Touma! of Renal Nutrition and Metabolism Vol 2 No 2 April- Tune 2016 Gliptins in CKD 2

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Original Article


Efficacy and Safety of Gliptins in Patients With Type 2 Diabetes Mellitus (T2DM} and Chronic Kidney Disease (CKD)


'Dr. Mita B. Shah, Dr. Prashant Rajput, Dr. Bharat V. Shah

Institute of Renal Sciences, Global Hospital Mumbai,' Director, Institute of Renal Sciences, Global Hospital, Mumbai, 35, Dr. E. Borges road, Hospital avenue, Opposite Shirodkar High School,

Parel, Mumbai 400012


Key words: Type 2 diabetes, gliptins, chronic kidney disease



Abstract


Introduction: Gliptins are a new class of oral hypoglycemic agents that inhibit Dipeptidyl peptidase-4 (DPP- 4) and improve glycemic control through enhancement of the incretin axis. They are not associated with hypoglycemia and they do not cause weight gain. However, there is no Indian study about the efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). The aim of the study was to determine the efficacy and safety of gliptins in patients with T2DM and CKD. Methods: Twenty nine (Male 17and female 12)patients with T2DM and CKD (creatinine clearance < 60 ml/min) were included in the study. These subjects were started on gliptin for increasing number of hypoglycemia episodes with existing therapy (insulin and/or secretogogue). With introduction of gliptin, the dose of existing antihyperglycemic therapy was reduced. All these patients were followed for a minimum period of 6 months. The glycemic control, number of hypoglycemic episodes, weight and creatinine clearance were monitored. Results: The mean (SD) age of study subjects was 64 (11) years. The mean (SD) HBA 1c at the start of gliptin was 8.1 (1.4). After 6 months it was 7.9 (1.5). There was only 1 episode of hypoglycemia in 1patient. The mean (SD) weight before the start of gliptin was 72.3 (10.6) kg and 6 months later it was 71.9 (10.9) kg. The mean (SD) creatinine clearance at the time of introducing gliptin was 29 (12) ml/min. After 6 months it was 28 (13) ml/min. All patients tolerated gliptin well and there was no adverse effect in any patient. Conclusion: Gliptins are effective hypoglycemic agents for T2DM with CKD. They are not associated with hypoglycemic episodes, do not cause weight gain and are well tolerated.

Introduction:

Type 2 (T2) diabetes (DM) is reaching epidemic proportions all over the world and in India, this problem is even more'. The epidemic of DM has led to increasing incidence of chronic kidney Disease (CKD). Therefore there is an increasing number of patients with diabetes and CKD. These patients also have an increased risk of cardiovascular-


related disease and death relative to those with normal renal function2. Improved glycemic control in patients with T2DM and CKD is associated with better clinical outcomes'.

6

6

7

7

Oral antihyperglycemic treatment options for patients with T2 DM and CKD are limited due to safety concerns. Metformin isnot preferred asthereis arisk of development of lactic acidosis, even in patients with mild impairment of kidney function4Sulfonylureas are associated with an increased incidence of hypoglycemia and weight gain'. Thiazolidinediones increase the risk of fluid retention and heart failure and hence are not preferred Dipeptidyl peptidase-4 (DPP-4) inhibitors called Gliptins are one of the latest therapeutic classes of glucose lowering medications. They improve glycemic control through enhancement of the incretin axis and hence are not associated with hypoglycemia. Further, they donot cause weight gain While gliptins are widely used, there is no Indian data as regards their efficacy and safety in patients with T2DM and CKD. The objective of this retrospective study was to analyse efficacy and safety of gliptins in patients with T2DM and CKD stage 3to 5.

Methods:

This is a retrospective study analyzing outcome of twenty nine stable adult (>18years) patients with T2DM and CKD (creatinine clearance < 60 ml/min/1.73 m2 for > 3 months) in whom gliptin was introduced as an oral hypoglycemic agent with reduction of insulin and/or secretogogue. All patients were taught self monitoring of blood glucose (SMBG). The creatinine clearance was estimated using Cockcroft-Gault formula". The study excluded those with impaired hepatic function and those on dialysis in whom assessment of efficacy of any drug would be difficult

The study subjects were started on gliptin (saxagliptin in 16, sitagliptin in 11, vildagliptin in 1and linagliptin in 1) because of increasing number of hypoglycemia episodes (SMBG level < 60 mg/dl) with existing therapy (insulin and/or secretogogue). With introduction of gliptin, the dose of existing antihyperglycemic therapy was reduced. The dose of saxagliptin andvildagliptin was reduced to 50% ofthe dose

Journal of Renal Nutrition and Metabolism Vol 2 No 2 April- June 2016 Gliptins in CKD 3

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used in those with creatinine clearance > 60 ml/min/1.73 m2. In case of sitagliptin the dose was reduced to 50% in those with creatinine clearance 30-59 ml/min/1.73 m2 and 25% in those with creatinine clearance < 30 ml/min/1.73 m2. The dose of linagliptin was maintained 5 mg/day irrespective of kidney function.

Follow-up monitoring

All studypatients were followed up monthly,2 monthly or 3 monthly depending on their condition. During each follow-up, weight, BP,SMBGvalues, PBS and creatinine were monitored. HBAlc was monitored 3 monthly. Each patient was followed for aminimum period of 6 months.

