Evaluation Of Renal and Cardiovascular Outcomes with Dapagliflozin Plus Telmisartan in Patients with Diabetic Nephropathy

It is often difficult to document these various stages in a diabetic patient in clinical practice because of confounding factors such as blood pressure medications, as they modify natural course of DN._[1,2]

EPIDEMOLOGY:

About 30-50% of persons with type 2 diabetes have albuminuria, and 20% have reduced kidney function (eGFR < 60 mL/min/1.73 m2). Each year, 2-3% of patients with T1DM and 8% of patients with T2DM have albuminuria, and 2-4% of patients with any kind of diabetes have a lower eGFR._[3]

Epidemiological data show that about 14% of adults in the United States have CKD, and nearly one-third of these individuals also have diabetes. Overall, 30–40% of people with diabetes develop diabetic nephropathy. With the global prevalence of diabetes expected to exceed 783 million by 2045, diabetic kidney disease will remain a major public health challenge and an important cause of morbidity and mortality._[4]

Diabetic kidney disease(DKD) is one of the most common and serious long-term consequences of diabetes mellitus. About 50% of people with type 2 diabetes (T2DM) and one-third of people with type 1 diabetes (T1DM) have it. DKD is a major contributor to chronic kidney disease (CKD) and has a significant effect on illness, medical costs, and mortality. About 30-50% of persons with type 2 diabetes have albuminuria and 20% have reduced kidney function (eEach

ETIOLOGY:

• Long-standing hyperglycaemia
• Thickening of the glomerular basement membrane
• Macrophage infiltration
• Endothelial cell injury
• Podocyte damage
• Polyol pathway:
• Genetic susceptibility _[4]

PATHOGENESIS:

The pathogenesis of DN entails a multifaceted interplay of factors, encompassing alterations in glomerular function, hormonal influences, and protein glycosylation. Elevated blood glucose levels induce the glycosylation of glomerular proteins, fostering mesangial cell proliferation, matrix expansion, and vascular endothelial impairment. Disease progression is marked by mesangial expansion, thickening of the glomerular basement membrane, and the emergence of characteristic lesions such as Kimmelstiel-Wilson nodules. Furthermore, renal vasodilation, heightened GFR, and elevated blood pressure are hallmark features of DN. While precise etiology remains incompletely understood, the pathogenesis is implicated in hyperglycaemia-induced renal injury, advanced glycation products, and cytokine activation. DN represents a primary cause of chronic kidney disease (CKD) in Western societies and a significant complication of diabetes, impacting up to 50% of individuals with longstanding diabetes._[5]

SYMPTOMS:

For the early diabetic nephropathy condition, there are no symptoms. When the kidney functioning gets worsen then the symptoms are:

• Swelling of the hands, feet, and face
• Trouble in sleeping or concentrating
• Poor appetite
• Nausea
• Weakness
• Dry skin and Itching (end-stage kidney disease)
• Drowsiness (end-stage kidney disease)
• Abnormalities in the heart's regular rhythm (because of increased potassium in the blood )
• Muscle twitching._[6]

RISK FACTORS:

• High blood sugar (hyperglycaemia).
• High blood pressure (hypertension).
• Smoking.
• High blood cholesterol.
• Obesity.
• Family history of diabetes and kidney disease. [7_]

COMPLICATIONS:

• Fluid buildup in the body which leads to the swelling of the arms and legs, high blood pressure or fluid in the lungs (Pulmonary oedema).
• Rise or increase of the potassium mineral levels in blood (Hyperkalaemia).
• Heart and blood vessel disease (Cardiovascular disease) which can lead to stroke.
• Decrease in RBC to carry oxygen (Anaemia).
• Pregnancy complications that may cause risk for the mother and foetus.
• Permanent damage to the kidneys (end stage kidney disease), for this the treatment is either dialysis or kidney transplant._[8]

PREVENTION:

• Regular managing of the diabetes, by taking the appointments.
• The whole body checkup should be done every 6 months or yearly.
• Treating the diabetes by keeping the target range of blood sugar levels as much as possible, this helps in preventing or slowing the diabetic nephropathy.
• Managing the high blood pressure or other medical conditions, as it raises the risk of kidney disease.
• If the OTC medications like pain relievers that include aspirin and NSAIDs, such as Naproxen sodium (Aleve) and Ibuprofen (Advil, Mortin IB, etc) are taken, then can lead to the kidney damage.
• Maintaining the healthy body weight by consulting the qualified physician.
• Quit Cigarette smoking and alcohol intake, these can cause kidney damage or worsen the condition of the kidneys.

