Metformin and Other Diabetes Drugs

What is Metformin?

Metformin belongs to a class of drugs known as biguanides which are used to treat diabetes mellitus (sugar diabetes). Biguanides were developed from guanidine which was extracted from a plant known as Goat’s rue. It was used to treat diabetes in medieval Europe. Phenformin was the first clinically used agent in the group, but it was withdrawn due to high incidence of lactic acidosis. Metformin however, is much safer and the only biguanide used commercially for the treatment of diabetes. It can be used alone or in combination with other oral agents, like sulfonylurea drugs (glimepiride, glyburide, glipizide).

Actions of Metformin

Metformin acts by decreasing glucose production in the liver and increasing glucose uptake from blood by enhancing the action of insulin on the muscle and fat. It has no effect on insulin release from the pancreas and therefore does not cause hypoglycemia.

Metformin also reduces the absorption of glucose from the intestines and may also reduce glucagon levels.  The effectiveness of metformin in lowering blood sugar is comparable to sulfonylureas. It also reduces the risk of vascular diseases associated with diabetes mellitus. Metformin can also reduce plasma triglycerides and can prevent weight gain.

Uses of Metformin

Metformin is used primarily for the treatment of type 2 diabetes. It can be used for the prevention of type 2 diabetes in high risk persons (obese with  a family history of type 2 diabetes, or impaired glucose tolerance).

Metformin is also often used in insulin resistance associated with fertility problems. While the action of metformin is also at times intended to target weight issues, it should only be prescribed and used under the close supervision of a medical professional.

Metformin is NOT a weight loss drug. It is an anti-hyperglycemic or anti-diabetic agent.

Side Effects of Metformin

Gastrointestinal disturbances (abdominal discomfort, diarrhea, loss of appetite, metallic taste) are commonly seen side effects of metformin. Metformin can rarely lead to lactic acidosis, an adverse effect for which its predecessor phenformin was withdrawn.

Contraindications of Metformin

Significant kidney and liver disease, a previous history of lactic acidosis, chronic alcoholics, cardiac failure, and chronic lung diseases predisposing to low oxygen (hypoxia) are contraindications for metformin therapy. Metformin should be discontinued following myocardial infarction (MI) or septicemia.

What are Thiazolidinediones?

Thiazolidinediones are drugs that are used in the treatment and management of type 2 diabetes and insulin resistance. Three of the drugs in this group aree pioglitazone, trovaglitazone (withdrawn from market due to hepatotoxicity) and rosiglitazone (is in the process of withdrawal).

Actions of Thiazolidinediones

Thiazolidinediones regulate certain genes involved in glucose and lipid metabolism by binding to a receptor called peroxisome proliferator-activated receptor-gamma (PPAR-gamma). In fat tissue the drug promotes the uptake of glucose and its utilization.

The thiazolidinediones are antihyperglycemic drugs that do not increase insulin secretion but do require insulin to have its effect on lowering the glucose levels. It increases insulin sensitivity in liver and muscle cells and reduces glucose output from liver. It does not cause hypoglycemia (low blood sugar levels) and its effect on glucose control is similar to sulfonylurea or metformin.

Thiazolidinediones also improve lipid profiles and is therefore used in cases of type 2 diabetes with hypercholesterolemia. It increases HDL cholesterol but its effect on triglycerides and LDL cholesterol are variable. Pioglitazone lowers triglyceride more significantly than rosiglitazone and has been shown to reduce major cardiovascular events like myocardial infarction and stroke.

Side Effects of Thiazolidinediones

The more common side effects of thiazolidinediones include

  • fluid retention (edema)
  • weight gain
  • anemia

Rosiglitazone has been shown to increase major cardiovascular events and is now being withdrawn from the market in several countries.

Contraindications of Thiazolidinediones

Thiazolidinediones are contraindicated in pregnancy, significant liver disease and cardiac failure. Patient using nitrates and other medication for heart disease may not be able to use thiazolidinediones. Close monitoring of the liver function in patients using thiazolidinediones is recommended.

What are alpha-glucosidase inhibitors?

Alpha-glucosidase inhibitors are drugs that inhibit the group of digestives enzymes that are involved in carbohydrate digestion. These drugs are also commonly referred to as starch blockers or carb blockers and include drugs like acarbose and miglitol.

Actions of Alpha-Glucosidase Inhibitors

Alpha-glucosidase enzymes include sucrase, maltase, glycoamylase, isomaltase and dextranase. When these enzymes act on carbohydrates in the gut, it breaks it down into simple sugars. This can then be absorbed by the intestine and enter the blood stream where it elevates the blood glucose levels unless insulin is able to act.

In type 2 diabetes (sugar diabetes), the action of insulin is not as effective meaning that the blood glucose levels stay elevated. By using alpha-glucosidase inhibitors, the absorption of carbohydrates is prevented. This essentially leads to a reduction in post-meal elevation of blood glucose levels.

Indications for Alpha-Glucosidase Inhibitors

These drugs are indicated for type 2 diabetics where conservative management (diet + exercise) is not being undertaken. Alpha-glucosidase inhibitors should only be used when prescribed by a medical doctor and its use for weight loss in non-diabetics is not advised. Diabetics who report a post-prandial (after a meal) spike in glucose levels may respond well to alpha-glucosidase inhibitors but this should not detract from a healthy eating plan and low GI (glycemic index) diet.

Side Effects of Alpha-glucosidase Inhibitors

The side effects from using alpha-glucosidase inhibitors include flatulence, diarrhea, and abdominal bloating can result from undigested carbohydrates. Intestinal flora (gut bacteria) can then consume these unabsorbed nutrients thereby eliciting a host of gastrointestinal symptoms. These side effects are most prominent at the start of the therapy.

Alpha-glucosidase inhibitors do not cause hypoglycemia because it does not affect insulin secretion. However if used in conjunction with insulin secretagogues like sulfonylurea or metformin, then hypoglycemia is a possibility. In the event of a hypoglycemic attack, patients on these alpha-glucosidase inhibitors should not be administered sucrose (sugar) orally as its digestion and absorption will be impaired. Sublingual administration of glucose may be a more effective option.

Contraindications of Alpha-glucosidase inhibitors

Alpha-glucosidase inhibitors should be avoided or used with caution in patients with the following conditions :

  • inflammatory bowel disease
  • intestinal obstruction
  • liver failure
  • kidney failure

What are amylin mimetics?

Amylin is a hormone that is secreted from the beta cells of the pancreas and aids with glucose control. It slows gastric emptying and reduces the secretion of gastrointestinal juices that contain the digestive enzymes. This decreases digestion and thereby minimizes a rise in blood glucose levels. It also inhibits glucagon secretion so that the glucose release from the liver glycogen is slowed. Amylin ultimately enhances the effects of insulin and also reduces the need for higher levels of insulin.

Amylin mimetics are agents that mimic the effects of amylin and contributes to glucose control after eating (post-prandial). Pramlintide is the only approved drug in this group at present and it is approved for use in type 1 and type 2 diabetic patients on insulin. It is given subcutaneously just before meals.

Actions of Pramlintide

Like amylin, pramlintide can modulate gastric emptying and prevent of the postprandial rise in glucagon levels in the blood. It can also reduce the appetite and potentially result in weight loss. It is an antihyperglycemic and does not cause hypoglycemia on its own.

Side Effects of Pramlintide

Pramlintide can cause severe hypoglycemia as it is used in insulin taking patients. Some of the common side effects include :

  • nausea
  • vomiting
  • anorexia
  • abdominal pain
  • headache
  • fatigue

A known allergy to pramlintide and unawareness to hypoglycemia are contraindications for its use.

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