Best alternatives to metformin for insulin resistance and type 2 diabetes

 Key takeaways:

• Metformin is a widely used medication for treating insulin resistance and type 2 diabetes.
• Various alternative diabetes medications, such as SGLT-2 inhibitors, sulfonylureas, and thiazolidinediones, are available for individuals who cannot tolerate metformin or those who require additional options.
• Consultation with a healthcare professional is essential before switching diabetes medications to determine the most suitable treatment plan.

Metformin (Glucophage) is a well-known medication used for treating insulin resistance and type 2 diabetes. It is an antidiabetic medication that belongs to the biguanides class.

Metformin reduces blood glucose levels by reducing glucose absorption from food and the production of glucose by the liver. Also, it increases the body’s sensitivity to insulin, a hormone responsible for managing blood glucose levels naturally.

Although metformin is prescribed globally, including in Nigeria, there may be cases where patients may experience severe side effects or insufficient blood sugar control. When either of these happens, it is best to seek other alternative treatment options.

Some other great alternatives to metformin for treating insulin resistance and type 2 diabetes include:

 1. Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors

SGLT-2 inhibitors reduce blood sugar levels by making the kidneys remove more sugar from the body through urine. They achieve this by causing the kidneys—the organ that filters and separates waste from blood—not to reabsorb glucose back into the blood. They also reduce HbA1c levels by approximately 0.7%.

There are currently four SGLT-2 Inhibitors that have been approved by the FDA for managing type 2 diabetes: 

• Canagliflozin
• Dapagliflozin
• Empagliflozin, and 
• Ertugliflozin. 

Their dosages are 100 mg, 5 mg, 10 mg, and 5 mg, respectively, to be taken once daily in the morning. However, these are starting doses. The doses may be increased to 300 mg, 10 mg, 25 mg, and 15 mg, respectively, in order to achieve the desired glycemic goal.

The most common side effects of SGLT-2 inhibitors are genital yeast infections in females, urinary tract infections, frequent urination, nausea, and constipation. 

One advantage SGLT-2i has over metformin is the potential decrease in adverse events related to heart failure hospitalization, acute coronary syndrome, and all-cause mortality. 

Studies show that using SGLT-2 inhibitors as the first treatment may help lower the number of these heart problems, improving a patient's overall health. However, the obvious disadvantage is an increase in ischemic stroke.

 2. Sulfonylureas

Sulfonylureas can also serve as an alternative medication to metformin. Having been used for managing type 2 diabetes since the 1950s, sulfonylureas is divided into two classes: first and second generation, the main difference being their potency. 

Sulfonylureas work by stimulating insulin hormone secretion from the cells of the pancreas responsible for releasing this hormone, called the pancreatic beta cells. This leads to decreased blood sugar levels. Various sulfonylureas are available for treating diabetes, each with different dosing regimens. 

Glibenclamide, a long-acting sulfonylurea, starts at 2.5 mg to 5 mg daily, with a maximum daily dose of 20 mg, ideally taken with meals. Glipizide begins at 5 mg daily, with a maximum of 40 mg for immediate-release (IR) and 20 mg for extended-release (ER) tablets, administered differently depending on meals.

Glimepiride, another IR tablet, starts at 1 to 2 mg daily, up to 8 mg, preferably taken with or shortly after meals. Gliclazide, in both IR and modified-release (MR) forms, is dosed differently - IR tablets, starting at 80 mg twice daily, and MR tablets, starting at 30 mg daily, both preferably taken before meals.

The most common side effect of sulfonylureas is hypoglycemia. Others include weight gain, diarrhea, headaches, and nausea.

Although sulfonylureas effectively control blood glucose, when used alone, they have been associated with an increased risk of all-cause mortality, major hypoglycemic episodes, and cardiovascular events when compared to metformin.

 3. Dipeptidyl Peptidase 4 (DPP-4) Inhibitors

DPP-4 inhibitors work by blocking an enzyme called DPP-4, which normally breaks down hormones called incretins, including GLP-1 (Glucagon-like peptide-1) and GIP (gastric inhibitory peptide). 

By inhibiting DPP-4, these medications increase the levels of GLP-1 and GIP in the body, which helps stimulate insulin secretion from the pancreas and reduce blood sugar levels after meals and throughout the day.

Examples of DDP-4 inhibitors include sitagliptin, saxagliptin, linagliptin, alogliptin, and vildagliptin. These medications are administered once a day, either before or after meals. Side effects are generally mild and may include hypoglycemia, headaches, and upper respiratory tract infections. 