Assessment ofefficacyandsafety

The efficacy of gliptins was assessed from SMBG readings and HBAlC measured in the laboratory. The number of hypoglycemic episodes and creatinine clearance and alladverse effects were also monitored

Statistics

Continuous data are reported as means and standard deviation. Student's test was used to compare the means between different groups.

Significance of P-values was defined asvalues < 0.05

Results

Of 29 patients, 17were males and 12females. The mean (SD) age of these patients was 64 (11) years. These patients were on insulin and/or secretogogue which was reduced with introduction of gliptin. Other concomitant medications of these patients were antihypertensive drugs andlipid lowering agents.

Themean (SD) HBAlebefore the start of gliptin was 8.1(1.4). After 6 months it was 7.9 (1.5). The difference was not statistically significant (p>0.05)

The mean (SD) weight before the start of gliptin was 72.3 (10.6) kgand6 monthslater itwas 71.9 (10.9) kg.

The mean (SD) creatinine clearance at the time of introducing gliptin was 29 (12) ml/min. After 6 months itwas 28 (13) ml/min.

Cr. Cl =Creatinine clearance

Table 1shows characteristic of patients and their response to different gliptins.

All patients tolerated gliptin well and there was no adverse effect in any patient. There was only 1 episode of hypoglycemia in 1patient.

Discussion

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With increasing incidence and prevalence of T2DM, there is an increasing incidence of CKD. According to Indian CKD registry, Diabetes mellitus as the cause of CKD was found in 31.2% of patients9 Poor glycemic control is associated with higher risk of microvascular complications like CKD. Further, these patients with T2DM and CKD have a higher risk of cardiovascular disease2 10 Therefore, good glycemic control is important in management of these patients with T2DM and CKD.

Use of oral antihyperglycemic agents in patients with CKD becomes difficult because most of them are cleared by the kidney and increase the risk of hypoglycemia with reducing renal function. Thiazolidinediones metabolism is not affected by kidney but these agents increase the risk of fluid retention and heart failure and hence are not preferred 0.

Gliptins except linagliptin are cleared bythe kidney and need dose modification but by working through enhancement of incretin axis achieve glycemic control without causing hypoglycemic episodes. Moreover, they do not cause weight gain. They are therefore useful oral antihyperglycemic agents inpatients with CKD

This is the first Indian study of efficacy and safety of DPP-4 inhibitors in subjects with T2 DM and CKD. It showed that addition of DPP-4 inhibiting gliptins with reduction of insulin and/or secretogogue was effective. There was no worsening of glycemic control despite reduction in baseline antihyperglycemic drugs. In fact, HBAlc slighltly improved although the improvement was not statistically significant (p>0.05). Actualy, no attempt was made to achieve intensive blood sugar control as most of the patients had recurrent hypoglycemic episodes before introduction of gliptin. Throughout the study, gliptins were well tolerated and in no patient it had to be withdrawn due to severe adverse effect. In



No.of patiie11ts

Saxagl'iptin

16

Sitagl'ipti11

11

Vildag'liptJin

Linagliptirn

1

Age·

65.5, (11.96)

64.7(11.S.)

5,2

80

Males

9

6

1

Female·s

7

5

0

0

HBA 1c at baseline

8.33(1.39)

7.74 (1.58)

101.2

7.1

HBA1c .at 6 mo11tihs

8.29 (1.84)

7.57 (0.82)

101.2

5.8,

Weig'ht at baselirne

69.61 (10.4)

73.1 (10i.86)

90

67.3

Weig.ht at 6 mo11tihs

69.29 (10.79)

73J)l3 (10i.87)

90

163.4

Grr. Cl at baseline

25.168 (101.65)

33.88 (13.32)

55

22.4

Cr. 01 at 6 montlhs

25.08 (12.09)

32.5 (13.59)

5,5

22.4


Table :Comparing Gliptins particular, there was a very low incidence of hypoglycemia.

Touma! of Renal Nutrition and Metabolism Vol 2 No 2 April- Tune 2016 Gliptins in CKD 4

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Only 1patient had a single hypoglycemic episode which could be attributed to his concomitant insulin therapy.Further, all patients maintained stable weight and stable renal function. A little reduction in creatinine clearance could be attributed to natural course of diabetic nephropathy.

Since gliptins were used as they became available in the market, we had only 1patient on vildagliptin and linagliptin. We could however compare saxagliptin and sitagliptin on which a majority of our patients were started. As canbe seen from table 1,there was no significant difference in characteristics of patients in the 2 groups. The glycemic control and changes in weight and creatinine clearance were not significantly different (p > 0.05).

The number of patients included in the study are few because this is an ongoing study and we have included only those patients who have completed atleast 6 months of follow-up

In our study, we excluded patients with end stage kidney disease requiring maintenance dialysis. Therefore, this study cannot be extrapolated to patients on maintenance dialysis. However, considering that linagliptin is not cleared by kidneys it should not be a problem using it in patients with ESKD on maintenance dialysis.

In summary,our studyshows that gliptins provide clinically useful glycemic control in patients with T2 DM and CKD. This is achieved without hypoglycemic episodes, without weight gain, and without unacceptable side effects. The renal function remained stablein all studypatients.

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