Adjunctive Metformin for Insulin Resistance in T1D: A Clinical Perspective

As a result of advances in treatment for type 1 diabetes (T1D) in recent decades, life expectancy of individuals with T1D has increased. However, along with the growing rates of overweight and obesity in both adolescents and adults with the disease, there has been an increase in insulin resistance, increased insulin dose requirements, and poor glycemic control in these patients.¹

In addition, insulin resistance “may have a greater role in the development of cardiovascular disease in [individuals with type 1 diabetes]” than in affecting glycemic control, according to the authors of a review published in February 2018 in Diabetes Therapy.¹ Studies have found that insulin resistance predicted coronary artery disease end points while HbA1c did not, and that it was a more significant predictor of the degree of coronary artery calcification than hyperglycemia.^2,3 Adolescents with T1D and insulin resistance were shown to have reduced cardiopulmonary fitness as well as diastolic dysfunction and left ventricular hypertrophy.⁴

These results further highlight the need to adequately address insulin resistance in individuals with T1D. To that end, researchers have been investigating the effects of metformin as an adjunct to insulin therapy in both adolescents and adults with T1D, with promising results reported thus far. Selected findings are highlighted below. 

• In a 2008 meta-analysis of 5 prospective controlled trials involving adolescent and adult patients with T1D who either demonstrated insulin resistance (total daily insulin dose >0.9 U/kg) or who had a body mass index ≥25 kg/m², a small but significant reduction in HbA1c (-0.27%), a moderate reduction in insulin dose, and improvement in total cholesterol were observed.⁵ However, no benefit was found regarding weight.
• A 2010 systematic review of 9 randomized trials noted reductions in insulin dose  (5.7 U/d to 10.1 U/d), HbA1c (0.6% to 0.9%), weight (1.7 kg to 6 kg), and total cholesterol (0.3 mmol/L to 0.41 mmol/L) in adolescent and adult patients.⁶ Combined effect estimates from 5 randomized, double-blind trials showed a significant reduction in insulin dose requirements (6.6 U/d, P <.001) and weight; no significant reduction in HbA1c was demonstrated (absolute reduction 0.11%, P =.42).
• A 2015 meta-analysis of 8 trials comparing metformin to placebo demonstrated reductions in weight (mean difference -2.41; 95% CI, -4.17 to -0.65; P =.007), total daily insulin dose (mean difference -1.36; 95% CI, -2.28 to -0.45; P =.004), and lipids (reduced total and low-density lipoprotein cholesterol (LDL-C); there were no observed effects on HbA1c, fasting plasma glucose, or triglycerides.⁷
• A large multicenter, double-blind, placebo-controlled trial published in 2017 examined the effects of metformin on 428 adults with T1D and at least 3 cardiovascular risk factors.⁸ While the results revealed small transient improvement in HbA1c with metformin vs placebo, this difference was not significant at 3 years. In line with previous findings, metformin was associated with reductions in insulin dose, body weight, and LDL-C.
• Another large, multicenter, double-blind, placebo-controlled, randomized clinical trial found that adjunctive metformin was associated with an at least 25% reduction in insulin dose in 23% of patients vs 1% with placebo and a 10% reduction in body mass index (BMI) in 24% of patients in the metformin group vs 7% of those in the placebo group.⁹ Although there was a small initial reduction in HbA1c, it was not sustained at 6months.
• In a meta-analysis of 6 randomized trials that included children and adolescents, no effect on HbA1c was observed with metformin vs placebo.¹⁰ However, significant improvement in BMI (mean difference -1.46; 95% CI, -2.54 to -0.38; P <.01) and reduction in insulin dose (mean difference -0.15 U/kg; 95% CI, -0.24 to -0.06; P <.01) were found with metformin.

Metformin was generally well tolerated across studies but often increased the risk of gastrointestinal side effects. Additionally, evidence suggests that the cardioprotective benefits associated with metformin use in patients with T2D may also apply to those with T1D.

Overall, the evidence to date suggests no sustained glycemic benefit of adjunctive metformin in T1D. “On the other hand, adjunctive use of metformin in T1D results in significant reductions in the insulin dose requirement and insulin-induced weight gain and may therefore, be particularly useful in overweight/obese [individuals with type 1 diabetes],” the authors concluded. “Therefore, overall, metformin has an insulin-sensitizing effect in [individuals with type 1 diabetes].”

To further explore this topic, Endocrinology Advisor interviewed Kevin M. Pantalone, DO, ECNU, FACE, staff endocrinologist and director of clinical research in the department of endocrinology at Cleveland Clinic, and Jason Ng, MD, endocrinologist and clinical assistant professor of medicine at the University of Pittsburgh Medical Center. 

