Metformin/Pioglitazone

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[edit] BRAND NAMES

[edit] STRUCTURE

[edit] MECHANISM OF ACTION

This is a combination of two antidiabetic medications with complementary mechanisms of action: Pioglitazone, a member of the thiazolidinedione class and Metformin hydrochloride, a member of the biguanide class.

  • Pioglitazone: Pioglitazone is a member of the thiazolidinedione class, it acts primarily by reducing insulin resistance in muscle and adipose tissue and by inhibiting hepatic gluconeogenesis. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.


  • Metformin is an antidiabetic medication, it acts primarily by decreasing endogenous hepatic glucose production (gluconeogenesis). Metformin also decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
    Metformin lowers both basal and postprandial plasma glucose and unlike sulfonylureas, it is not associated with substantial risk for hypoglycemia.
    Metformin as monotherapy remains the only agent associated with weight loss in patients with obesity with non-insulin-dependent diabetes mellitus (NIDDM). The mechanism may be attributed to decreased food intake [1].
    Metformin is currently considered to be one of the first-choice drugs for type 2 diabetes mellitus, in particular, in overweight and obese people.
    Metformin also has neutral to positive effects on LDL cholesterol and triglyceride levels.

[edit] INDICATIONS

Second line treatment of type 2 diabetes mellitus in adult patients, particularly overweight patients, who are unable to achieve sufficient glycemic control at their maximally tolerated dose of oral metformin alone.

After initiation of therapy with pioglitazone, patients should be reviewed after 3 to 6 months to assess adequacy of response to treatment (e.g. reduction in HbA1c). In patients who fail to show an adequate response, pioglitazone should be discontinued. In light of potential risks with prolonged therapy, prescribers should confirm at subsequent routine reviews that the benefit of pioglitazone is maintained

[edit] DOSAGE

One tablet of Metformin/Pioglitazone 15 mg/850 mg, taken twice a day.

Tablets should be swallowed with a glass of water. Taking tablets with, or just after food, may reduce gastrointestinal symptoms associated with metformin.

[edit] CONTRAINDICATIONS

  • Hypersensitivity to Pioglitazone or Metformin
  • Cardiac failure or history of cardiac failure (Pioglitazone can cause fluid retention, which may exacerbate or precipitate heart failure).
  • Acute alcohol intoxication, alcoholism
  • Metabolic acidosis including diabetic ketoacidosis with or without coma. (Diabetic ketoacidosis should be treated with insulin)
  • Kidney problems: Renal failure or renal dysfunction (creatinine clearance <60 ml/min) and acute conditions with the potential to alter renal function such as dehydration, severe infection and shock.
  • Current bladder cancer or a history of bladder cancer (Pioglitazone use for more than one year may be associated with an increased risk of bladder cancer [2].
  • Intravascular administration of iodinated contrast agents
  • Hepatic impairment
  • Breastfeeding

[edit] PRECAUTIONS

  • Congestive Heart Failure: Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications, especially with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone must be considered
  • Lactic acidosis is a very rare (0.03 cases/1000 patient/year), but serious, metabolic complication that can occur due to metformin accumulation (primarily reported in diabetic patients with significant renal failure). The risk increases also with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure. Symptoms include respiratory distress, abdominal pain , malaise, myalgias, increasing somnolence and hypothermia. If metabolic acidosis is suspected, treatment with the medicinal product should be discontinued and the patient hospitalised immediately.
  • Elderly: In light of age-related risks (especially bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully both before and during treatment in the elderly.
  • Bladder Cancer: Available epidemiological data suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone in particular in patients treated for the longest durations and with the highest cumulative doses. A possible risk after short term treatment cannot be excluded. For this reason both France and Germany have withdrawn pioglitazone products from the market.
  • Hepatic Effects: Measure liver enzymes promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. (Because of postmarketing reports of fatal and non-fatal hepatic failure)
  • Weight should be closely monitored (weight gain can be due to fat accumulation, fluid retention or may be be a symptom of cardiac failure)
  • Ovulation: Therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. Patients with polycystic ovarian syndrome as well may result in resumption of ovulation. Therefore patients should be aware of the risk of pregnancy
  • Fractures: Increased incidence in female patients.
  • Macular edema has been reported in postmarketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione, therefore patients should have regular eye exams by an ophthalmologist

