.5–7% (48–53 mmol/mol)

(or fasting/preprandial plasma glucose 110–130 mg/dl [6.0–7.2 mmol/l] where assessment of HbA1c is not possible) when safe and appropriate.

• Monitor HbA1c every 3 months in addition to appropriate glucose self-monitoring.

• Appropriately manage all cardiovascular risk factors.

• Refer all newly diagnosed patients to a unit specializing in diabetes care where possible.

• Address the underlying pathophysiology of diabetes, including the treatment of β-cell dysfunction and insulin resistance.

• Treat to achieve appropriate target HbA1c within 6 months of diagnosis.

• After 3 months, if patients are not at the desired target HbA1c, consider combination therapy.

• Consider initiating combination therapy or insulin for patients with HbA1c ≥9% (≥75 mmol/mol).

• Use combinations of antihyperglycaemic agents with complementary mechanisms of action.

• Implement a multidisciplinary team approach that encourages patient self-management, education and self-care, with shared responsibilities to achieve goals.

The Global Partnership for Effective Diabetes Management recommends:1

1. Bailey CJ et al. Diab Vasc Dis Res 2013;10:397–409.

HbA1c, glycosylated haemoglobin.

For more case studies visit www.effectivediabetesmanagement.com

© 2013 International Medical Press. All rights reserved. No responsibility is assumed by the Global Partnership for Effective Diabetes Management or International Medical Press for any injury and/or damage to persons or property through negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Due to rapid advances in the medical sciences, the Global Partnership and International Medical Press recommend that independent verification of diagnoses and drug dosages should be made. Neither the Global Partnership for Effective Diabetes Management or International Medical Press assume liability for any material contained herein.

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Individual with type 2 diabetes of long duration who ... with type 2 diabetes of long duration who ... Individual with type 2 diabetes of long duration who develops renal problems