2. CASE 1
Patient Raj, aged 63 years retired from corporate consulting firm visits his primary care physician with
complaints of increased fatigue, frequent urination, and unexplained weight loss over the past few weeks
and also 2 episodes oh hypoglycemia.
He was K/C/O of
Diabetes since 11 years
Hypertension since 6 years
Dyslipidemia since 3 years
He also mentions that his diabetes management has become more challenging recently, even though he
has been following his prescribed diet and exercise regimen.
3. CASE STUDY
63 M - DM2 x 11 yrs, HT x 6 yrs, Dyslipidemia x 3 yrs
• Strong family history of Diabetes – Mother had been diagnosed with CKD
• Examination-
• Obese, Ht 158, Wt. 93.5 Kg, BMI 37.5 kg/m2, Vitals - BP 140/90 mmHg
• Systemic Exam - NAD
• Poor compliance - Morning walk x 30 min - General weakness
• FPG:190 mg/dL
• HbA1c: 9.2% with few recent 2 episodes of hypoglycemia
• Occasional Drinking of alcohol and smoking 4 cigarette/day
4. LAB INVESTIGATIONS -1 YEAR BACK
FPG 124 mg/dL , PPG 183 mg/dL, HbA1c 7.8%, Urine R/M: N
TC 185mg/dL, LDL: 101 mg/dL , TG: 180 mg/dL, HDL: 38 mg/dL
B. urea 24 mg/dL, S. creatinine 0.9, UACR: 345 mg/g, eGFR 65mL/min/1.73m2
• LFT - N
• Chest X-ray - NAD , USG Abdomen - Normal
• ECG - WNL
5. ON-GOING TREATMENT
Metformin 1000 mg/d - Glimepiride 2 mg OD
Rosuva 10 mg OD + Aspirin 75 mg
Telmi 40 + HCT 12.5mg OD
5
6. LAB INVESTIGATIONS - PRESENT
FPG 145 mg/dL , PPG 233 mg/dL, HbA1c 8.4%, Urine R/M: N
TC 215, LDL: 127 , TG: 180, HDL: 42
B. urea 24.5, S. creatinine 1.0, UACR: 435 mg/g, eGFR 58
• LFT - N
• Chest X-ray - NAD , USG Abdomen - Normal
• ECG - sinus tachycardia
9. TREATMENT OPTIONS
Met 1000 + Glim 2 mg OD
Telmi + Amlo or ( CTZ less effective eGFR < 50 - substitute Furosemide )
Next ADD on
1. DPP-4 inhibitors
2. Voglibose
3. SGLT2-I
4. GLP1-Analog/Insulin
• Why glycemic control is
necessary in this patient?
• Is there any benefit of modern
DPP-4 inhibitors in this
patient?
10. WHAT IS DKD?
Reference: Kidney International Supplements, 2013; 3(1): 5-14
Slide 9 of 53
Kidney function
• Glomerular filtration rate (GFR) <
60 mL/min/1.73 m2 for > 3
months with or without kidney
damage
Kidney damage
• > 3 months, with or without decreased GFR,
manifested by either
• Pathological abnormalities
• Markers of kidney damage, i.e.,
proteinuria (albuminuria)
• Urine albumin-to-creatinine ratio
(UACR) > 30 mg/g
DKD
AND/ OR
11. Diabetes found to be a common cause of hemodialysis
among 15 dialysis units in North and South Kerala.
Kidney International Reports (2019)4,390–398.
Bradshaw, Christina, et al. "Paying for hemodialysis in Kerala, India: a description of household financial hardship in the context of
medical subsidy." Kidney international reports 4.3 (2019): 390-398.
DIABETES MELLITUS – A LEADING CAUSE FOR NEPHROPATHY
12. • In patients with type 2 diabetes the risk of diabetic
complications was strongly associated with previous
hyperglycaemia.
• Any reduction in HbA1c is likely to reduce the risk of
complications, with the lowest risk being in those with
HbA1c values in the normal range ( < 6.0%).
