Linagliptin Endocrinologist Prespective - Case.pptx

Chronic Kidney Disease with Type 2 Diabetes Mellitus

CASE 1
• Patient Sawami, aged 63 years retired from government office working in firm
visits his primary care physician with complaints of increased fatigue, also 2
episodes oh hypoglycemia.
• He was K/C/O of
• Diabetes since 11 years
• Hypertension since 6.5 years

Patient Profile
• 60 F - DM2 x 11 yrs, HT x 6.5 yrs
• Strong family history of Diabetes - Brother, Mother died of CKD
• Examination- Obese, BMI 30 kg/m2
• BP 134/86 mmHg
• Systemic Exam - NAD
• Poor compliance - Morning walk x 30 min - General weakness
• SMBG - FPG 160 -175 mg/dl, PPG 235-250 mg/dl
• Patient has reported mild hypoglycemia

Current Treatment
• Metformin 1500 mg/d
• Glimepiride 2 mg OD
• Sitagliptin 100 mg OD
• Aspirin 75 mg
• Telmisartan 40 + Amlodipine 5mg OD

Laboratory Investigations
• FPG 175 mg/dl , PPG 150 mg/dl, HbA1c 9.0%, Urine R/M: N
• TC 185 mg/dl, LDL: 112 mg/dl, TG: 140, HDL: 72 mg/dl
• B. Urea 24.5, UACR: 435 mg/g, eGFR: 51 mL/min/1.73m2
• Serum albumin 3.3 g/dl
• LFT - Normal
• Chest X-ray - NAD , USG Abdomen - Normal
• ECG - Sinus Tachycardia

Diagnosis
Uncontrolled Type 2 Diabetes with high Risk of ASCVD and
Declining Renal Function

Overview of DPP-4 inhibitors
• Novel Approach to T2DM Treatment:
• Incretin effect is a novel line of treatment for T2DM.
• DPP-4 inhibitors are gaining attention for complementing and extending traditional therapeutic avenues.
• Therapeutic Benefits of DPP-4 Inhibitors:
• Improve T2DM by delaying gastric emptying, reducing postprandial glucose levels, and inhibiting glucagon
secretion.
• Efficiently used in combination therapy.
• Address medical needs in metabolic disorders, especially in elderly diabetic patients or those with obesity and
T2DM.
• Potential for Pancreatic β Cell Function:
• Evidence suggests a potential reversal of pancreatic β cell dysfunction.
• Antiapoptotic and proliferative characteristics of DPP-4 inhibitors may contribute to the regeneration of
pancreatic β cells.
• Safety Profile Concerns:
• Questions raised about safety, particularly in pancreatitis and pancreatic cancer areas.
• Limited evidence available; caution advised, and further research needed.
Saini K, Sharma S and Khan Y (2023), DPP4 inhibitors for treating T2DM - hype or hope? an analysis based on the current literature. Front. Mol. Biosci. 10:1130625. doi: 10.3389/fmolb.2023.1130625

Overview of DPP-4 inhibitors
• Cardiovascular and Renal Outcomes:
• Disappointing outcomes in terms of cardiovascular and renal benefits compared to SGLT-2 inhibitors or GLP-1
receptor agonists.
• Ongoing Research and Development:
• Ongoing development of new DPP-4 inhibitor candidates globally, many in clinical trials.
• Demonstrates the importance of targeting incretin effect and DPP-4 as a drug target for T2DM therapy.
• Ideal Treatment Option for Diabetes:
• Best treatment option should control blood sugar levels and manage overall risk factors.
• DPP-4 inhibitors considered excellent candidates due to:
• No hypoglycemia or weight gain.
• No requirement for dose escalation.
• Favorable anti-inflammatory and safety profiles.
• Relatively safer for elderly diabetic patients and those with kidney disease.
• Extensive usage and experience support their efficacy.
• Justification of Hype Surrounding DPP-4 Inhibitors:
• All the hype surrounding DPP-4 inhibitors is well justified based on their safety profile, efficacy, and suitability
for various patient groups.

