The use of vildagliptin in patients with type 2 diabetes with renal impairment
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The use of vildagliptin in patients with type 2 diabetes with renal impairment By Dr. Usama Ragab Youssif Agenda ---------- Case presentation Diabetes and CKD: What is the problem Drug treatment in patient with CKD: choice of treatment Vildagliptin in mild renal impairment Vildagliptin in moderate and severe renal impairment Vildagliptin in ESRD (patients on HD) Vildagliptin in kidney transplant patients with NODAT Final bottom-line
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The use of vildagliptin in patients with type 2 diabetes with renal impairment
- 1. The use of vildagliptin in patients with type 2 diabetes with renal impairment Dr. Usama Ragab Youssif, MD Lecturer of Medicine Zagazig University ISMA CME Series – Toilp Elgalala – Elsokhna 16 June 2022 – 5.30 PM Contact: Dr. Usama Ragab Youssif 00201000035863 usamaragab@medicine.zu.edu.eg Slideshare: dr4spring
- 2. Agenda • Case presentation • Diabetes and CKD: What is the problem • Drug treatment in patient with CKD: choice of treatment • Vildagliptin in mild renal impairment • Vildagliptin in moderate and severe renal impairment • Vildagliptin in ESRD (patients on HD) • Vildagliptin in kidney transplant patients with NODAT • Issue of glycemic variability: vildagliptin versus comparator • Final bottom-line
- 3. Case • Mr X. 60-year-old man with a 15-year history of T2DM has a HbA1c of 8.7%. • He has been referred by his PCP to discuss management of his diabetes. • He is taking glibenclamide at 5 mg twice daily and metformin at 1,000 mg twice daily along with candesartan and atorvastatin.
- 4. Case (cont.) • On examination his BMI is 29 kg/m2, his BP is 150/90 mm Hg, and he has evidence of peripheral neuropathy. • He has an eGFR of 33 mL/min/m2 and a urinary ACR of 317 mg/g.
- 5. Case (cont.) • He developed episodes of hypoglycemia, now he was told by his physician that he has no longer diabetes • He stopped his medications
- 7. Diabetes and CKD Kidney disease is a frequent diabetic complication ‒ Type 1 diabetes ~30% ‒ Type 2 diabetes ~40% Diabetes is the most common cause of CKD and ESRD in the developed and developing worlds ‒ Diabetes prevalence in US ESRD patients: 66%-86% depending on race Diabetic kidney disease amplifies CVD risk ‒ Much of diabetes-associated excess CVD risk occurs in diabetic kidney disease National Kidney Foundation. https://www.kidney.org/atoz/content/diabetes
- 8. CKD is reduced kidney function and/or kidney damage • • Reference: Kidney International Supplements, 2013; 3(1): 5-14
- 11. People with diabetes 6-12X more likely to be hospitalized for CKD or End-stage renal disease Public Health Agency of Canada (August 2011); using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada).
- 12. Where is the problem
- 13. 1- Hypoglycemia in Diabetes With CKD Clin J Am Soc Nephrol 4: 1121–1127, 2009
- 14. 2- Mortality Excess Afkarian et al. J Am Soc Nephrol 2013. 24:302308
- 15. 3- Choice of treatment https://doi.org/10.1016/j.kint.2020.06.019
- 16. Rational of treating diabetes in CKD You are treating diabetes → reducing albuminuria → reducing CKD The benefits of intensive glycemic control must be balanced against the potential harm i.e., hypo and drug AE Hypoglycemia may occur = may be a sign that CKD has progressed.
- 17. My Doctor told me that diabetes has gone
- 18. Dilemma • Stop medications • Hypoglycemia vs hyperglycemia • Insulin myths • Medication shift
- 19. What should we know Neumiller et al. J Am Soc Nephrology 2017; 28:2263–2274; Defronzo et al. Nat Rev Nephrol 2017:13:11-26
- 20. Vildagliptin and different CKD scenarios
- 22. Meta-analysis comparing the efficacy of DPP-4 inhibitors vs. placebo in % HbA1C reduction. Walker, Simon R., et al. Nephron 136.2 (2017): 85-94.
- 25. Incidences of AEs and SAEs in patients with normal renal function and mild renal impairment
- 26. 1- Vildagliptin in Patient with Mild RI GALIANT study." diabetes research and clinical practice 90.2 (2010): 182-190.
- 27. GALIANT study." diabetes research and clinical practice 90.2 (2010): 182-190.