Hazard ratios, with 95% confidence intervals as floating
absolute risks, as estimate of association between
category of updated mean haemoglobin A1c
concentration
Each 1% reduction in updated mean HbA1c was
associated with reductions in risk of 37% for microvascular
complications (33% to 41%, P < 0.0001)
Stratton IM, BMJ. 2000 Aug 12;321(7258):405-12. doi: 10.1136/bmj.321.7258.405. PMID: 10938048; PMCID: PMC27454.
RELATION OF MICROVASCULAR DISEASE AND HBA1C
13. IMPORTANCE OF EARLY AND INTENSIVE CONTROL OF
HYPERGLYCEMIA
Greater reduction in albuminuria
occurred over time, therefore
early and intensive control of
hyperglycemia is important
UKPDS: Prevention of microalbuminuria with glycemic control over
time
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes
Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837-53. Erratum in: Lancet 1999 Aug 14;354(9178):602. PMID: 9742976.
CI: Confidence Interval; RR: Relative Risk
Microalbuminuria defined as urine albumin
>50mg/L
14. RISK FACTORS FOR DKD –
RESULTS FROM THE SEEK STUDY
(SCREENING AND EARLY EVALUATION OF KIDNEY DISEASE)
1. Singh, A.K.,. BMC Nephrol 14, 114 (2013). https://doi.org/10.1186/1471-2369-14-114
2. Clinical Kidney Journal, Volume 15, Issue 1, January 2022, Pages 60–69, https://doi.org/10.1093/ckj/sfab149
• Chronic kidney disease (CKD) is emerging
to be an important chronic disease
globally. 1
• One reason is the rapidly increasing
worldwide incidence of diabetes and
hypertension. 1
• Between 1990 and 2017, the global all-age
prevalence and mortality from CKD
increased by 29.3 and 41.5%, respectively 2
CKD: Chronic kidney disease
15. PREVALENCE OF UNDERLINE CAUSES OF CKD IN INDIA
Kumar V., et al. Clin Kidney J 2021 Aug 13;15(1):60-9
16. Oshima, M et al. Nat Rev Nephrol 17, 740–750 (2021)
TRAJECTORIES OF KIDNEY FUNCTION IN DKD
18. RISK OF GENITAL INFECTIONS WITH SGLT- 2 INHIB-ITORS
Limiting follow-up to less than 1 year after cohort entry:
• SGLT-2 inhibitors associated with higher risk of genital infections compared to DPP-4 inhibitors (HR: 3.77,
95% CI: 3.03–4.70).
• Use of SGLT-2 inhibitors linked to significantly increased risk of UTIs compared to DPP-4 inhibitors (HR: 2.64,
95% CI: 2.21–3.14).
• Similar patterns observed with other comparators (SU and TZD).
High-risk age group defined as "age >60 years":
• SGLT-2 inhibitors associated with significantly increased risk of genital infections compared to DPP-4
inhibitors (HR: 4.20, 95% CI: 2.63–6.71), SU (HR: 4.27, 95% CI: 2.70–6.75), and TZD (HR: 4.11, 95% CI: 2.25–
7.50).
• Risk of UTIs higher than DPP-4 inhibitors (HR: 1.82, 95% CI: 1.32–2.52), SU (HR: 1.72, 95% CI: 1.27–2.34), and
TZD (HR: 1.50, 95% CI: 1.03–2.18).
Pharmacol Res Perspect. 2022;10:e00910.
20. Forst T, et al. Diabetes Obes Metab. 2011;13: 542–550
Source: Adapted from Heise et al., Diabetes Obes Metab. 2009;11(8):786–94
1
21
41
61
81
101
0 4 8 12 16 20 24
Time (h)
% DPP-4 Inhibition
5 mg tablet, in type 2 diabetes patients
LINAGLIPTIN PROVIDES LONG-LASTING DPP-4 INHIBITION
IN PATIENTS WITH T2DM
Linagliptin
Peak in 1.5
hours
> 91% DPP-4 inhibition achieved
Steady state Achieved by 3rd dose
Linagliptin
trough
6-8 nmol/L, resulting in >80% DPP-4
inhibition over 24 hours
GLP rise 3.2 fold rise in post-prandial active GLP-1 levels
21. RISK OF HEART FAILURE HOSPITALISATION IN CVOT
CVOTs with DPP-4 inhibitors (saxagliptin, alogliptin, sitagliptin, and linagliptin) have
demonstrated non-inferiority to placebo in respect to primary 3-point MACE, but they have not
shown superiority.