Renal dosing of dipeptidyl peptidase 4
inhibitors
Florentin M, Kostapanos MS, Papazafiropoulou AK. Role of dipeptidyl peptidase 4 inhibitors in the new era of antidiabetic treatment. World J Diabetes. 2022 Feb 15;13(2):85-96. doi: 10.4239/wjd.v13.i2.85. PMID:
35211246; PMCID: PMC8855136.

Modification of dosing for dipeptidyl
peptidase 4 inhibitors in hepatic impairment
35211246; PMCID: PMC8855136.

Improvement of Microalbuminuria by Linagliptin (UACR<30 mg/dl)
% of improvement in microalbuminuria (UACR<30
mg/g) in Linagliptin group was significantly higher
than that of the control group during 24 weeks of
intervention
• A double-blind randomized placebo-controlled
(n=92)
• Linagliptin 5 mg OD for 24 weeks
Karimifar M et al. Sci Rep. 2023 Mar 1;13(1):3479.

Efficacy of Linagliptin in Patients with T2DM and Renal Dysfunction
MARLINA-T2D Trial
• a 24-week, randomized, double-blind,
placebo-controlled, phase 3b clinical trial
• n=360 for 24 weeks
Conclusion: The MARLINA-T2D study found that Linagliptin improved glycaemic control in
individuals with type 2 diabetes and early stages of diabetic kidney disease
Groop PH et al. Diabetes Obes Metab. 2017 Nov;19(11):1610-1619.

Oxidative Stress and
Diabetic Kidney Disease
Oxidative stress is linked with metabolic changes and
alterations in renal haemodynamics.
Nina Vodošek Hojs et al. Antioxidants 2020, 9(10), 925

Effect of Linagliptin on Oxidative Stress Markers in T2DM
 A single-center single-arm interventional study (n=30)
 Linagliptin 5 mg for 3 Months
 Following linagliptin treatment,
• Serum MDA-LDL
• Serum HbA1c
• Urinary L-FABP levels significantly decreased
 Urinary 8-OHdG tended to decrease
Hisashi Makino et al. Diabetology International (2019) 10:148–152

Date of Download: 8/2/2023
1. Diabetes Care. 2020;43(11):2889-2893. doi:10.2337/dc20-0902
2. Diabetologia (2016) 59:2579–2587
Renal hemodynamic and tubular effects of linagliptin and glimepiride after 8 weeks of
treatment. Mean ± SEM (A–C and F), median [IQR] (D and E), and baseline-corrected mean
difference (95% CI). Multivariable linear regression models were used to examine baseline-
corrected linagliptin-induced effects compared with glimepiride. Paired t tests (A–C and F) or
Wilcoxon signed rank tests (D and E) were used for within-group comparisons. Significant
differences are indicated in boldface type. PAH, para-aminohippuric acid; Wk, week.
Compared to Glimepiride,
• Linagliptin had no significant impact on fasting GFR
and ERPF. 1
Compare to Glimepiride, Linagliptin tended to
• Reduce UACR by 26% from baseline
• No between-group differences were observed.1
This neutral effect of Linagliptin on
• GFR and ERPF is consistent with previous placebo-
controlled trials involving T2DM patients without
renal impairment. 2
Effects of DPP-4 Inhibitor Linagliptin Versus Sulfonylurea Glimepiride as Add-on to
Metformin on Renal Physiology in Overweight Patients With Type 2 Diabetes (RENALIS):
A Randomized, Double-Blind Trial
GFR: Glomerular Filtration Rate
ERPF: Effective Renal Plasma Flow
UACR: urinary albumin-to-creatinine ratio

Effects of Linagliptin on Cardiovascular and Kidney
Outcomes in People With Normal and Reduced
Kidney Function: Secondary Analysis of the
CARMELINA Trial
Linagliptin vs. placebo effect on 3P-MACE (major
adverse cardiovascular events): No significant
difference (HR 1.02 [95% CI 0.89, 1.17])
Linagliptin vs. placebo effect on secondary
kidney outcome: No significant difference (HR
1.04 [95% CI 0.89, 1.22])
Albuminuria progression reduced with
linagliptin regardless of eGFR
HbA1c levels decreased with linagliptin without
increasing hypoglycemia risk
Adverse events (AEs) balanced among groups overall
and across eGFR categories
Diabetes Care 2020;43(8):1803–1812
Study population:
• 6,979 subjects, mean age 65.9 years
• eGFR 54.6 mL/min/1.73 m², 80.1% with albuminuria
• Follow-up duration: 2.2 years
Overall effects on eGFR (MDRD) slope from baseline to last value on treatment and by
eGFR category G ≤ 2 to ≥ G4 for linagliptin (Lina) vs. placebo (pbo)