- 33. Overall summary of adverse events by treatment and severity of renal impairment
- 35. Diabetes, Obesity and Metabolism 14: 1032–1039, 2012
- 36. Diabetes, Obesity and Metabolism 14: 1032–1039, 2012
- 37. Overall summary of adverse events by treatment and severity of renal impairment Diabetes, Obesity and Metabolism 14: 1032–1039, 2012
- 38. Hypoglycemic events was less in vildagliptin treated arm • The incidence of hypoglycemia with vildagliptin in this study (26% in patients with moderate renal impairment and 18% in those with severe renal failure) appears to be lower than the one expected (<50%) in patients with long-standing T2DM and low baseline HbA1c receiving insulin with or without OADs.
- 40. • The most likely mechanistic explanation for vildagliptin's protective effect is increased GIP-mediated stimulation of glucagon release in response to initial plasma glucose reduction.
- 42. Changes in hemoglobin A1c (HbA1c) level during treatment Endocrine Journal 2011, 58 (11), 979-987.
- 43. Changes in mean postprandial plasma glucose (PPG) levels during treatment Endocrine Journal 2011, 58 (11), 979-987.
- 44. Efficacy in patients receiving vildagliptin when divided by age and body mass index Endocrine Journal 2011, 58 (11), 979-987.
- 45. Efficacy in patients receiving vildagliptin when divided by baseline glycemic state Endocrine Journal 2011, 58 (11), 979-987.
- 47. Mera et al. Journal of Diabetes & Metabolic Disorders (2015) 14:83
- 52. Choice of antidiabetic treatment in CKD patients
- 53. Remember
- 54. Hypoglycemia risk and drugs
- 56. Treatment algorithm for selecting glucose-lowering drugs for patients with T2D and CKD
- 57. Patient factors influencing the selection of glucose-lowering drugs other than SGLT2i and metformin in T2D and CKD
- 58. Recommended dose adjustment for DPP4i patients with CKD Abe, Masanori, and Kazuyoshi Okada. Chronic kidney diseases-recent advances in clinical and basic research 185 (2015): 98-115
- 60. Vildagliptin and glucose fluctuation
- 61. Problem • There is increasing evidence that glycemic disorders such as rapid glucose fluctuations over a daily period might play an important role on diabetic complications
- 63. Study Design • The efficacy of sitagliptin 100 mg once daily vs. vildagliptin 50 mg twice daily on daily blood glucose fluctuations in patients with type 2 diabetes that was inadequately controlled by metformin • Number: 38 • Duration: 3 months
- 64. Procedure • 48-hour CGM was performed in patients treated with metformin plus vildagliptin (n=18) or sitagliptin (n=20) over a period of 3 months. • The mean amplitude of glycemic excursions (MAGE) was used for assessing glucose fluctuations during the day. • During a standardized meal, glucagon-like peptide- 1 (GLP-1), glucagon, and insulin were measured.
- 65. Vildagliptin • Although similar in DPP-4 inhibition, the differences in PK profiles may induce a different activity over day Journal of Diabetes and Its Complications 24 (2010) 79–83
- 66. Inter-prandial plasma GLP-1 • Significant higher level of inter-prandial plasma GLP-1 levels following 3 month compared to sitagliptin Journal of Diabetes and Its Complications 24 (2010) 79–83
- 67. Significant more inter-prandial plasma glucagon suppression levels following 3 months compared to sitagliptin Journal of Diabetes and Its Complications 24 (2010) 79–83
- 68. Vildagliptin showed significant reduction in glucose fluctuation, MAGE, by 51 % compared with Sitagliptin... Hence reduces oxidative stress... Reduces free radical... Less complications Journal of Diabetes and Its Complications 24 (2010) 79–83
- 69. Final Bottom-line • Vildagliptin could be used in any degree of renal impairment if used according to product labeling • Fit in any renal scenario • Safety similar to placebo • Less glycemic fluctuation
- 70. In CKD with diabetes “after utilizing nephroprotective SGLT2i” there is no treatment of choice, rather there is choice of treatment
- 71. Thank you
Editor's Notes
- Evidence that intensive glycemic control reduces the kidney complications of diabetes is based almost exclusively on prevention of micro- and macro-albuminuria.
- The risk for hypoglycemia may increase as CKD progresses. Circulating levels of insulin are higher due to reduced catabolism by the kidneys. Insulin prescription may be reduced. Oral medications may change. Discuss importance of notifying healthcare team of any increase in hypoglycemia with the patient.
- In a double-blind, randomized, parallel-group, 52-week clinical trial with 369 patient of T2DM and moderate or severe Renal impairment for comparing safety and efficacy of vildagliptin (50mg qd, n= 216) and placebo (n= 153) when added to ongoing stable antihyperglycaemic treatment, Kothny et al demonstrated that vildagliptin in addition to on going antihyperglycemic therapy had a safety profile similar to placebo during 1-year observation with a clinically significant and consistent decrease in A1C throughout 1-year with vildagliptin treatment.
