Review Of the Combination Dosage Form of Sitagliptin Phosphate Monohydrate and Dapagliflozin Propanediol Monohydrate as an Anti-Diabetic Agent

Diabetes mellitus is a phenomenon in which ingested glucose is not absorbed in the body, accumulates in the blood, and is excreted in the urine due to insufficient secretion or poor secretion of insulin for various reasons. Diabetes mellitus occurs when the insulin secretion function of the pancreas decreases as the body’s demand for insulin increases. In addition, diabetes mellitus can be associated with congenitally low insulin secretion and is commonly caused by insulin resistance due to genetic/environmental factors. The symptoms of diabetes mellitus include severe thirst, polyuria, and polydipsia. Diabetes mellitus is the lack of insulin and can be divided into type 1 diabetes and type 2 diabetes. Type I diabetes mellitus is an insulin-dependent diabetes mellitus that is caused by a deficiency in the secretion of insulin in the pancreas due to the destruction of pancreatic β-cells. Type I diabetes mellitus requires insulin administration because of the lackof blood sugar control. Type 2 diabetes mellitus is non-insulin-dependent diabetes; inthis condition, insulin is secreted by pancreatic β-cells, but insulin resistance occurs inthe body, causing a decrease in insulin secretion or a breakdown in the insulin responsesystem. In particular, type 2 diabetes mellitus has multiple causes, and the symptomsare severe due to _-cell inactivation, insulin resistance, and inflammatory responses dueto environmental factors (obesity, dietary habits, lack of exercise) and genetic factors.According to a presentation by the International Diabetes Federation (IDF), the prevalenceof diabetes mellitus in adults aged 20 to 79 worldwide was 9.3% as of 2019, and theapproximately 285 million patients with diabetes mellitus are estimated to increase to 438 million by 2030. Approximately 1.5 million people worldwide died in 2019 dueto diabetes mellitus. In Korea, the prevalence rate of diabetes mellitus among adults aged 30 years and older was 13.8% in 2018, and the death rate due to diabetes mellitus was 28.9per 100,000 in 2013 ^[1-10]. Diabetes mellitus has been identified as the leading cause of lifeexpectancy decline and death. Sitagliptin phosphate monohydrate ((R)-3-Amino-1-(3-(trifluoromethyl)-5,6-dihydro [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one phosphate monohydrate, a treatment for type 2 diabetes mellitus, is the first commercially commercialized oral hypoglycemic agent among dipeptidyl peptidase-4 (DPP-4) inhibitors and is taken as monotherapy or combination therapy at a dose of 100 mg once a day. DPP-4 inhibitors control blood glucose by increasing insulin secretion and suppressing glucagon release by restricting the DPP-4 enzyme that decomposes incretin, a hormone secreted in the gastrointestinal tract when food is ingested. DPP-4 inhibitors do not cause weight gain compared with the impact of a rapid decrease in blood glucagon, and because they act dependently on blood glucagon concentrations in the body, they have a low risk of hypoglycemia and are used as an adjuvant to dietary and exercise therapy. Sitagliptin phosphate monohydrate, a DPP-4 inhibitor, has a molecular weight of 523.32 g/mol, and has good solubility and permeability as its biopharmaceutics classification system (BCS) is Class 1. In addition, sitagliptin phosphate monohydrate has a time to maximum plasma concentration (Tmax) of 1 to 4 h and has a suitable distribution volume and rapid oral absorption in vivo with a bioavailability of approximately 87%. Dapagliflozin propanediol hydrate ((1S)-1,5-Anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol (S)-propane-1,2-diol (1:1) monohydrate, BMS 512148 propanediol monohydrate, Dapagliflozin (S)-propylene glycol monohydrate, (2S,3R,4R,5S,6R)-2-(3-(4-Ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyl-tetrahydro-2H-pyran-3,4,5-triol propanediol monohydrate) is a type 2 oral antidiabetic drug that is a sodium-glucose cotransporter-2 (SGLT-2) inhibitor and reduces blood glucose independently of insulin action. SGLT-2 inhibitors reduce glucose reabsorption in the kidneys by inhibiting SGLT-2, which affects glucose reabsorption in the kidneys, and lower blood glucagon by excreting glucose in the urine. ^[10-18] In addition, regardless of diabetes mellitus treatment, there is an effect of reducing the risk of hospitalization and death due to chronic heart failure and cardiovascular disease. Dapagliflozin propanediol hydrate can be taken at a dose of 10 mg once a day as monotherapy or combination therapy regardless of the meal, and the Tmax and bioavailability are 2 h and 78%, respectively. In addition, as its BCS is Class 3, its solubility is good when orally administered. Currently, patients with type 2 diabetes mellitus require combination therapy with other oral drugs before increasing the dose to the maximum dose when the goal of glycemic control is not reached with monotherapy as diabetes mellitus progresses. Therefore, the combination prescription rate of DPP-4 inhibitors and SGLT-2 inhibitors is high for blood glucose control in patients with diabetes mellitus. However, due to the inconvenience of taking two drugs simultaneously, drug compliance is low ^[19-26].

