Insulin Intensification: Understanding the Why, How, and When 

Paolo Pozzilli, MD
Rome, Italy

Current guidelines call for insulin initiation in patients with Type 1 or latent autoimmune diabetes in adults (LADA), symptomatic hyperglycemia, weight loss or evidence of ketosis, quick deterioration of metabolic control, therapeutic failure of non-insulin therapies (in those with LADA or Type 2 diabetes [T2D]), and/or pregnancy.1

The first step in determining if a patient whose diabetes remains uncontrolled with oral hypoglycemic agents requires insulin is confirming their type of diabetes, best done by measuring C-peptide levels as well as autoantibodies to β cells.2

Then, of course, comes the more challenging part: designing an individualized treatment plan.

Despite the wide variety of injectable and oral glucose-lowering therapies available for patients with T2D, a significant number of patients will still need insulin to achieve good metabolic control. This is the result of the pathophysiology of T2D, which generally begins with obesity-related insulin resistance and progresses to hyperinsulinemia. This, in turn, leads to β-cell overload and the subsequent reduction of β-cell mass. Finally, β-cell failure occurs and it’s time for insulin.3,4

While insulin increases the risk of hypoglycemia and weight gain, those effects may be mitigated by combining it with SGLT-2 inhibitors or GLP-1 receptor agonists.5 Not only can these medications reduce the risk of weight gain, but studies also find significant cardiovascular benefits.6

There are two recent publications that I think are important in any decision regarding insulin intensification. One comes from Forst et al, who provide an excellent review article on the clinical challenges of initiating basal insulin and practical approaches to overcome those challenges.7 The other, from Tuccinardi et al, describes the results of their study on the use of plasma C-peptide levels to measure residual β-cell function in patients treated with basal insulin only versus those on multiple dose insulin injections (MDI). They found a significant inverse correlation between C-peptide levels and disease duration (P=0.03). They also found that patients on MDI present with lower fasting C-peptide (P<0.005) and higher fasting glucose (P=0.01) compared with patients on basal insulin only. They surmise that C-peptide concentrations <1.09 ng/mL could predict a future need for MDI treatment (P<0.04).

Are you confused about when to prescribe basal versus long-acting? When to start insulin? How to manage weight gain and/or hypoglycemia in your patients? Please leave a comment below.

1 Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669-2701.
2 Buzzetti R, Tuomi T, Mauricio D, Pietropaolo M, Zhou Z, Pozzilli P, Leslie RD. Management of Latent Autoimmune Diabetes in Adults: A Consensus Statement from an International Expert Panel. Diabetes 2020 Oct;69(10):2037-2047.
3 Saisho Y. Postprandial C-Peptide to Glucose Ratio as a Marker of β Cell Function: Implication for the Management of Type 2 Diabetes. Int J Mol Sci. 2016;17(5):744.
4 U.K. prospective diabetes study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes. 1995;44(11):1249-1258.
5 Mantsiou C, Karagiannis T, Kakotrichi P, et al. Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors as combination therapy for type 2 diabetes: A systematic review and meta-analysis. Diabetes Obes Metab. 2020. doi: 10.1111/dom.14108. Online ahead of print.
6 Kaul S. Mitigating Cardiovascular Risk in Type 2 Diabetes with Antidiabetes Drugs: A Review of Principal Cardiovascular Outcome Results of EMPA-REG OUTCOME, LEADER, and SUSTAIN-6 Trials. Diabetes Care. 2017;40(7):821-831.
7 Forst T, Choudhary P, Schneider D, Linetzky B,Pozzilli P. A practical approach to the clinical challenges in initiation of basal insulin therapy in people with type 2 diabetes, Diab Metab Res Rev. 2020;e3418. Published online:
8 Tuccinardi , Giorgino R, Pieralice S, et al. The Utility of Assessing C-peptide in Patients with Insulin-Treated Type 2 Diabetes: a Cross-Sectional Study. Acta Diabetologica. 2020.



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