Saturday , November 18 2017
Home / Conditions / Type 2 Diabetes / The Safest First-Line Therapy for Type 2 Diabetes

The Safest First-Line Therapy for Type 2 Diabetes

According to more than 200 studies involving 1.4 million patients, metformin reduces heart disease risk in diabetes patients more effectively than its competitors.

A recent meta-analysis, published in the Annals of Internal Medicine, found metformin, widely used for treating type 2 diabetes (T2D), was safer for the heart than many newer  competitors. Metformin showed particularly dramatic results when compared to  sulfonylurea, its closest competitor drug, reducing the relative risk of a patient dying from heart disease by about 30 – 40 percent.

To evaluate the comparative effectiveness and safety of monotherapy (thiazolidinediones, metformin, sulfonylureas, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium–glucose cotransporter 2 [SGLT-2] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists) and selected metformin-based combinations in adults with type 2 diabetes were evaluated.  English-language studies from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, indexed from inception through March 2015 (MEDLINE search updated through December 2015).

Paired reviewers independently identified 179 trials and 25 observational studies of head-to-head monotherapy or metformin-based combinations. And two reviewers independently assessed study quality and serially extracted data and graded the strength of evidence. The results showed that cardiovascular mortality was lower for metformin versus sulfonylureas; the evidence on all-cause mortality, cardiovascular morbidity, and microvascular complications was insufficient or of low strength. Reductions in hemoglobin A1C values were similar across monotherapies and metformin-based combinations, except that DPP-4 inhibitors had smaller effects. Body weight was reduced or maintained with metformin, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors and increased with sulfonylureas, thiazolidinediones, and insulin (between-group differences up to 5 kg). Hypoglycemia was more frequent with sulfonylureas. Gastrointestinal adverse events were highest with metformin and GLP-1 receptor agonists. Genital mycotic infections were increased with SGLT-2 inhibitors.

From the results it was concluded that the evidence supports metformin again as the first-line therapy for type 2 diabetes, given its relative safety and beneficial effects on hemoglobin A1c, weight, and cardiovascular mortality (compared with sulfonylureas). Added to the conclusions was that metformin is the only antidiabetic agent that has shown reduced macrovascular outcomes, which is likely explained by its effects beyond glycemic control. It has also been employed as an adjunct to lifestyle modifications in prediabetes and insulin-resistant states. A large amount of evidence in literature supports its use even in cases where it would be contra-indicated mainly due to the fear of lactic acidosis, which has been over-emphasized as the available data suggest that lactate levels and risk of lactic acidosis do not differ appreciably in patients taking this drug versus other glucose-lowering agents. It has also recently gained attention as a potential treatment for neurodegenerative diseases such as Alzheimer’s disease.

Metformin acts primarily at the liver by reducing glucose output and, secondarily, by augmenting glucose uptake in the peripheral tissues, chiefly muscle. These effects are mediated by the activation of an upstream kinase, liver kinase B1 (LKB-1), which in turn regulates the downstream kinase adenosine monophosphatase protein kinase (AMPK). AMPK phosphorylates a transcriptional co-activator, transducer of regulated CREB protein 2 (TORC2), resulting in its inactivation, which consequently downregulates transcriptional events that promote synthesis of gluconeogenic enzymes. Inhibition of mitochondrial respiration has also been proposed to contribute to the reduction of gluconeogenesis since it reduces the energy supply required for this process.

Metformin’s efficacy, security profile, benefic cardiovascular and metabolic effects, and its capacity to be associated with other antidiabetic agents makes this drug the first glucose lowering agent of choice when treating patients with type 2 diabetes mellitus (TDM2).

Several other classes of oral antidiabetic agents have been recently launched, introducing the need to evaluate the role of metformin as initial therapy and in combination with these newer drugs. There is increasing evidence from in vivo and in vitro studies supporting its anti-proliferative role in cancer and possibly a neuroprotective effect. Metformin’s negligible risk of hypoglycemia in monotherapy and few drug interactions of clinical relevance give this drug a high safety profile. The tolerability of metformin may be improved by using an appropriate dose titration, starting with low doses, so that side-effects can be minimized or by switching to an extended release form.

Practice Pearls:

  • Metformin acts primarily at the liver by reducing glucose output and, secondarily, by augmenting glucose uptake in the peripheral tissues, chiefly muscle.
  • The first glucose-lowering agent of choice when treating patients with type 2 diabetes mellitus (TDM2).
  • Metformin is the only antidiabetic agent that has shown reduced macrovascular outcomes which is likely explained by its effects beyond glycemic control.

Ann Intern Med. Published online 19 April 2016 doi:10.7326/M15-2650