CHEMISTRY OF SITAGLIPTIN PHOSPHATE MONOHYDRATE ^[27,28]

Sitagliptin phosphate monohydrate has a molecular formula of C₁₆H₂₀F₆N₅O₆P and a molecular weight of 523.32 g/mol (anhydrous form). Its chemical structure consists of a β-amino acid moiety and a trifluorophenyl group and IUPAC name of 3R)-3-amino-1-[3-(trifluoromethyl)-6,8-dihydro-5H-triazolo[4,3-a] pyrazin-7-yl]-4-(2,4,5-trifluorophenyl) butan-1-one;phosphoric acid; hydrate. Sitagliptin phosphate monohydrate is a white crystalline powder that is highly soluble in water and slightly soluble in organic solvents. It has a melting point of around 200°C. Sitagliptin phosphate monohydrate is used as an oral antidiabetic medication to improve glycemic control in patients with type 2 diabetes. It is often used in combination with other medications, such as metformin, to achieve optimal glucose control.

Figure 1: Sitagliptin phosphate monohydrate

CHEMISTRY OF DAPAGLIFLOZIN PROPANEDIOL MONOHYDRATE

Dapagliflozin propanediol monohydrate has a molecular formula of C₂₄H₃₅ClO₉ and a molecular weight of 502.99 g/mol (anhydrous form). IUPAC name of (2S)-propane-1,2-diol (2S,3R,4R,5S,6R)-2-{4-chloro-3-[(4-ethoxyphenyl) methyl] phenyl}-6-(hydroxymethyl) oxane-3,4,5-triol hydrate. Dapagliflozin propanediol monohydrate is a white crystalline powder that is highly soluble in water and slightly soluble in organic solvents. It has a melting point of around 80-100°C. Dapagliflozin propanediol monohydrate is used as an oral antidiabetic medication to improve glycemic control in patients with type 2 diabetes. It is often used in combination with other medications, such as metformin, to achieve optimal glucose control.

Figure 2: Dapagliflozin propanediol monohydrate

MECHANISM OF ACTIONSITAGLIPTIN PHOSPHATE MONOHYDRATE

• Sitagliptin works to competitively inhibit the enzyme dipeptidyl peptidase 4 (DPP-4). This enzyme breaks down the incretins GLP-1 and GIP, gastrointestinal hormones released in response to a meal.

• By preventing breakdown of GLP-1 and GIP, they are able to increase the secretion of insulin and suppress the release of glucagon by the alpha cells of the pancreas. This drives blood glucose levels towards normal.

