Metformin : Profile

Metformin is a biguanide antihyperglycemic agent, with over three decades of established use as a safe and efficacious agent in the management of type 2 diabetes. Metformin’s glucose lowering effect is well known. It slows the rate of glucose production through a reduction in hepatic gluconeogenesis. Additionally, Metformin improves peripheral sensitivity to insulin in the muscle and adipose tissue, enhancing glucose uptake by these tissues.

More recently, the landmark United Kingdom Prospective Diabetes Study (UKPDS) demonstrated significant reduction in the risk of myocardial infarction and overall mortality in overweight patients with type 2 diabetes treated with metformin. Effective glycemic control with additional long-term cardiovascular protection have earned Metformin a unique place as the first-line pharmacologic therapy in diabetes management.

Metformin is the best studied agent for treatment of diabetes as it is:
  • Not associated with weight gain
  • Reduces cardiovascular events
  • Can be used for overweight patients in UKPDS
  • Not associated with hypoglycemia risk
Mode of Action:

Metformin is an insulin sensitizer. It is now well established that the glucose-lowering effects of Metformin are mainly a consequence of reduced hepatic glucose output (primarily through inhibition of gluconeogenesis and, to a lesser extent, glycogenolysis) and increased insulin stimulated glucose uptake in skeletal muscle and adipocytes.

The major action of Metformin is to reduce hepatic glucose production, which is increased at least twofold in patients with type 2 diabetes. Metformin treatment decreases fasting plasma glucose concentrations by 25 to 30%. Metformin also reduces glucose production by reducing the rate of gluconeogenesis.

The exact mechanism through which Metformin reduces hepatic glucose production remains unclear, but its primary site of action appears to be hepatocyte mitochondria, where it disrupts respiratory chain oxidation of complex substrates. Inhibition of cellular respiration decreases gluconeogenesis.

Antihyperglycemic effects of Metformin
  • Corrects elevated hepatic glucose output
  • Inhibit gluconeogenesis from substrates like lactate, pyruvate, glycerol and amino acids
  • Inhibits Glycogenolysis
    • – Opposes gluconeogenic actions of glucagon
    • – Enhances the glucose transport activity of insulin in muscles and glycogen and lipid synthesis
    • – Does not increase insulin secretion
  • Not hypoglycemic, even at high doses
Metformin Evidence
Metformin is the best studied agent for treatment of diabetes 1. Multicenter Metformin Study Group

Study Summary:

Two protocols:

First : 289 moderately obese T2DM inadequately controlled by diet (M = 143. Pl =146 pts) – Metformin lowered FBG and A1c v/s placebo

Second: 632 patients not controlled by diet & Max Glibenclamide – Combination MG (213) > M or G (209) alone – Metformin did not cause increase in lactate concentrations or increase insulin concentration or cause hypoglycemia

Conclusion: Metformin monotherapy is well tolerated and improves glycaemic control & lipid concentrations in patients with NIDDM

3. Combination of Insulin and Metformin in the Treatment of Type 2 Diabetes

Study Summary




Conclusions: In type 2 diabetic patients who are intensively treated with insulin, the combination of insulin and Metformin results in superior glycemic control compared with insulin therapy alone, while insulin requirements and weight gain are less.

2. COSMIC study

Study Summary

  • Comparative Outcomes Study of Metformin Intervention versus Conventional
  • Metformin group 7227 and usual care: 1,505 patients
  • 500 mg bid with meals, increased weekly
  • Incidence of SAE was similar
  • Lactic acidosis was not observed
  • Metformin safely prescribed, if take care of contraindications and warnings
4. Metabolic Effects of Metformin in NIDDM

Study Summary

(Obese pts with NIDDM, isotope dilution, indirect calorimetry, etc)

  • Metabolic effects of M were to inhibit gluconeogenesis, reduce hepatic glucose output and lower FBG
  • Lower FBG sets the stage for better glycaemic control throughout the day

Conclusions: Metformin acts primarily by decreasing hepatic glucose output, largely by inhibiting gluconeogenesis. It also seems to induce weight loss preferentialy involving adipose tissue.