2 year study: Linagliptin was non-inferior to
glimepiride in treatment effect1
Rate of patients achieving HbA1c
target <7%
75.6 76.4
0
20
40
60
80
100
Linagliptin Glimepiride
0.5
0
-0.5
-1.0
-1.5
Adjusted
mean change
in HbA1c (%)
from baseline
at week 104
n
Mean baseline
HbA1c, percent
-0.60 -0.60
7.7
7.7
Rate of patients achieving HbA1c
target <7%
271 233
Gallwitz B., et al. ADA 2011 Late Breaker 39-LB
Linagliptin vs glimepiride2 p <0.0001*

Why substituted Glimepiride with Gliclazide in
addition to Linagliptin?
Is there any benefits with Gliclazide
Linagliptin !!!

Effectiveness and safety of Gliclazide and
Linagliptin switched from Glimepiride
J Endocr Soc. 2021 May 3; 5(Suppl 1): A407–A408.

T2DM patients with stage 1–3 CKD
Mean eGFR: 50.4 ± 8.56 ml/min/1.73 m2
Inadequately controlled with glimepiride (mean dose 3.24mg) for the last 3 months
Objective:
• To assess the efficacy and safety of
• Switching from glimepiride to Gliclazide MR in combination with linagliptin, in T2DM patients
with kidney disease
Patient Selection:

Patient Selection and Treatment:
• Switched to gliclazide MR with an appropriate
equivalent dose.
• Gliclazide dose titrated by 30 mg every 15 days
to target PPG ≤180 mg/dL.
• Follow-up for 24 weeks,
• Assessing changes in glycemic control,
hypoglycemia risk, and renal function
parameters.
79%
14%
7%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Linagliptin Sitagliptin Vildagliptin
Continued DPP-4 inihitors therapy (%)

• 218 eligible patients (110 female & 108 male) with CKD (stages 1–3) participated.
• Baseline characteristics:
• Mean age: 62.94 ± 8.72 years
• Body weight: 67.9 ± 9.33 kg
• Baseline HbA1c: 8.51 ± 0.81%
• FPG: 148.53 ± 16.72 mg/dL
• PPG levels: 202 ± 18.45 mg/dL
• Mean eGFR: 50.49 ± 8.56 ml/min/1.73 m2
• UACR: 154.34 mg/g

Results: Switching from glimepiride to
Gliclazide
• Gliclazide MR initiated, replacing glimepiride, with appropriate dosing.
• At 24-week follow-up:
• Significant reductions in HbA1c (-0.63%), FPG (-10.33 mg/dL), and PPG levels (-30.04 mg/dL)
(p< 0.001).
• Notable reduction in overall hypoglycemia events (22.25%).
• Improvements in renal function: eGFR increased by +1.77 ml/min/1.73 m2, and albuminuria
decreased by -45.56 mg/g.

Modified Current Treatment based on eGFR
• Metformin 1000 mg SR + Gliclazide 30 mg XR as FDC OD
• Linagliptin 5 mg OD
• Aspirin 75 mg
• Telmisartan 40
• Clorthalidone 12.5mg OD

Follow-up Results After 3 Months & 6 Months
FPG 145 mg/dl , PPG 130 mg/dl, HbA1c 8.2%, Urine R/M: N
TC 176 mg/dl, LDL: 100 mg/dl, TG: 128, HDL: 80 mg/dl
3 Months
FPG 112 mg/dl , PPG 122 mg/dl, HbA1c 8.0%, Urine R/M: N
UACR: 398, TC 170 mg/dl, LDL: 97 mg/dl, TG: 128, HDL: 82
mg/dl
6 Months