MECHANISM OF ACTION DAPAGLIFLOZIN PROPANODIOL MONOHYDRATE

• Dapagliflozin inhibit subtype 2 of the sodium-glucose transport proteins (SGLT2), Which are responsible for at least 90% of the glucose reabsorption in the kidney. Blocking the transporter mechanism causes blood glucose to be eliminated through the urine
• Its protective effects in heart failure is attributed primarily to hemodynamic effect, where SGL2 inhibitors potently reduce intravascular volume through osmotic diuresis and natriuresis.

PHARMACOKINETIC OF COMBINED DOSAGE FORM ^[29]

A study assessed the potential for pharmacokinetic DDI between dapagliflozin and different glucose-lowering agents, among which sitagliptin, in healthy subjects. In this open-label, randomised, crossover study, 18 subjects received a single-dose administration of 100 mg sitagliptin or 100 mg sitagliptin plus 20 mg dapagliflozin. Mean dapagliflozin plasma concentration versus time profile were similar with and without co-administration of sitagliptin. The prespecified criteria to conclude a lack of interaction between dapagliflozin and sitagliptin were met for C_maxand AUC, as the 90% CIs were within the no-effect interval of 0.8–1.25 (Table 5). The t_max and t_1/2 for dapagliflozin were also unaffected by co-administration of sitagliptin. The median (range) t_max for dapagliflozin was 1.5 (1.0–4.0) h without and 1.7 (1.0–6.0) h with sitagliptin co-administration. The mean t_1/2 values for dapagliflozin were 14.3±10.1 h without and 15.9±7.1 h with sitagliptin co-administration. Similarly, there were no meaningful differences in C_max and AUC for sitagliptin in the presence of dapagliflozin, as the 90% CIs were within the no-effect interval (Table 5). Again, the t_max and t_1/2 for sitagliptin were unaffected by co-administration of dapagliflozin. The median tmax for sitagliptin was 3.0 (0.5–5.8) h without dapagliflozin and 4.0 (1.5–8.0) h with dapagliflozin. The respective t_1/2 values for sitagliptin were 14.2±2.0 h and 14.4±2.0 h in the absence and presence of dapagliflozin.

CLINICAL EFFICACY OF COMBINED DOSAGE FORM ^[30]

A RCT assessed the efficacy and safety of dapagliflozin 10 mg (n=225) versus placebo (n=226) as add-on therapy to sitagliptin 100 mg with or without metformin in patients with inadequately controlled T2D. At 24-week add-on treatment with dapagliflozin provided additional clinical benefit with a significant reduction in HbA1c (-0.5% versus 0% with placebo) and body weight (-2.1 kg versus -0.3 kg). Dapagliflozin also decreased HbA1c significantly versus placebo when added to sitagliptin alone (placebo-subtracted, – 0.6%; p<0.0001) or to sitagliptin plus metformin dual therapy (placebo-subtracted, –0.4%; p<0.0001). Glycaemic and body weight benefits observed at week 24 were maintained through week 48 and fewer patients receiving dapagliflozin were discontinued or rescued for failing to achieve glycaemic targets compared with placebo.

RATIONALE FOR USE OF DAPAGLIFLOZIN AND SITAGLIPTIN ^[31-36]

A ‘‘pathophysiological approach’’ using initial combination therapy with agents known to address the established defects in T2DM seems more rational. It is preferable to use combination therapies having complementary mechanisms of action that target different pathways addressing the multiple pathophysiologic abnormalities of T2DM. Reported evidence with SGLT2i and several clinical trials of DPP4i have demonstrated that these agents reduce glycaemic variability in patients with T2DM. Both of these classes of medications are associated with lower risks for hypoglycaemia. Fixed-dose combination (FDC) of SGLT2i and DPP4i is the unique non-metformin-based FDC been available in India. After metformin initiation or even prior to metformin initiation in suitable patients (metformin contraindicated or intolerant), or in patients with high HbA1c who fail on metformin, this combination may give excellent clinical benefit(s) to the patients, thus facilitating the ‘‘treat early and treat right’’ approach. Below figure depicts the beneficial role of both these drugs in patients with diabetes and associated CV risk especially the risk of HF.