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Janumet Review Article

 

TextJanumet tablets, contains sitagliptin and metformin and can be used in combination with diet and exercise in order to lower blood sugar in adults with type II diabetes. It works by helping your pancreases to make and release more insulin, improving the insulin sensitivity and decreasing the excess of sugar that body makes. You should not take this drug if you have a type I diabetes. It is also important to keep a healthy weight because this is very good for your heart and can help you lower the levels of sugar in your blood.

Janumet is a combination drug composed of sitagliptin phosphate, which belongs to the novel class of dipeptidyl peptidase inhibitors, and metformin hydrochloride, which belongs to the biguanide drug class. Both drugs are used for the treatment of type 2 diabetes mellitus. The molecular formulas of sitgaliptin phosphate and metformin are C16H15F6N5O•H3O4P•H2O and C4H11N5, respectively.

Janumet is approved for use in the treatment of diabetes mellitus, type 2, when diet and exercise alone do not provide adequate glycemic control. It also used as an adjunct when metformin or sitagliptin alone does not control glucose levels. Continue reading...

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Mechanism of Action

Janumet exerts its action by two complementary effects, because to the two components. This provides an improved glycemic control for patients with type 2 diabetes mellitus.

The first component, sitagliptin phosphate, belongs to the dipeptidyl peptidase inhibitors. It addresses the first problem of diabetes mellitus type 2, which is low insulin level. As the name implies, drugs belonging to this class inhibits the enzyme dihydropeptidyl peptidase-4 (DPP-4). DPP-4 is an enzyme that indirectly regulates glucose in the body by regulating insulin and glucagon. As mentioned, blood glucose levels are controlled by two hormones – insulin which catabolizes (breaks down) glucose thus reducing its levels, and glucagon, which anabolizes (builds up) glucose, thus increasing its levels. These two hormones are in turn regulated by a group of hormones called incretin hormones, which include glucagon-like peptide 1 (GLP-1) and gastric-dependent insulinotropic polypeptide (GIP). Incretin stimulates insulin secretion and at the same time, inhibits glucagon release, leading to a decreased glucose levels. Therefore, high levels of incretin are beneficial for diabetes management.

Incretin hormones are regulated by DPP-4. DPP-4 inactivates incretin, leading to decreased insulin release and increased glucagon release, which leads to increased blood glucose levels. Therefore, inhibition of DPP-4 leads to higher incretin levels, overall leading to lower glucose levels (Holst & Deacon, 1998).

Increasing incretin hormones by DPP-4 inhibition have other beneficial effects in the treatment of diabetes, which includes delayed gastric emptying (Naslund, et al., 1999) and induced satiety (Ahren, 1998; Holst, 2002) leading to reduced food intake (Gutzwiller, 1999), enhanced glucose metabolism (D’Alessio, Prigeon & Enswick, 1995), and weight loss (Zander, et al., 2002).

An advantage of DPP-4 inhibitors such as sitgaliptin has over other insulin secretagogues such as sulfonylureas is that it increases insulin secretion only when glucose levels are high, since incretins are dependent on glucose levels. Thus, when glucose levels are low, insulin release is not stimulated, thus avoiding sulfonylurea-induced hypoglycemia.

The second component of Janumet is metformin hydrochloride, which belongs to the biguanide drug class. Metformin resolves the second problem of diabetes type 2 which is insulin resistance. Acting as an insulin sensitizer, metformin sensitizes the cells of the body, increasing the uptake and utilization of glucose by skeletal muscle cells, which leads to lower blood glucose levels (Hundal, et al., 1992). Aside from that, studies by Stumvoll and colleagues (1995), Schafer (1983) and Hundal and colleagues (2000) have found that metformin suppresses glucose production. Metformin also decreases intestinal absorption of glucose, leading to excretion and decreased glucose blood levels.

Discovery of the AMPK or AMP-activated protein kinase have provided a suitable explanation on the exact mechanism of action of metformin. It has been found that AMPK is stimulated by metformin, which leads to increased glucose uptake in the muscles (Goodyear, 2000; Fryer et al., 2002), inhibition of hepatic glucose production (Lochhead, et al., 2000) and inhibition of fatty acid synthase, which increases glucose levels. (Foretz, et al., 1998). Thus metformin can reduce glucose levels by itself, aside from sensitizing the cells to insulin.

Efficacy

Several studies have proven the efficacy of sitagliptin and metformin combination therapy for Type 2 diabetes. In a clinical trial study made by Bazg and colleagues (2007), they found that there was an improvement in the glycemic control and β-cell function (β-cells secrete insulin. Studies made by Goldstein and colleagues (2008) and Charbonnel and colleagues (2006) also supports these findings, that addition of sitagliptin to on-going metformin therapy was effective. Because of the positive findings with the combination, several standard guidelines have recommended it as an alternative to monotherapy (Vilsboll, 2008). Vilsboll’s initial review of Janumet has also yielded positive results.In a study made by Reynolds and Neumiller (2008), they have stated that Janumet is a suitable drug product for patients with Type 2 diabetes, with a complementary and possible additive effect.

In a study by Gallwitz (2007), he stated that the combination has several advantages: it does not increase the risk of hypoglycemia and it does not promote weight gain, which other antidiabetic drugs cause. This was supported by Scheen (2010).

An interesting study was made by Katz, in the American Diabetes Association meeting last 2010. In his study, he found that Janumet provides better glycemic control than Actos. In addition, weight control was better, with Janumet providing an average of 1.4 kg of weight loss, while Actos giving a 3 kg weigh gain.