Seferović, Petar M., et al. "European Society of Cardiology/Heart Failure Association position paper on the role and safety of new glucose‐lowering drugs in patients
with heart failure." European journal of heart failure 22.2 (2020): 196-213.
22. SUMMARY OF CLINICAL TRIAL RESULTS WITH DPP-4 INHIBITORS IN
PATIENTS WITH TYPE 2 DIABETES MELLITUS
Seferović, Petar M., et al. "European Society of Cardiology/Heart Failure Association position paper on the role and safety of new glucose‐lowering drugs in patients
with heart failure." European journal of heart failure 22.2 (2020): 196-213.
23. DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS:
DOSING, DOSE ADJUSTMENT AND PRECAUTIONS IN CKD
Seferović, Petar M., et al. "European Society of Cardiology/Heart Failure Association position paper on the role and safety of new glucose‐lowering drugs in patients
with heart failure." European journal of heart failure 22.2 (2020): 196-213.
24. EFFECTS OF LINAGLIPTIN ON RENAL ENDOTHELIAL FUNCTION IN
PATIENTS WITH TYPE 2 DIABETES: A RANDOMIZED CLINICAL TRIAL
Baseline and 4 weeks of placebo treatment resulted in
• Significant increase in UACR in response to L-NMMA (a
drug affecting NO activity).
The increase in UACR response was even more
pronounced after 4 weeks of placebo treatment compared
to baseline,
• Suggesting an upregulation of NO activity in the
placebo group.
In contrast, the linagliptin group showed
• No change in UACR response to L-NMMA
• Indicating that linagliptin treatment did not impact NO
activity in this aspect (p=0.276).
UACR: urinary albumin-to-creatinine ratio
NO: Nitric oxide
L-NMMA: NG-monomethylL-arginine
Change in RPF in response to L-NMMA after 4 weeks of treatment with
placebo or linagliptin. Data are shown as mean ± SD; *p < 0.05
Diabetologia (2016) 59:2579–2587
25. EFFECTS OF LINAGLIPTIN ON RENAL ENDOTHELIAL FUNCTION IN
PATIENTS WITH TYPE 2 DIABETES: A RANDOMIZED CLINICAL TRIAL
After 4 weeks of treatment with linagliptin compared to
placebo,
• Change in RPF due to L-NMMA (a drug inhibiting NO
production) was smaller
• Indicating lower basal NO activity with linagliptin.
Regardless of whether expressed in absolute values
(p=0.045) or percentage values (p=0.046),
• Reduction in RPF was observed with linagliptin.
When baseline was compared with treatment groups,
• Change in RPF due to L-NMMA was greater after
placebo (p=0.058)
• But unchanged after linagliptin treatment (p=0.823).
• However, this difference was not statistically
significant.
Diabetologia (2016) 59:2579–2587
Change in UACR in response to L-NMMA at baseline and after placebo
or linagliptin treatment. Data are shown as median, interquartile
range and outliers (open circles)
26. Date of Download: 8/2/2023
1. Diabetes Care. 2020;43(11):2889-2893. doi:10.2337/dc20-
0902
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
27. EFFECT OF LINAGLIPTIN ON RENAL PROGRESSION IN TYPE-2 DIABETES
MELLITUS PATIENTS WITH CHRONIC KIDNEY DISEASE: A PROSPECTIVE
RANDOMIZED CONTROLLED STUDY
Yagoglu AI et al. Nefrologia (Engl Ed). 2020 Nov-Dec;40(6):664-671.
HbA1C changes of patients during 12
month follow up
eGFR significantly increased in linagliptin group (p = 0.033), but decreased in
other group (p = 0.003).
No significant change was observed in total insulin dose in linagliptin group
(p = 0.111), but in other group, total insulin dose significantly increased (p <
0.001).
Proteinuria levels decreased in both groups, but there was no significant
change.
• Stage 3–4 CKD patients were randomized into 2 groups
• First group, linagliptin 5mg was added in addition to the background
insulin therapy.
• Second group, patients continued their insulin therapy.