Exploring the Therapeutic
Potential of DPP-4 Inhibitors in
Chronic Kidney Disease

CURRENT USE OF DPP-4 INHIBITORS
• Historical Significance of DPP-4 Inhibitors:
• DPP-4 inhibitors were initially the primary therapeutic choice following metformin initiation.
• Offered improved glycemic control without causing hypoglycemia or weight gain.
• Shift in Therapeutic Landscape:
• Recent years have seen a shift in the management of hyperglycemia.
• Large-scale cardiovascular outcome trials (CVOTs) for newer agents (SGLT2 inhibitors and
GLP-1 receptor agonists) demonstrated significant benefits, influencing the position of DPP-4
inhibitors in treatment algorithms.
• Prescription Trends in Greece (2018):
• DPP-4 inhibitor prescription rate: 43.4%.
• GLP-1 receptor agonist prescription rate: 18.5%.
• SGLT2 inhibitor prescription rate: 16.5%.
35211246; PMCID: PMC8855136.

CURRENT USE OF DPP-4 INHIBITORS
• Evolution Over a Decade (United States, 2006-2008):
• DPP-4 inhibitor usage increased significantly from 0.4% to 7.3%.
• Noteworthy relative change of 0.15% per month.
• Analysis excluded GLP-1 receptor agonists and SGLT2 inhibitors, which were not available
during the study period.
• Trends in Germany (2011-2015):
• Among elderly patients with type 2 diabetes, DPP-4 inhibitor use rose from 13.4% to 19.8%.
• Safety profile highlighted as a preference for elderly patients.
• Challenges and Gaps:
• Lack of evidence regarding prescription trends for DPP-4 inhibitors.
• Significant variations in prescription patterns between countries, reflecting diverse
approaches to screening and managing type 2 diabetes.
35211246; PMCID: PMC8855136.

PLACE OF DPP-4 INHIBITORS IN THE THERAPEUTIC
ALGORITHM OF HYPERGLYCEMIA
• General Characteristics of DPP-4 Inhibitors:
• Clinically meaningful reduction in blood glucose.
• Low risk of hypoglycemia.
• Neutral effect on body weight.
• Favorable safety profile.
• No dose titration required; can be taken at any time of day.
• Non-Glycemic Favorable Effects of DPP-4 Inhibitors:
• Reductions in systolic blood pressure, total cholesterol, and triglycerides.
• Improvement in β-cell function.
35211246; PMCID: PMC8855136.

• Evolution of Treatment Landscape:
• Historically considered a safe choice for antidiabetic therapy after metformin.
• Recent large cardiovascular outcome trials (CVOTs) with GLP-1 receptor agonists (GLP-1 RA)
and SGLT2 inhibitors (SGLT2-i) have altered treatment algorithms.
• Special Considerations for DPP-4 Inhibitors:
• Still relevant for specific patient populations:
• Patients on multiple medications with longstanding DM2 and multiple co-morbidities.
• Those with renal impairment where other options might be contraindicated.
• Frail elderly population due to low hypoglycemia risk.
35211246; PMCID: PMC8855136.

• Renoprotective Effects and Experimental Mechanisms:
• Emerging evidence suggests renoprotective properties.
• Potential mechanisms include modulation of innate immunity, inflammation, oxidative stress,
fibrosis, and cellular apoptosis in the kidney.
• Guideline Recommendations:
• GLP-1 RA or SGLT2-i with proven cardiovascular (CV) safety preferred in DM2 patients with
established atherosclerotic CVD.
• In patients with HF or CKD, SGLT2-i is recommended unless contraindicated; GLP-1 RA is an
alternative based on GFR levels.
35211246; PMCID: PMC8855136.

• Combination Therapies:
• Combination with a DPP-4 inhibitor recommended as a possible third-line therapy.
• Triple therapy of metformin with DPP-4 and SGLT2-i associated with low hypoglycemia risk,
reduced HbA1c, weight loss, and blood pressure reduction.
• Practical Use in Therapy:
• Still reasonable as a second-line add-on therapy to metformin.
• Suitable for individuals at high risk for hypoglycemia, especially the elderly.
• Can be combined with insulin therapy, offering practicality without the need for multiple
injections and frequent glucose self-measurements.
35211246; PMCID: PMC8855136.

