The evolution of metformin therapy through the decades.
Studies such as the Diabetes Control and Complications Trial (DCCT) and its Epidemiology of Diabetes Interventions and Complications (EDIC) post-randomization follow-up have established that the risk of cardiovascular and microvascular complications in patients with type 1 diabetes can be mitigated with stringent glucose control. However, maintaining blood glucose levels within goal range remains difficult for patients to achieve. The DCCT demonstrated that as HbA1c goals are approached the incidence of hypoglycemia increases exponentially. The risk and fear associated with hypoglycemia is a key factor in patient’s and practitioner’s difficulties in reaching target blood glucose levels. As such, healthcare providers err on the side of caution when setting goals for their patients.
Another issue facing patients with type 1 diabetes is the prevalence of insulin-induced weight gain and eventual insulin resistance and subsequent insulin dose requirement increases. Patients often experience increased blood pressure and LDL-cholesterol levels as consequence. Because of these challenges non-insulin therapies have emerged as possible solutions for patients with type 1 diabetes. Following the UK Prospective Diabetes Study (UKPDS) published in 1998 the world was introduced to metformin hydrochloride as a safe option for all type 2 diabetes patients and was no longer reserved only for obese patients. The UKPDS demonstrated that obese patients with type 2 diabetes gained less weight compared to other oral medication options, had less incidence of hypoglycemic events and had a 33% reduction in the risk of experiencing a myocardial infarction1. Because of these findings more healthcare practitioners are issuing metformin hydrochloride as an off-label adjunctive therapy for their type 1 diabetes patients.
Researchers evaluated the use of metformin as a treatment option for patients with type 1 diabetes from small studies dating back to the 1980’s to the most recent REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL) study. Beginning in the mid 1980’s researchers in France performed a small double-blinded placebo-controlled crossover trial. Metformin was added to the insulin regimen of 10 non-obese patients with type 1 diabetes for 1 week. Their results indicated improved insulin sensitivity, which led to another similar trial that was conducted over 3 weeks. While there was no change in fasting glucose, insulin dose requirements or body weight researchers did note significant improvement in patient’s seven-point capillary glucose profile1. These small, underwhelming trials failed to ignite much interest in the use of metformin in patients with type 1 diabetes and it wasn’t until the 2000’s that more, larger trials were conducted. In 2003, two double-blinded, placebo-controlled trials both randomizing 30 adolescent type 1 patients with diabetes reported HbA1c reductions of 0.6% and 0.9% following 3 months of metformin use. Fast-forward to the REMOVAL study, the largest trial to date evaluating the use of metformin in the management of type 1 diabetes, and the results are impressive.
The primary outcome of the REMOVAL trial was change in mean carotid artery IMT and secondary outcome measures included changes in: HbA1c, LDL-cholesterol, eGFR, albuminuria, weight, insulin dosage and endothelial function. Maximal far wall carotid intima-media thickness (cIMT) was reduced by twice as much as previously shown in the DCCT/EDIC, this was an exciting and positive finding as the majority of patients were on a statin regimen. It should be noted that further studies are warranted to find if metformin’s effect on cIMT results in clinical outcomes. Along with changes in vascular structures, the REMOVAL study showed sustainable reduction in weight, small reductions in insulin dose requirements, and LDL-cholesterol. The effect on HbA1c was variable as there was slight improvement initially, but after 6 months of metformin use patient’s HbA1c reverted to baseline. This may have been due to subsequent decreases in insulin dosing as metformin was added, but the results were inconclusive.
The larger, more recent trials offered new insight on the use of metformin in patients with type 1 diabetes. While there is evidence that metformin use can limit insulin dosing requirements in type 1, there is little evidence to suggest its recommendation in current guidelines. Larger trials evaluating the cardiovascular outcomes in patients with type 1 diabetes taking metformin is warranted. However, the data from the last 30 years of clinical trials might suggest broadening the use of metformin to improve cardiovascular risk in patients with type 1 diabetes.
- Metformin can lower weight, insulin dose requirements and LDL-cholesterol in type 1 patients with diabetes.
- Metformin lowered maximal carotid intima-media thickness substantially in the REMOVAL trial.
- Fear of hypoglycemia is a major contributing factor to patients being unable to achieve glycemic control and a low-risk of hypoglycemia, oral medication such as metformin can play a significant role in helping both type 1 and type 2 diabetes patients achieve target blood glucose levels.
Livingstone, Rachel, et al. “A new perspective on metformin therapy in type 1 diabetes.” Diabetologia (2017): 1-7.
Petrie JR, Chaturvedi N, Ford I et al (2017) Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. doi:10.1016/S2213-8587(17)30194-8
Jessica Lambert, University of South Florida College of Pharmacy, Doctor of Pharmacy Candidate