Safety

In several studies, like the ones conducted by Brazg et al. (2007), Goldstein et al. (2008), and Scheen (2010), it was found that Janumet was generally well torelated. Common adverse effects (around 10%) that are associated with Janumet includes gastointesinal disturbance such as nausea, vomiting, diarrhea, abdominal pain, and loss of appetite; metallic taste (around 3%). Rarer side effects include acute pancreatitis, lactic acidosis (which is very a very serious side effect) and hypersensitivity reactions (<0.01%). To avoid possible gastrointestinal adverse effects, it is recommended to take Janumet with food. Should lactic acidosis occur, it is recommended to discontinue the drug and report to the nearest hospital.

Janumet is contraindicated in patients with renal disease or dysfunction, as well as those with acute lactic acidosis and diabetic ketoacidosis, because one of its components (metformin hydrochloride) can aggravate the said conditions. Janumet should not be used for patients undergoing radiologic examination with IV administration of iodinated contrast media due to a possible alteration of renal function. Any signs of hypoxemia, dehydration or sepsis

Due to the problems with the kidneys, it is recommended to monitor renal functioning especially for elderly patients to avoid possible accumulation and eventual formation of lactic acidosis. Renal function should be assessed before use and at least annually thereafter.

Dosage

Janumet dosing is individualized, depending on the patient’s tolerability, current use of other antihyperglycemic agents. It is important to consult with the health care provider prior to administration. Generally, Janumet is given twice a day after meals of to reduce gastrointestinal discomfort. The initial tablet strength is 50mg/500mg, gradually increased to the 50mg/1000mg tablet.

Janumet is available as 50mg/500mg, 50mg/850mg and 50/1000mg tablets of sitagliptin phosphate and metformin hydrochloride. It is also available as an extended-release formulation (Janumet XR), for a convenient once a day dosing. This formulation was approved only last February 2, 2012. Approval was based on a bioequivalence study on coadministration of sitagliptin and metformin extended release preparation.

Diabetes Mellitus, Type 2

Diabetes mellitus is a metabolic disorder characterized by high glucose levels in the blood. This may be caused by a variety of reasons, which commonly deals with the hormone insulin, which regulates glucose levels. Low insulin secretion due to an autoimmune response (immune cells attacking its own cells) of the body to the β-cells, decreased glucose utilization due to resistance of cells to insulin, or increased glucose production due to glucagon (another hormone regulating glucose levels, but this time, to increase it) may cause an increase in glucose levels in the blood.

Diabetes mellitus is classified into four types: Type 1 or insulin dependent diabetes mellitus (IDDM); Type 2 or non-insulin dependent diabetes mellitus (NIDDM); Gestational Diabetes; and Diabetes secondary to other conditions. Of all these types, 90% of diabetic patients belong to the type 2.

Type 2 diabetes mellitus is a type of diabetes in which there is an increased muscular insulin resistance, increased hepatic glucose production, relative hyperglucagonaemia (high glucagon levels in the blood, which increases glucose), coupled with low insulin secretion (Scheen, 2010). This etiologic combination makes the disease difficult to manage. Because of this, combination therapies are frequently indicated. One such drug is Janumet.

Bibliography

Ahren, B., 1998, Glucagon-like peptide 1 (GLP-1)-a gut hormone of potential interest in the treatment of diabetes. Bioessays 20:642-651

Brazg, R., Xu, L., Dalla Man, C., et al., Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycaemic control and beta-cell function in patients with type 2 diabetes

Charbonnel, B., Karasik, A., Liu, J., et al., 2006, Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone

D’alessio, D. A., Prigeon, R. L. & Enswick, J. W., 1995., Enteral enhancement of glucose disposition by both insulin-dependent and insulin-independent processes. A physiological role of glucagon-like peptide I. Diabetes 44:1433-1437

Gallwitz, B., 2007, Sitagliptin with metformin: Profile of a combination for the treatment of type 2 diabetes

Goldstein, B. J., Feinglos, M. N., Lunceford, J. K., et al., 2008, Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes

Gutzwiller, J. P., Drewe, J., Goke, B., et al., 1999, Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol 276:R1541-1544

Holst,, J. J., 2002, Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabet Metab Res Rev 18:430-431

Holst, J. J. & Deacon, C. F., 1998, Inhibition of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes 47:1663-1670

Hundal, R. S., et al., 2000, Mechanism by which metformin reduces glucose production in type 2 diabetes, Diabetes. 49:2063-2069

Naslund, E., Bogefors, J., Skoger, S., et al., 1999, GLP-1 slows solid gastric emptying and inhibits insulin, glucagon, and PYY release in humans. Am J Physiol 277:R910-R916

Reynolds, J. K., and Neumiller, J. J., 2008, Janumet™: a combination product suitable for use in patients with Type 2 diabetes

Schafer, G., 1983, Biguanides. A review of history, pharmacodynamics and therapy, Diabete Metab. 9:148-163

Scheen, A. J., 2010, Medication of the month. Sitagliptin-metformin fixed combination (Janumet)

Stumvoll, M., Nurjhan, N., Perriello, G., Dailey, G., and Gerich, J. E., 1995, Metabolic effects of metformin in non-insulin-dependent diabetes mellitus, N. Engl J. Med. 333:550-554

Vilsboll, T., 2008, Initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin for patients with Type 2 diabetes mellitus

Walter, A., 2010, American Diabetes Association Meeting Highlights

Zander, M., Madsbad, S., Madsen, J. L., & Holst, J. J., 2002, Effect of 6-week course of glucagon-like peptide 1 on glycemic control, insulin sensitivity and B-cell function in type 2 diabetes: a parallel-group study. Lancet 359:824-830


 

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