• Patients were followed up at 3-month intervals for one year
28. 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)
29. 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*
Hypothetical Case: Patient with Type 2 Diabetes Mellitus and Decreasing eGFR
Patient Information: Name: Raj Age: 58 years Gender: Male Medical History: Type 2 Diabetes Mellitus (diagnosed 10 years ago) Current eGFR: 50 mL/min/1.73m² (decreasing from 60 mL/min/1.73m² six months ago)
Presenting Complaint: John Smith visits his primary care physician with complaints of increased fatigue, frequent urination, and unexplained weight loss over the past few weeks. He also mentions that his diabetes management has become more challenging recently, even though he has been following his prescribed diet and exercise regimen.
Medical Examination Findings: Upon examination, the physician observes that John's blood pressure is slightly elevated (140/90 mmHg), and his body mass index (BMI) is 29 (indicating overweight). Laboratory tests reveal the following results:
Fasting Blood Glucose: 190 mg/dL (elevated)
HbA1c: 9.2% (elevated, indicating poor long-term glucose control)
Serum Creatinine: 1.5 mg/dL (elevated)
eGFR (estimated Glomerular Filtration Rate): 50 mL/min/1.73m² (decreasing from 60 mL/min/1.73m² six months ago)
Diagnosis and Management Plan: Based on John's medical history, clinical presentation, and laboratory results, the primary care physician diagnoses him with uncontrolled Type 2 Diabetes Mellitus and declining kidney function (decreasing eGFR). The declining eGFR suggests that John is experiencing diabetic kidney disease (DKD), which is a common complication of poorly managed diabetes.
To manage John's diabetes and preserve his kidney function, the physician formulates a comprehensive management plan:
Lifestyle Modifications:
The physician advises John to adhere strictly to a diabetic-friendly diet, which focuses on balanced meals, reduced carbohydrate intake, and increased consumption of vegetables and lean proteins.
John is encouraged to engage in regular physical activity, such as brisk walking or swimming, to improve his glucose control and overall health.
Weight management is emphasized, and John is counseled on achieving gradual weight loss to lower insulin resistance and improve blood glucose levels.
Medication Adjustment:
The physician reviews John's current diabetes medication regimen, which includes metformin and a sulfonylurea. Due to declining kidney function, the physician decides to discontinue the sulfonylurea, as it may pose a risk of hypoglycemia in patients with compromised kidney function.
Instead, the physician initiates a new medication called Linagliptin, a Dipeptidyl Peptidase-4 (DPP-4) inhibitor, which is known for its safety and efficacy in patients with reduced kidney function.
How Linagliptin Helps in the Management of Diabetes and DKD: Linagliptin is an oral antidiabetic medication that works by inhibiting the DPP-4 enzyme. By doing so, it increases the levels of active incretin hormones (GLP-1 and GIP), which stimulate insulin secretion and suppress glucagon release from the pancreas. The following are the benefits of Linagliptin in the management of diabetes and DKD:
Kidney Safety: Linagliptin is primarily eliminated through the liver, not the kidneys. This characteristic makes it a favorable choice for patients with declining eGFR, as it does not place additional stress on the kidneys or require dosage adjustments based on kidney function.
Glucose Control: Linagliptin helps improve glycemic control by reducing fasting and post-meal blood glucose levels. This can lead to better HbA1c levels, as seen in John's case, and lower the risk of diabetes-related complications.
Cardiovascular Benefits: Studies have shown that Linagliptin has neutral effects on cardiovascular outcomes, making it a suitable option for patients with diabetes who may also have cardiovascular comorbidities.
Weight-Neutral: Linagliptin is considered weight-neutral, which means it does not cause significant weight gain, making it an appropriate choice for patients like John who are already overweight.
Combination Therapy: Linagliptin can be used as a monotherapy or in combination with other antidiabetic medications, making it versatile in individualized treatment plans.
The primary care physician educates John about the importance of adherence to his new medication and lifestyle modifications. Regular follow-ups are scheduled to monitor his progress, adjust medications if necessary, and closely monitor kidney function, blood pressure, and blood glucose levels.
Please note that this is a hypothetical case, and any actual medical condition should be diagnosed and managed by a qualified healthcare professional based on a thorough assessment of the patient's individual medical history and condition.