Immediate Release & Extended release Metformin

Over many years of extensive use, the therapeutic profile of Metformin has been largely established, using immediate-release formulations that require administration two or three times daily. An otherwise safe drug, trusted with time and experience, Metformin is associated with mild, yet disturbing side effects.

The principal side effects of immediate release Metformin are gastrointestinal in nature. The incidence of gastrointestinal side effects has been reported to be approximately 20–30% inpatients receiving Metformin 500–2500 mg/day. The incidence of such adverse effects with Metformin is highest in the period immediately after the initiation of treatment and tends to diminish over time. Thus far, gastrointestinal side effects have been managed in patients by cautious dose titration, administration after meals or by reducing the total daily dosage.

Despite such care adverse events can be troublesome and may limit the dosage of Metformin and impair compliance with therapy in some patients. It is well accepted that patients’ compliance with therapy tends to decrease as the dosage frequency and side effects increase and that regimens should be simplified as far as possible to support good compliance with therapy .

To address this clinical need and to lower drug related morbidity in type 2 diabetics, novel extended release formulations of Metformin (Metformin XR ) have been developed. Such formulations release the active drug through a polymer matrix gradually over the dosing period, resulting in a once-daily dosing option for patients with type 2 diabetes.

Extended-release formulations of Metformin have been shown to lead to improved tolerability, by smoothing the peaks and troughs in plasma Metformin concentrations and delaying the achievement of peak plasma Metformin concentrations, compared with an immediate-release formulation. Thus, the use of an extended-release formulation of Metformin provides benefits in terms of improved patient management, by enabling once-daily dosing and reducing the incidence of side effects. Retrospective reviews of patients with type 2 diabetics switched from immediate release Metformin to Metformin-XR resulted in an approximate halving of the incidence of any gastrointestinal side effect, or of diarrhea. Metformin-XR thus has the potential to improve the convenience and tolerability of Metformin-based therapy. Indeed, patient adherence to once-daily extended-release Metformin therapy has been as high as 97.2%.

The added clinical advantage of a once-daily, 24 hour therapy is the effective management of physiological variations in glucose levels which can compound complications in diabetics. It is well known that many diabetes patients experience a “dawn phenomenon” in which glucose levels rise quite high in the early morning due to increased hepatic glucose output in response to rising levels of hormones, such as cortisol, that peak in the early mornings. For such conditions a 24 hour effective glycemic control through extended release formulations is ideal.

Optimum glycemic control is after all, the key to short-term and long-term benefits for a patient with type 2 diabetes.

Cetapin XR : Unique MPHM Technology used for extended Release
The technology advantage – The science behind the formulation Absorption of Metformin

Oral absorption of Metformin hydrochloride is confined to the upper part of the intestine. The oral bioavailability of Metformin is in the range of 40 to 60% decreasing with increasing dosage. Studies by Vidon N et al strongly suggest that there is permeability limited absorption of Metformin. The drug will transit down the small intestine following dissolution from an ingested dosage form and, if the absorption rate is slow, it is possible that the drug can reach regions of poor permeability before absorption of a given dose is complete. Thus an immediate release formulation transit rapidly through the digestive system. Known as “dose dumping” the immediate release tablet rapidly dissolves and the drug moves too quickly through the gastrointestinal system before complete absorption takes place. This often causes a disturbance in the colon resulting in side effects such as nausea and diarrhea.

About 20% of the amount of drug emptied from the stomach was absorbed from the duodenum. The delivery process was the rate-limiting factor for Metformin absorption from the duodenum. The AUC/24 increased as the absorption rate from the duodenum increased.