Their advantages over metformin include weight management, a low risk of hypoglycemia, an extensive safety profile, and the restoration of beta cell function, while a disadvantage is that they may contribute to congestive heart failure by breaking down B-type peptides.

 4. Glucagon-like Peptide 1 Receptor Agonists

These are antihyperglycemic drugs used in managing type 2 diabetes and can also be used as alternatives to metformin. 

GLP-1 RAs work by binding to GLP-1 receptors on various cells, including pancreatic beta cells, gastrointestinal cells, and the central nervous system, stimulating insulin secretion, slowing down stomach emptying, and inhibiting glucagon release. This leads to improved blood sugar control in individuals with type 2 diabetes.

There are different formulations of GLP-1 RAs available, most of which are injections. Lixisenatide and liraglutide are taken once daily, while albiglutide, dulaglutide, and semaglutide are taken once weekly. Exenatide can be injected twice daily or once weekly.

Common side effects of GLP-1 agonists include nausea, vomiting, and diarrhea, which can sometimes cause acute kidney injury due to reduced fluid levels in the body. Other possible side effects may include dizziness, a slight increase in heart rate, infections, headaches, and indigestion. 

GLP-1 RAs tend to have milder gastrointestinal effects and lower discontinuation rates than metformin. On the other hand, they are more expensive and mainly involve injections that may cause pain, swelling, and irritation around the injection site.

 5. Thiazolidinediones (TZDs)

TZDs are a class of medications that increase insulin sensitivity by affecting the adipose tissues, muscle, and liver, thereby leading to an increase in glucose utilization and a reduction in glucose production.

Rosiglitazone and pioglitazone are the two TZDs approved by FDA. These medications are oral drugs taken with or without food, once a day. It is usually advisable to combine TZDs with lifestyle modifications for optimum results.

Side effects include weight gain, fluid retention, and an increased risk of heart failure. These are its disadvantages when compared to metformin. Despite these, they have higher glucose-lowering efficacy and more favorable impacts on lipid profile when compared to metformin.

 6. Alpha-glucosidase Inhibitors

Alpha-glucosidase inhibitors are medications used to lower blood sugar levels by slowing down the breakdown and absorption of complex carbohydrates during digestion. This causes a reduction in blood glucose levels after eating.  

The most common example of AGIs is acarbose. Voglibose and miglitol are other examples. They are typically administered three times daily with meals. Acarbose and miglitol have an initial dose of 25 mg thrice daily, with a maximum of 100 mg. Viglibose has an initial dose of 0.2 mg three times daily, with a maximum of 0.3 mg.

Flatulence, diarrhea, and abdominal pain are side effects of these medications. When compared to metformin, they are especially advantageous for patients at risk of developing hypoglycemia and lactic acidosis.

 7. Metiglinides

Just like sulfonylureas, they work by stimulating insulin secretion from pancreatic beta cells, leading to decreased blood sugar levels. A typical example is Repaglinide.

The usual dose is 0.5 to 4 mg two to three times daily, to a maximum of 16 mg administered about 30 minutes before meals. Common adverse effects include hypoglycemia, weight gain, and upper respiratory tract infections. 

Meglitinides offer rapid and short-lived glycemic control, making them suitable for prandial glucose management, but they may increase the risk of hypoglycemia.

 Other diabetes medicines

Other medications that may be prescribed for treating diabetes include:

• Insulin
• Pramlintide
• Telotristat ethyl
• Bromocriptine
• Colesevelam
• Ozempic
• Dulaglutide
• Chromium picolinate (off-label)
• Kombiglyze XR

 Can you stop metformin once you start taking it?

Discontinuing metformin should be done under the guidance of a healthcare professional. It is not advisable to stop taking it abruptly without medical advice because your symptoms might worsen.

 How to safely stop metformin

Always consult with a healthcare provider before discontinuing metformin or switching to another medication. Slowly reduce the dose with your doctor's guidance to avoid withdrawal symptoms or blood sugar problems.

Lifestyle modification is important when trying to stop metformin. Keep up a moderate weight and eat healthy foods. Also, exercise regularly and reduce alcohol intake and smoking. These would help prevent withdrawal symptoms or destabilization of blood sugar levels.

 Cost of metformin (Glucophage) and where to buy it

Glucophage can be found across several pharmacies worldwide. The cost of Glucophage varies depending on the pharmacy and location. In Nigeria, the price range is N3,500 – N5,000 per 30 tablets. In the US, the cost of metformin ranges from $0.30 - $0.90 per tablet.