[edit] INTERACTIONS

  • Insulin and pioglitazone: There have been post-marketing cases of cardiac failure reported when pioglitazone was used in combination with insulin. Insulin and Pioglitazone are both associated with fluid retention, concomitant administration of insulin and Metformin/Pioglitazone may increase the risk of edema and heart failure.
  • Avoid consumption of alcohol (Can increase the risk of lactic acidosis)
  • Gemfibrozil (an inhibitor of CYP2C8) increases Pioglitazone exposure approximately 3-fold

[edit] PREGNANCY AND LACTATION

  • Metformin/Pioglitazone should not be used during pregnancy. If a pregnancy occurs, treatment should be discontinued
  • Metformin/Pioglitazone not be used in women who are breast-feeding

[edit] SIDE EFFECTS

  • At the initiation of the treatment: abdominal pain, diarrhea, loss of appetite, nausea and vomiting may occur, these reactions are very common but usually disappear spontaneously in most cases.
  • Other possible side effects include: bone fracture and arthralgia, weight increase, edema, visual disturbance, hematuria, erectile dysfunction, taste disturbance, headache, upper respiratory tract infection and anemia.
  • Lactic acidosis (in less than 1 case per 10,000 patients)

[edit] RELATED LINKS

Understanding Type 2 Diabetes
A simple explanation of what diabetes is

[edit] BIBLIOGRAPHY

EPAR Product Information

[edit] REFERENCES

  1. http://www.ncbi.nlm.nih.gov/pubmed/9526970
  2. http://www.fda.gov/drugs/drugsafety/ucm259150.htm
Diabetes (Antidiabetic drugs)
Insulin Secretagogues (drugs that increase insulin release from pancreas) Sulfonylureas Chlorpropamide (Diabinese)   Glibenclamide or Glyburide (Diabeta, Micronase, Glynase, Daonil, Euglycon)   Gliclazide (Diamicron)   Glimepiride (Amaryl, Solosa)   Glipizide (Glucotrol, Minidiab, Glibenese)   Gliquidone (Glurenorm)
Meglitinides Repaglinide (Prandin, Novonorm)   Nateglinide (Starlix)
Dipeptidyl peptidase-4 inhibitors Linagliptin (Trajenta)   Saxagliptin (Onglyza)   Sitagliptin (Januvia)   Vildagliptin (Galvus)
Incretin mimetics (GLP-1 agonists and analogs) Exenatide (Byetta)   Liraglutide (Victoza)   Lixisenatide (Lyxumia)   Dulaglutide (Trulicity)
Insulin Sensitizers (drugs that decrease insulin resistance)
Biguanides Metformin (Glucophage)
Thiazolidinediones Pioglitazone (Actos)
Drugs that retard the digestion and absorption of carbohydrates in the small intestine
Alpha-glucosidase inhibitors Acarbose (Glucobay, Precose)
Drugs that reduce glucose absorption in the kidney and increase glucose excretion in the urine
Sodium glucose cotransporter 2 (SGLT2) inhibitors Canagliflozin (Invokana)   Dapagliflozin (Farxiga)   Empagliflozin (Jardiance, Glyxambi, Synjardi)
Insulin and insulin analogs
Intermediate acting insulins Insulin lispro protamine (Humalog BASAL)   Isophane human insulin : Human insulin protamine (NPH) (Humulin I, Protaphane)
Long-acting insulins‎ Insulin detemir (Levemir)   Insulin glargine (Lantus)
Fast-acting insulins‎ Regular insulin : Insulin (Human recombinant) (Actrapid, Humulin R)
Ultra-rapid-acting insulins‎‎ Insulin aspart (Novorapid)   Insulin glulisine (Apidra)   Insulin lispro (Humalog)   Insulin human (Inhalation Powder) (Afrezza)
Premixed insulin‎‎‎ (ultra-rapid-acting + intermediate acting Insulin aspart / Insulin aspart protamine (Novomix)   Insulin lispro / Insulin lispro protamine (Humalog Mix)
Inhaled Insulin Insulin human (Inhalation Powder) (Afrezza)
Combination therapy
Sulfonylurea + Metformin Glibenclamide / Metformin (Bieuglicon M, Diaglimet, Glibomet, Gliconorm, Glicorest, Suguan M)
Thiazolidinedione + Metformin Pioglitazone / Metformin (Competact, Glubrava)
Thiazolidinedione + Sulfonylurea Pioglitazone / Glimepiride (Tandemact)
Dipeptidyl peptidase-4 inhibitors + Metformin Linagliptin / Metformin (Jentadueto)   Sitagliptin / Metformin (Efficib, Janumet, Velmetia)   Vildagliptin / Metformin (Eucreas)