The key features of an ideal extended release formulation

An improved bioavailability from an extended release dosage form of Metformin that releases Metformin at a rate likely to provide the desired plasma levels of drug for an extended time period would be possible from a dosage form that has extended residence time in the upper gastrointestinal tract, resisting mechanisms that promote normal transit time for solid materials.

Furthermore it is quite clear that a controlled-release oral formulation of Metformin should ensure a complete release during transit from stomach to jejunum. The drug retention in a gastric medium can be achieved by modifying drug delivery systems comprised of swellable matrix tablets activated by water and drug release control depending on the interactions between water, polymer and drug. These are designed to be sufficiently small on administration so as not to make ingestion of the dosage form difficult. On ingestion they rapidly swell to a size that precludes passage through the pylorus until after drug release has progressed to a required degree. This delivery system is called gastro retentive delivery system. Using normal physiological processes by which the stomach retains large food particles for further digestion the gastro retentive delivery system swells following ingestion and is retained in the stomach for a number of hours while it continuously releases the incorporated drug at a controlled rate to optimal absorption sites in the upper intestinal tract.“ A system designed for longer gastric retention will extend the time within which drug absorption can occur in the small intestine”

The unique release-controlling properties of the polymer compounds allows for a gradual and complete release of Metformin hydrochloride from stomach to jejunum, unaffected by gastric pH fluctuations. Cetapin XR the Sanofi formulation of Metformin XR uses a patented multiple polymer hydrophilic matrix technology as a gastroretentive delivery system, to achieve prolonged release of Metformin hydrochloride. The polymers are a novel combination of non ionic and ionic hydrophilic polymers. Metformin hydrochloride granules are compressed into tablets along with the polymers in a ratio that is optimized to provide pH independent drug release from the tablet.

When the tablet comes in contact with the gastrointestinal fluids(fig A), Metformin imbibes water hydrates and forms a gelatinous swellable matrix (fig B). The drug release from the matrix occurs via a process of dissolution of the drug and subsequent diffusion through the gel matrix in a controlled manner (fig C). The matrix controls the rate and extent of release of Metformin XR (fig D).

As the tablet swells, it is retained in the stomach and upper intestines for a longer time, thereby providing maximum drug available at the site of absorption (fig D). his technology has given consistent and reproducible results providing :

  • Optimal absorption
  • Less irritation
  • Improved plasma levels
  • and better bioavailability

Single dose bioequivalence study of Cetapin XR ( 500 mg Metformin SR ) tablets and Glucophage XR (500 mg Metformin XR tablets) in healthy volunteers
Objective

For many drugs it has been demonstrated that their pharmacodynamic action is related to their plasma concentration. Because of this critical relationship, the proof of bioequivalence of products is most important to assure equal therapeutic efficacy. This will also confirm the usage of the new formulation as therapeutic alternative to the reference formulation.

The bioavailability of Cetapin XR was evaluated in comparison with the reference formulation - Glucophage XR

Patients and methods

Twelve healthy volunteers participated in the study conducted according to a two way crossover design. The bioavailability was compared using the parameter : total area under the plasma concentration-time curve (AUC - infinity), peak plasma concentration (Cmax) and time to reach peak plasma concentration (Tmax).

Results

Both formulations were found to be equvalent in all three parameters measured. There was no statistically significant difference in values. The plasma metformin levels versus time of two formulations are depicted in Figure 1. Both formulations meet the bioequivalence criteria for AUC and C max parameters and are hence bioequivalent


Cetapin XR : Cardio protective effects

In addition to its actions on glucose metabolism, several other metabolic effects have been ascribed to Metformin. Several of these are beneficial to the cardiovascular risk profile of the typical type 2 diabetic patient. (Table)

