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Dec 7, 2023



Metformin Not Working? What’s Next?

About Metformin

Metformin is commonly chosen as the first medication for treating type 2 diabetes. It's popular for several reasons:

  • Effectiveness: It's proven to be effective in controlling blood sugar levels
  • Safety: It has a strong safety profile
  • Tolerability: Most people tolerate Metformin well
  • Affordability: It's generally less expensive compared to other diabetes medications

Unlike many diabetes medications, Metformin has fewer serious side effects and is more cost-effective. Its unique action reduces blood sugar without affecting insulin levels. Some people might experience side effects like nausea, vomiting, or stomach upset, but these can often be lessened by taking Metformin with food. Notably, Metformin is less likely to cause weight gain, low blood sugar, or heart failure compared to other diabetes treatments.

Metformin: Not Always Enough?

Metformin is a common first choice for treating type 2 diabetes, but there are times when it might not control blood sugar levels effectively. This could be due to a combination of incorrect usage and lifestyle factors. For Metformin to work properly, it needs to be taken as prescribed, typically twice daily with food, starting with a low dose and gradually increasing to avoid stomach upset. Alongside correct usage, maintaining a healthy lifestyle, including a balanced diet and regular exercise, is crucial. Both these factors—how Metformin is taken and lifestyle choices—play a significant role in its effectiveness in controlling blood sugar levels.

Need for Additional Medication

If you're adhering to the prescribed Metformin regimen and lifestyle adjustments but still experience high blood sugar, it might indicate the need for an additional medication. The selection of this next treatment option will be based on its effectiveness, potential side effects, tolerability, and cost.

Beyond Metformin: Other Treatment Options

While Metformin is a common first-line treatment for type 2 diabetes, there are other medications available. The three main alternatives include SGLT-2 inhibitors, DPP-4 Inhibitors, and GLP-1 RAs. Each of these medications works differently and offers distinct benefits.

SGLT-2 Inhibitors

SGLT-2 inhibitors, such as Jardiance and Farxiga, represent a modern class of medications used primarily for the management of type 2 diabetes. They offer a unique mechanism of action that not only helps in controlling blood sugar levels but also provides additional health benefits, particularly for the heart and kidneys. This makes them a favorable option for individuals with multiple health concerns. These medications operate by enhancing the excretion of glucose in the urine, an approach that differentiates them from other diabetes treatments.

  • Examples: Jardiance, Farxiga, Invokana, Brenzavvy
  • Uses: Treats type 2 diabetes; some also used for heart failure and chronic kidney disease
  • How They Work: They increase sugar excretion in urine, which also results in more sodium loss. This can have protective effects on the heart and kidneys
  • Side Effects: Mainly urinary and genital infections, more common in women
  • Administration: Taken orally once a day
  • Retail cost: Around $600 for a one-month supply

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DPP-4 Inhibitors

DPP-4 inhibitors, including medications like Tradjenta and Januvia, are another important group in the diabetes treatment arsenal. They work by influencing the body's hormonal response, specifically targeting the incretin system which plays a pivotal role in regulating blood sugar levels. By enhancing the action of hormones such as GLP-1, these inhibitors effectively increase insulin secretion post-meals, aiding in better glycemic control. Their ease of use and low risk of side effects make them a popular choice, especially as supplementary treatment in combination with other diabetes medications.

  • Examples: Tradjenta, Januvia
  • Function: Boost insulin levels after meals by acting on hormones like GLP-1, aiding blood sugar control
  • Usage: Often used in addition to other medications like Metformin
  • Side Effects: Relatively low, but can include headaches
  • Administration: Oral, once daily
  • Retail cost: About $600 for a one-month supply


GLP-1 receptor agonists (GLP-1 RAs), with examples like Ozempic and Victoza, are a class of injectable medications used in the management of type 2 diabetes. They mimic the action of the naturally occurring hormone GLP-1, thereby increasing insulin secretion in response to meals and decreasing blood sugar levels. This group of drugs not only assists in blood sugar management but also has an impact on weight control, which can be beneficial for diabetic patients. However, they are known for a more significant side effect profile compared to other diabetes medications, necessitating a careful consideration of patient tolerance and preferences.