DIAGNOSIS:

1. Physical examination: Clinical signs and symptoms, general examination like vitals, pedal oedema or fluid retention, any skin infections or changes.
2. Laboratory investigations: Renal function tests, Complete blood picture.
3. Urine Albumin-Creatinine Ratio (UACR): Checks for albumin in urine, an early sign of damage.
4. Estimated Glomerular Filtration Ratio (eGFR): Calculates kidney filtering ability using serum creatinine.
5. Serum Creatinine: Measures waste product filtered by kidney.
6. Blood Urea Nitrogen (BUN): Measures the urea nitrogen in blood.
7. Electrolytes: Sodium, chloride, potassium, bicarbonates.
8. Renal Biopsy: A tissue sample examined for detailed damage, used when alternative diagnosis is suspected.
9. Imaging (Ultrasound, CT, MRI): Shows the size, shape, blockage or blood flow issues in the kidney._[9]

TREATMENT:

NON-PHARMACOLOGICAL TREATMENT:

Dietary modification – Low sodium intake, controlled protein diet, and low glycaemic index foods help reduce albuminuria and slow disease progression.

Regular physical activity – Aerobic and resistance exercises improve insulin sensitivity and may delay progression of diabetic nephropathy.

Weight management – Lifestyle-based weight reduction improves metabolic control and reduces renal hyperfiltration.

Lifestyle blood pressure control – Salt restriction, exercise, and stress reduction help prevent worsening of renal damage.

Smoking cessation – Avoidance of tobacco slows progression of kidney disease and reduces cardiovascular risk.

Patient education and self-management – Diabetes education and lifestyle counselling improve adherence and long-term renal outcomes.

PHARMACOLOGICAL TREATMENT:

ABOUT DRUG:

DAPAGLIFLOZIN + TELMISARTAN

INTRODUCTION:

Dapagliflozin is an SGLT2 inhibitor that lowers blood sugar by encouraging the excretion of glucose in the urine. It also has other advantages like helping people lose weight and protecting their hearts. Angiotensin II receptor blockers (ARBs) like telmisartan help protect the kidneys and heart while also successfully regulating blood pressure.

For the treatment of patients with type 2 diabetes mellitus (T2DM) and concurrent hypertension, the fixed-dose combination of dapagliflozin and telmisartan is a sensible therapeutic approach. The high cardiovascular and renal risk burden linked to type 2 diabetes is addressed by this combination which permits efficient control of hyperglycaemia and hypertension while providing organ protection.

MOLECULAR STRUCTURE:

MOLECULAR FORMULAE:

Dapagliflozin: C₂₁H₂₅ClO₆
Telmisartan: C₃₃H₃₀N₄O₂

BRAND NAME:

• DAPA-T
• DAPTEL
• DAPTEL-T

CATEGORY:

• Dapagliflozin – Sodium Glucose Cotransporter 2 (SGLT2) inhibitor.
• Telmisartan – Angiotensin II Receptor Blockers (ARBs)

DOSAGE:

• Dosage of Dapagliflozin + Telmisartan (Combination Therapy)

• Dapagliflozin: 10 mg once daily (oral)
• Telmisartan: 40 mg or 80 mg once daily (oral), depending on blood pressure control and patient response

• Common fixed-dose combinations available:

• Dapagliflozin 10 mg + Telmisartan 40 mg
• Dapagliflozin 10 mg + Telmisartan 80 mg

MECHANISM OF ACTION:

Dapagliflozin inhibits the SGLT2 transporter in a selective and reversible manner. SGLT2 proteins are expressed in the kidney’s proximal convoluted tubule (PCT), where they are in charge of reabsorbing sodium and glucose from the glomerular filtrate. Everyday, the body filters and reabsorbs about 180 gm of glucose primarily through SGLT2 and partially through SGLT1. Therefore, in healthy people, no glucose is eliminated through urine. SGLT2 is upregulated during hyperglycaemia such as in type 2 diabetes which promotes additional glucose reabsorption and contributes to hyperglycaemia. Eventually the capacity is exceeded resulting in the development of glycosuria. SGLT2 inhibitors prevent the reabsorption of glucose of about 80 gm daily causing glycosuria which directly lowers glucose levels without the need for insulin._[11]