GLP-1 Receptor Agonists vs. DPP-4 inhibitors

Advantages of DPP-4 inhibitors in clinical
practice.

Safety profile of DPP-4 inhibitors.

Implementing DPP-4 inhibitors in clinical
practice
• Ease of Use and Lack of Dose Titration:
• DPP-4 inhibitors offer simplicity in clinical practice compared to other oral antidiabetic drugs
(OADs).
• No need for dose titration or adjustment when used with other prescribed medications.
• Monotherapy Potential:
• DPP-4 inhibitors can challenge traditional OADs in monotherapy settings.
• Drug-Drug Interactions:
• Saxagliptin is associated with appreciable drug–drug interactions.
• Sitagliptin and vildagliptin demonstrate minor inclination for drug–drug interactions.
• Relevance in T2DM and Pre-diabetes:
• DPP-4 inhibitors may hold significant relevance in treating T2DM or even pre-diabetes by
supporting the physiological roles of endogenous GLP-1.
• Comprehensive clinical trials are needed to confirm their efficacy in these conditions.

practice
• Clinical Trial Evidence:
• Cochrane review mentions 12 to 52-week evaluations of sitagliptin and vildagliptin, showing
a reduction in HbA1c levels of approximately 0.7% and 0.6%, respectively, compared to
placebo.
• Lipid Profile Effects:
• DPP-4 inhibitors, in a meta-analysis, were slightly more effective in lowering total cholesterol
and triglycerides compared to other anti-hyperglycemic agents.
• Unique Action Pathway:
• DPP-4 inhibitors have a unique action pathway compared to other orally taken glucose-
lowering agents.
• They enhance β-cell proliferation and neogenesis while inhibiting apoptosis.

practice
• Combination Therapies:
• DPP-4 inhibitors show promise in combinations with other glucose-lowering agents.
• Most favored combination is with metformin, resulting in higher GLP-1 concentrations.
• Dual therapy with metformin/DPP-4 inhibitor allows additional treatment intensification with
SGLT-2 inhibitor or TZD.
• Caution in Combination with GLP-1RAs:
• Not advisable to combine GLP-1 receptor agonists (GLP-1RAs) with DPP-4 inhibitors due to
the lack of clinically significant auxiliary benefit.
• Patients unable to tolerate GLP-1RAs are recommended for DPP-4 inhibitor therapy.
• Transition to Injectable Therapy:
• DPP-4 inhibitor therapy should cease when treatment advances to injectable (GLP-1RAs)
therapy at later stages, as advised by the American Diabetes Association.

Standards of Care in
Diabetes—2023

PHARMACOLOGIC APPROACHES TO GLYCEMIC TREATMENT
Pharmacologic Approaches to Glycemic Management:
Standards of Care in Diabetes - 2023. Diabetes Care 2023;46(Suppl. 1):S140-S157

| 42
CARDIOVASCULAR DISEASE AND RISK MANAGEMENT
Cardiovascular Disease and Risk Management:

Facilitating Positive Behaviors and Well-
being to Improve Health Outcomes

 Should engage in 150 min or more of moderate – to vigorous intensity activity
weekly , spread over atleast 3 days / week
 No more than 2 consecutive days without activity
 Resistance training in 2 -3 sessions / week on non consecutive days
 Flexibility training and balance training are recommended 2-3 times / week for older
adult with DM
EXERCISE PLAN
Facilitating Positive Health Behaviors and Well-being to Improve Health Outcomes:

FACILITATING POSITIVE HEALTH BEHAVIORS AND WELL-BEING TO IMPROVE HEALTH
OUTCOMES
Medical Nutrition Therapy (continued)

| 29
 Time restricted eating and intermittent fasting
 Time restricted eating is generally easier to follow compared with alternative day
fasting or the 5:2 plan
 No significant difference in weight loss when compared with contious calorie
restriction
Update 2023

Linagliptin Endocrinologist Prespective - Case.pptx

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