Endocrinology Advisor: What are the potential benefits and risks of metformin as adjunctive therapy in T1D?

Dr Pantalone: Metformin is a very safe medication for treating T2Ds. Its use in patients with T1D has been the topic of discussion a lot as of late, but this is a practice that has been going on for many years, particularly among endocrinologists. Patients with T1D often gain weight over time – in part related to the insulin therapy they are receiving – and thus can become insulin resistant. Metformin therapy may provide value in some of these patients by improving insulin sensitivity and reducing the glucose output from the liver, thereby improving glycemic control and helping to avoid further increases in insulin doses.  

Dr Ng: Metformin is not approved for use in T1D, owing to the basic pathology that individuals with T1D do not make insulin and thus require insulin to keep their sugar under control. However, if an individual with T1D has any insulin-resistant component to their sugar control, metformin may help to improve insulin sensitivity. Research is underway to assess the effectiveness of metformin therapy in T1D. Studies have shown some reduction in insulin requirements with the use of metformin in T1D but no significant decrease in long-term HbA1c. The risks of taking metformin are the same as they are for those with T2D taking metformin (increased risk of lactic acidosis).

Endocrinology Advisor: What are the treatment implications and other top takeaways for clinicians?

Dr Pantalone: I think it is important for physicians to recognize that, just like a person in the general population can develop insulin resistance and subsequently T2D, people who are diagnosed with T1D can also become insulin resistant over time, and their diabetes may then behave more like that of T2D – higher insulin requirements, more weight gain, etc. This has sometimes been referred to as diabetes type 1.5. 

Dr Ng: There are no long-term randomized controlled trials or other large studies, to my knowledge, that show effectiveness of metformin in T1D. For now, the studies do not suggest a role for metformin therapy in patients with T1D.

Endocrinology Advisor: What should be the focus of future research in this area?

Dr Pantalone: Continued research regarding the newer therapies that have been approved for
T2D, not just metformin, in the population with T1D would be important. The role of these newer therapies, when they should be considered, and how they may influence glycemic control, glycemic variability, and perhaps mitigate further weight gain would be the areas that should be prioritized. There has been research on glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors in this population of patients as well, and in certain patients these therapies may also provide value in helping to obtain better glycemic control in patients with T2D. 

Dr Ng: Many patients with diabetes in the current environment have both an inability to make enough insulin and increasing insulin resistance. With obesity rates on the rise, even patients with T1D are at risk for increasing obesity and insulin resistance, which would affect how much insulin they would require medically. Treatments such as metformin that are indicated in T2D may be effective in patients with T1D who also have worsening obesity. This area requires further research to assess the effectiveness of medications indicated for this patient group.

References

1. Priya G, Kalra S. A review of insulin resistance in type 1 diabetes: is there a place for adjunctive metformin? Diabetes Ther. 2018;9(1):349-361.
2. Orchard TJ, Olson JC, Erbey JR, et al. Insulin resistance-related factors, but not glycemia, predict coronary artery disease in type 1 diabetes: 10-year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care. 2003;26(5):1374-1379.
3. Schauer IE, Snell-Bergeon JK, Bergman BC, et al. Insulin resistance, defective insulin-mediated fatty acid suppression, and coronary artery calcification in subjects with and without type 1 diabetes: the CACTI study. Diabetes. 2011;60(1):306-314.
4. Nadeau KJ, Regensteiner JG, Bauer TA, et al. Insulin resistance in adolescents with type 1 diabetes and its relationship to cardiovascular function. J Clin Endocrinol Metab. 2010;95(2):513-521.
5. Pang TT, Narendran P. Addressing insulin resistance in type 1 diabetes. Diabet Med. 2008;25(9):1015-1024.
6. Vella S, Buetow L, Royle P, Livingstone S, Colhoun HM, Petrie JR. The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia. 2010;53(5):809-820.
7. Liu C, Wu D, Zheng X, et al. Efficacy and safety of metformin for patients with type 1 diabetes mellitus: a meta-analysis. Diabetes Technol Ther. 2015;17(2):142-148.
8. Petrie JR, Chaturvedi N, Ford I, et al; REMOVAL Study Group. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017;5(8):597-609.
9. Libman IM, Miller KM, DiMeglio LA, et al; T1D Exchange Clinic Network Metformin RCT Study Group. Effect of metformin added to insulin on glycemic control among overweight/obese adolescents with type 1 diabetes: a randomized clinical trial. JAMA. 2015;314(21):2241-2250.
10. Al Khalifah RA, Alnhdi A, Alghar H, Alanazi M, Florez ID. The effect of adding metformin to insulin therapy for type 1 diabetes mellitus children: a systematic review and meta-analysis. Pediatr Diabetes. 2017;18(7):664-673.