Telmisartan is related to the renin angiotensin-aldosterone system (RAAS) which is crucial for controlling blood pressure and fluid balance in the body. The RAAS pathway starts when the kidneys release renin which is an enzyme released in reaction to low blood pressure, low blood sodium or activation of the sympathetic nervous system. Angiotensinogen is a protein which is produced by the liver gets changed into angiotensin-I by renin. Angiotensin-converting enzyme (ACE) then transforms angiotensin-I into angiotensin-II mostly in the lungs. Angiotensin II is a strong vasoconstrictor which causes blood vessels to narrow and raises blood pressure. Additionally, it causes the adrenal glands to release aldosterone which causes the kidneys to retain water and salt raising blood pressure even more. Telmisartan selectively blocks the angiotensin II type 1 (AT1) receptors to produce its antihypertensive effects. Telmisartan blocks the vasoconstrictive effects of angiotensin II by attaching itself to these receptors. This causes blood vessels to dilate and relax which lowers blood pressure.

PHARMACOKINETICS:

Dapagliflozin is a highly selective, competitive, reversible and oral SGLT2 inhibitor. Dapagliflozin was found to provide close-to-maximal SGLT2 inhibition in healthy subjects at doses of about 20-50mg for at least 24 hours indicating that once daily dosages are appropriate. In oral administration, dapagliflozin is quickly absorbed and typically reaches peak plasma concentration in 2 hours. _[12]

Telmisartan’s maximum plasma concentrations increased proportionally with dose and the median time to maximum plasma concentrations after oral dosing was between 0.5 and 2 hours. _[13]

INDICATIONS:

• Dapagliflozin indicates for 3 major conditions-

Type 2 diabetes mellitus

Heart failure

Chronic kidney disease.

• Telmisartan lowers the blood pressure, preventing cardiovascular events like myocardial infarction and stroke, reduction of cardiovascular risk in individuals who are intolerant to ACE inhibitors.

ADVERSE EFFECTS:

The adverse effects of dapagliflozin includes-

• Urinary tract infections
• Genital infections
• Frequent urination
• Electrolyte imbalance
• Hypoglycaemia _[14]

The adverse effects of telmisartan includes-

• Dizziness 
• Headache
• Back pain
• Sinus congestion with rare serious issues including hyperkalaemia, renal impairment, severe hypotension, angioedema (throat/face swelling) and a rare sprue-like enteropathy (severe diarrhoea).

CONTRAINDICATIONS:

• Dapagliflozin is contraindicated in anaphylactic reactions or angioedema, patient on dialysis _[15]

Telmisartan is contraindicated in pregnant and breastfeeding women, history of hypersensitivity to specific drug, severe liver or biliary issues.

CASE DISCUSSION:

The laboratory parameters of all the patients are mentioned in Table – 1, 2, 3, 4 and 5.

CASE STUDY – 1:

Age : 55 years
Sex : Male
Diagnosis : Type 2 Diabetes mellitus with Diabetic Nephropathy
Treatment:
     Dapagliflozin – 10mg OD
     Telmisartan – 40mg OD
Follow up: 6 months

Table 1: Laboratory parameters of Case study-1

CASE STUDY – 2:

Age : 75 years
Sex : Male
Diagnosis : Type 2 Diabetes mellitus with Diabetic Nephropathy
Treatment:
     Dapagliflozin – 10mg OD
     Telmisartan – 40mg OD
Follow up: 6 months

Table 2: Laboratory parameters of Case study-2

CASE STUDY – 3:

Age : 46 years
Sex : Female
Diagnosis : Type 2 Diabetes mellitus with Diabetic Nephropathy
Treatment:
     Dapagliflozin – 10mg OD
     Telmisartan – 40mg OD
Follow up: 6 months

Table 3: Laboratory parameters of Case study-3

CASE STUDY – 4:

Age : 55 years
Sex : Female
Diagnosis : Type 2 Diabetes mellitus with Diabetic Nephropathy
Treatment:
     Dapagliflozin – 10mg OD
     Telmisartan – 40mg OD
Follow up: 6 months

Table 4: Laboratory parameters of Case study-4

CASE STUDY – 5:

Age : 55 years
Sex : Male
Diagnosis : Type 2 Diabetes mellitus with Diabetic Nephropathy
Treatment:
     Dapagliflozin – 10mg OD
     Telmisartan – 40mg OD
Follow up: 6 months

Table 5: Laboratory parameters of Case study-5