Empagliflozin, Metformin hydrochloride
Indications
Empagliflozin, Metformin hydrochloride is used for:
Empagliflozin
Empagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes.
Metformin
**Metformin tablet** Metformin is indicated as an adjunct to diet and exercise to increase glycemic control in _adults and pediatric patients_ 10 years of age and older diagnosed with type 2 diabetes mellitus [FDA label]. **Metformin extended-release tablet (XR)** The extended-release form is indicated as an adjunct to diet and exercise to improve glycemic control in only _adults_ with type 2 diabetes mellitus. Safety in children has not been determined to this date [FDA label].
Empagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes.
Metformin
**Metformin tablet** Metformin is indicated as an adjunct to diet and exercise to increase glycemic control in _adults and pediatric patients_ 10 years of age and older diagnosed with type 2 diabetes mellitus [FDA label]. **Metformin extended-release tablet (XR)** The extended-release form is indicated as an adjunct to diet and exercise to improve glycemic control in only _adults_ with type 2 diabetes mellitus. Safety in children has not been determined to this date [FDA label].
Adult Dose
Child Dose
Renal Dose
Administration
Contra Indications
Precautions
Pregnancy-Lactation
Interactions
Adverse Effects
Side effects of Empagliflozin, Metformin hydrochloride :
Mechanism of Action
Empagliflozin
Empagliflozin is a sodium glucose co-transporter-2 (SGLT-2) inhibitor. SGLT2 co-transporters are responsible for reabsorption of glucose from the glomerular filtrate in the kidney. The glucuretic effect resulting from SGLT2 inhibition reduces renal absorption and lowers the renal threshold for glucose, resulting in increased glucose excretion. Additionally, it contributes to reduced hyperglycaemia, assists weight loss, and reduces blood pressure.
Metformin
Metformin's mechanisms of action are unique from other classes of oral antihyperglycemic drugs. Metformin decreases blood glucose levels by decreasing hepatic glucose production (gluconeogenesis), decreasing the intestinal absorption of glucose, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization [FDA label]. It is well established that metformin inhibits mitochondrial complex I activity, and it has since been generally postulated that its potent antidiabetic effects occur through this mechanism [A36534, A36557]. The above processes lead to a decrease in blood glucose, managing type II diabetes and exerting positive effects on glycemic control. After ingestion, the organic cation transporter-1 (OCT1) is responsible for the uptake of metformin into hepatocytes (liver cells). As this drug is positively charged, it accumulates in cells and in the mitochondria because of the membrane potentials across the plasma membrane as well as the mitochondrial inner membrane. Metformin inhibits mitochondrial complex I, preventing the production of mitochondrial ATP leading to increased cytoplasmic ADP:ATP and AMP:ATP ratios [A36534]. These changes activate AMP-activated protein kinase (AMPK), an enzyme that plays an important role in the regulation of glucose metabolism [A176348]. Aside from this mechanism, AMPK can be activated by a lysosomal mechanism involving other activators. Following this process, increases in AMP:ATP ratio also inhibit _fructose-1,6-bisphosphatase_ enzyme, resulting in the inhibition of gluconeogenesis, while also inhibiting _adenylate cyclase_ and decreasing the production of cyclic adenosine monophosphate (cAMP) [A36534], a derivative of ATP used for cell signaling [A176351]. Activated AMPK phosphorylates two isoforms of acetyl-CoA carboxylase enzyme, thereby inhibiting fat synthesis and leading to fat oxidation, reducing hepatic lipid stores and increasing liver sensitivity to insulin [A36534]. In the intestines, metformin increases anaerobic glucose metabolism in enterocytes (intestinal cells), leading to reduced net glucose uptake and increased delivery of lactate to the liver. Recent studies have also implicated the gut as a primary site of action of metformin and suggest that the liver may not be as important for metformin action in patients with type 2 diabetes. Some of the ways metformin may play a role on the intestines is by promoting the metabolism of glucose by increasing glucagon-like peptide I (GLP-1) as well as increasing gut utilization of glucose [A36534]. In addition to the above pathway, the mechanism of action of metformin may be explained by other ways, and its exact mechanism of action has been under extensive study in recent years [A36535, A36554, A36555, A36557].
Empagliflozin is a sodium glucose co-transporter-2 (SGLT-2) inhibitor. SGLT2 co-transporters are responsible for reabsorption of glucose from the glomerular filtrate in the kidney. The glucuretic effect resulting from SGLT2 inhibition reduces renal absorption and lowers the renal threshold for glucose, resulting in increased glucose excretion. Additionally, it contributes to reduced hyperglycaemia, assists weight loss, and reduces blood pressure.
Metformin
Metformin's mechanisms of action are unique from other classes of oral antihyperglycemic drugs. Metformin decreases blood glucose levels by decreasing hepatic glucose production (gluconeogenesis), decreasing the intestinal absorption of glucose, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization [FDA label]. It is well established that metformin inhibits mitochondrial complex I activity, and it has since been generally postulated that its potent antidiabetic effects occur through this mechanism [A36534, A36557]. The above processes lead to a decrease in blood glucose, managing type II diabetes and exerting positive effects on glycemic control. After ingestion, the organic cation transporter-1 (OCT1) is responsible for the uptake of metformin into hepatocytes (liver cells). As this drug is positively charged, it accumulates in cells and in the mitochondria because of the membrane potentials across the plasma membrane as well as the mitochondrial inner membrane. Metformin inhibits mitochondrial complex I, preventing the production of mitochondrial ATP leading to increased cytoplasmic ADP:ATP and AMP:ATP ratios [A36534]. These changes activate AMP-activated protein kinase (AMPK), an enzyme that plays an important role in the regulation of glucose metabolism [A176348]. Aside from this mechanism, AMPK can be activated by a lysosomal mechanism involving other activators. Following this process, increases in AMP:ATP ratio also inhibit _fructose-1,6-bisphosphatase_ enzyme, resulting in the inhibition of gluconeogenesis, while also inhibiting _adenylate cyclase_ and decreasing the production of cyclic adenosine monophosphate (cAMP) [A36534], a derivative of ATP used for cell signaling [A176351]. Activated AMPK phosphorylates two isoforms of acetyl-CoA carboxylase enzyme, thereby inhibiting fat synthesis and leading to fat oxidation, reducing hepatic lipid stores and increasing liver sensitivity to insulin [A36534]. In the intestines, metformin increases anaerobic glucose metabolism in enterocytes (intestinal cells), leading to reduced net glucose uptake and increased delivery of lactate to the liver. Recent studies have also implicated the gut as a primary site of action of metformin and suggest that the liver may not be as important for metformin action in patients with type 2 diabetes. Some of the ways metformin may play a role on the intestines is by promoting the metabolism of glucose by increasing glucagon-like peptide I (GLP-1) as well as increasing gut utilization of glucose [A36534]. In addition to the above pathway, the mechanism of action of metformin may be explained by other ways, and its exact mechanism of action has been under extensive study in recent years [A36535, A36554, A36555, A36557].