Additional Effects :
  • Hypercoagulability : Insulin resistance is associated with decreased fibrinolysis resulting in an increased propensity towards intravascular thrombosis. Metformin causes a reduction in fibrinogen levels and increased activity of the fibrinolytic system, as well as diminished platelet aggregation and plasminogen activator inhibitor-1 activity all of which improves hypercoagula bility.
  • Dyslipidemia : Type 2 diabetes is also characterized by elevated free fatty acids and triglycer ide levels, low HDL and increased numbers of LDL which are highly atherogenic. Metformin improves lipid parameters.
  • Endothelial Dysfunction: Metformin has been shown to improve endothelial dysfunction - a common characteristic in insulin resistant states.
  • C-Reactive protein : Metformin therapy is also associated with reduced levels of C-reactive protein- an important inflammatory marker and an emerging risk factor for cardiovascular disease.
Clinical Effects of Metformin
  • Decreases FBG by 25 to 30%
  • Decreases A1c by 1 to 2 %,
  • Improve the response of muscle to insulin
  • Weight neutral or weight reduction
  • Lipid profile improvement
Cetapin XR : Composition, Profile
Absorption and Bioavailability

Following a single oral dose of Metformin extended release, Cmax is achieved with a median value of 7 hours and a range of 4 hours to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of Metformin, however, the extent of absorption (as measured by AUC) is similar to Metformin.

At steady state, the AUC and Cmax are less-than dose proportional for Metformin extended release within the range of 500 mg to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1,1.4 and 1.8 mcg/mL for 500, 1000, 1500 and 2000 mg once-daily doses, respectively. The extent of Metformin absorption (as measured by AUC) from Metformin extended release at a 2000 mg once-daily dose is similar to the same total daily dose administered as Metformin tablets 1000 mg twice daily.

After repeated administration of Metformin extended release, Metformin did not accumulate in plasma.

Although the extent of Metformin absorption (as measured by AUC) from the Metformin extended release tablet increased by approximately 50% when given with food, there was no effect of food on Cmax and Tmax of Metformin. Both high and low fat meals had the same effect on the pharmacokinetics of Metformin extended release.

Metabolism and Elimination

Intravenous single-dose studies in normal subjects demonstrate that Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of Metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution


Distribution

Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of Metformin, steady state plasma concentrations of Metformin are reached within 24-48 hours and are generally < 1 mcg/mL

The clinical significance

“ When administered with food, the extended-release Metformin tablet gradually releases drug over 8 h into the upper gastrointestinal tract , where Metformin is primarily absorbed. Prolonged release of Metformin from extended- release Metformin tablets has been demonstrated in pharmacokinetic studies . Extended release Metformin showed slightly lower maximum concentrations, longer times to maximum concentration (7–8 vs. 4–5 h) and similar bioavailability compared with immediate- release products . This extended release could potentially reduce dosing frequency to once daily compared with two or three times daily for immediate release formulations.”

Cetapin XR : Important safety Information
Contraindications :

Known hypersensitivity to metformin hydrochloride; renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥ 1.5mg/dL (males), ≥ 1.4 mg/dL (females) or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse, acute myocardial infarction and septicaemia; congestive heart failure; acute or chronic metabolic acidosis including diabetic ketoacidosis, with or without coma, history of ketoacidosis with or without coma. Cetapin XR should be temporarily discontinued in patients undergoing radiologic studies.

Warnings :

Lactic acidosis is a medical emergency. Cetapin XR must be discontinued

Drug interactions

Clinically significant drug interactions involving Metformin are rare. While the α-glucosidase inhibitor acarbose has been reported to cause a significant reduction in bioavailability and peak plasma levels of Metformin when co-administered ; this did not prevent improvement in HbA1c when acarbose was added to the treatment of patients inadequately controlled on diet plus Metformin.

Cimetidine reduces renal clearance of Metformin, but toxicity resulting from this has not been reported nor any interaction of Metformin with other H2-receptor blockers has been reported. Certain drugs (thiazide and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, and sympathomimetics, calcium channel blocking drugs and isoniazid) tend to produce hyperglycaemia and may lead to loss of glycaemic control. When such drugs are administered to a patient receiving Metformin, the patient should be closely monitored.

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