- In summary, this is the largest long-term experience with a DPP-4 inhibitor reported thus far in patients with T2DM and moderate or severe RI. Treatment with vildagliptin (50 mg qd) added to ongoing antidiabetic therapy was well tolerated, with a safety profile comparable to placebo. Key findings for the clinician are that the robust improvements in glycaemic control seen after 24 weeks were maintained at 52 weeks, with A1C reductions of ∼0.6% (from a baseline of 7.8% in moderate RI and ∼0.8% (from a baseline 7.8% in severe RI), and that the long-term safety data continue to support vildagliptin safety in this vulnerable patient population, with no new safety signals identified.
- The effect of vildagliptin in T2DM patients with ESRD on hemodialysis has been directly assessed in a 24-week, prospective, open-label, controlled study. Vildagliptin, given to 30 patients at 50–100 mg/day, decreased HbA1c levels from 6.7% to 6.1%. Consensually, postprandial plasma glucose decreased from 186 to 140 mg/dL in the absence of serious AEs such as severe hypoglycemia or liver impairment. Although long-term follow-up of these patients is necessary to confirm this efficacy, vildagliptin could be considered as an alternative to insulin in patients on hemodialysis. Long-term observation is also advisable with respect to safety. Very recently, two cases of pancreatitis associated with incretin-based therapies in ESRD patients undergoing dialysis have been reported: a 75-year-old woman with a history of liraglutide use and a 68-year-old man on vildagliptin.36 Whether, ESRD may represent a condition at high risk for pancreatitis remains to be elucidated.
- New-onset diabetes after transplantation (NODAT) is a serious complication after kidney transplantation, but therapeutic strategies remain underexplored. Dipeptidyl peptidase-4 (DPP-4) inhibitors selectively foster insulin secretion without inducing hypoglycemia, which might be advantageous in kidney transplant recipients (KTRs) with NODAT. We conducted a randomized, double-blind, placebo-controlled, phase II trial to assess safety and efficacy of the DPP-4 inhibitor vildagliptin. Intraindividual differences in oral glucose tolerance test (OGTT)-derived 2-h plasma glucose (2HPG) from baseline to 3 months after treatment served as primary endpoint. Among secondary outcomes, we evaluated HbA1c, metabolic and safety parameters, as well as OGTTs at 1 month after drug discontinuation. Of 509 stable KTRs who were screened in our outpatient clinic, 63 (12.4%) had 2HPG 200 mg/dL, 33 of them were randomized and 32 completed the study. In the vildagliptin group 2HPG and HbA1c were profoundly reduced in comparison to placebo (vildagliptin: 2HPG ¼ 182.7 mg/dL, HbA1c ¼ 6.1%; placebo: 2HPG ¼ 231.2 mg/dL, HbA1c ¼ 6.5%; both p 0.05), and statistical significance was achieved for the primary endpoint (vildagliptin: 2HPG-difference 73.7 51.3 mg/dL; placebo: 5.7 41.4 mg/dL; p < 0.01). Adverse events were generally mild and occurred at similar rates in both groups. In conclusion, DPP-4 inhibition in KTRs with overt NODAT was safe and efficient, providing a novel treatment alternative for this specific form of diabetes.
- We were able to demonstrate that the DPP-4 inhibitor vildagliptin was highly efficient in achieving adequate glycemic control after short-term treatment. Furthermore, vildagliptin was expectably safe regarding hypoglycemic episodes. Adverse events were mild and appeared at similar rates in both study arms. Thus, vildagliptin proved to be a safe and efficient treatment option against NODAT in KTRs, and provides a suitable alternative for this specific form of diabetes.
- Although similar in DPP-4 inhibition, the differences in pharmacokinetic profiles may induce a different activity over a daily period: Plasma DPP-4 activity is inhibited by almost 100% already at 15–30 min, and 80% inhibition lasts for almost 14 h after a single dose of sitagliptin at 100 mg Vildagliptin at 50 mg bid inhibits DPP- 4 activity by almost 97% over a 24 hrs period
- Plasma DPP-4 activity is inhibited by almost 100% already at 15–30 min, and 80% inhibition lasts for almost 14 h after a single dose of sitagliptin at 100 mg Vildagliptin at 50 mg bid inhibits DPP- 4 activity by almost 97% over a 24 hrs period
- This data suggests that the DPP-4 inhibition therapy should target not only reducing HbA1c, PPG, and mean hyperglycemia but also flattening acute glucose fluctuations over a daily period
- When administered according to the product labelling, vildagliptin is an effective and well tolerated therapy choice for individuals with type 2 diabetes mellitus, including those with any degree of renal impairment. Patients with advanced type 2 diabetes and poor renal function who require insulin therapy and present a severe therapeutic challenge in clinical practice may benefit from vildagliptin. From my opinion, in CKD with diabetes “after utilizing nephroprotective SGLT2i” there is no treatment of choice, rather there is choice of treatment