  • Examples: Ozempic (injection) , Victoza (injection), Rybelsus (oral)
  • Function: Increase insulin release after meals by elevating GLP-1 levels
  • Usage: Not to be used with DPP-4 inhibitors as they work on the same pathway
  • Side Effects: More pronounced, including nausea, vomiting, diarrhea, stomach pain, and constipation
  • Retail cost: Around $1,100 per month, making it the most expensive option

Choosing the Best Medication for Type 2 Diabetes

Factors in Selecting the Right Medication: Determining the "best" medication for type 2 diabetes varies based on individual needs and health situations. The choice depends on factors such as the effectiveness of blood sugar control, the presence of side effects, and any additional health conditions a person might have.

Comparing DPP-4 Inhibitors and GLP-1 RAs: Research comparing DPP-4 inhibitors and GLP-1 RAs shows that GLP-1 RAs generally provide better blood sugar control. However, this advantage comes with a higher likelihood of experiencing side effects like nausea.

When to Consider SGLT2 Inhibitors: SGLT2 inhibitors emerge as the ideal choice in certain cases, particularly for individuals with additional health concerns such as heart failure or chronic kidney disease, alongside type 2 diabetes. This is due to their unique mechanism that benefits not just blood sugar levels but also heart and kidney health.

The decision on which medication type is best for managing type 2 diabetes hinges on balancing blood sugar control, side effect profiles, and other individual health factors. It’s important to have a comprehensive discussion with a healthcare provider to determine the most suitable medication based on your specific health needs and circumstances.

SGLT-2 Inhibitors DPP-4 Inhibitors GLP-1 RA
Use Type 2 diabetes mellitus
Heart failure
Chronic kidney disease
Type 2 diabetes mellitus Type 2 diabetes mellitus
Examples Jardiance (empagliflozin)
Brenzavvy (bexagliflozin)
Farxiga (dapagliflozin)
Invokana (canagliflozin)
Tradjenta (linagliptin)
Nesina (alogliptin)
Januvia (sitagliptin)
Onglyza (saxagliptin)
Ozempic (semaglutide)
Rybelsus (semaglutide)
Victoza (liraglutide)
Trulicity (dulaglutide)
Byetta (exenatide)
Function Increases the amount of sugars excreted in the urine Increases insulin release after a meal Increases insulin release after a meal
Side effects Urinary tract infections
Genital infections
Headache Nausea
Stomach pain
Retail cost ~$600 per month ~$600 per month ~1,000 per month


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  2. Wexler, D. J. Initial management of hyperglycemia in adults with type 2 diabetes mellitus. UpToDate. (2023, September 18). Retrieved November 20, 2023, from
  3. Padda, I. S., Mahtani, A. U., & Parmar, M. (2023). Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors. StatPearls Publishing [Internet]. November 24, 2023, from
  4. Latif, W., Lambrinos, K. J., & Rodriguez, R. (2023). Compare and Contrast the Glucagon-Like Peptide-1 Receptor Agonists (GLP1RAs). StatPearls Publishing [Internet]. November 24, 2023, from
  5. Kasina, S. V. S. K., & Baradhi, K. M. (2023). Dipeptidyl Peptidase IV (DPP IV) Inhibitors. StatPearls Publishing [Internet]. November 24, 2023, from
  6. Brunton S. (2014). GLP-1 receptor agonists vs. DPP-4 inhibitors for type 2 diabetes: is one approach more successful or preferable than the other?. International journal of clinical practice, 68(5), 557–567.
  7. OZEMPIC (semaglutide) injection, for subcutaneous use. Food and Drug Administration. (2017; revised 12/2017). Retrieved November 20, 2023, from
  8. JANUVIA (sitagliptin) Tablets. Food and Drug Administration. (2006; revised 04/2011). Retrieved November 20, 2023, from
  9. JARDIANCE (empagliflozin) tablets, for oral use. Food and Drug Administration. (2014; revised 12/2016). Retrieved November 20, 2023, from
  10. Jardiance. GoodRx. (n.d.). November 24, 2023, from
  11. Ozempic. GoodRx. (n.d.). November 24, 2023, from
  12. Sitagliptin (generic Januvia). GoodRx. (n.d.). November 24, 2023, from

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