Insulin therapy in type 2 diabetes mellitus TROUBLESHOOTING 1

TROUBLESHOOTING

Insulin resistance — In severely insulin-resistant patients (eg, requiring more than 200 total units of insulin daily), concentrated insulins can be used to control hyperglycemia. Concentrated insulin formulations permit equivalent dosing in smaller volumes and without the need for numerous injections to deliver high doses. Because the high concentration of insulin delays absorption, the pharmacokinetics are often affected. As an example, the pharmacologic profile of U-500 regular insulin is most similar to that of NPH. (See "General principles of insulin therapy in diabetes mellitus", section on 'U-500 regular insulin'.)

Glargine 300 units/mL is very similar to glargine but has a volume one-third of that for the same dose of glargine 100 units/mL. The pharmacokinetics are slightly different, with less of a peak and a longer duration of action. Consequently, glargine 300 units/mL is more similar to degludec than glargine 100 units/mL [50]. (See "General principles of insulin therapy in diabetes mellitus", section on 'U-300 insulin glargine'.)

Insulin-associated weight gain — Patients initiating insulin therapy should be aware of the potential for weight gain, and major emphasis should be placed on diet and lifestyle modification to prevent it. It is important to educate patients about insulin dose reduction for anticipated increases in physical activity and with changes in diet to reduce the risk of hypoglycemia as well as weight gain.

Patients with type 2 diabetes, insulin resistance, and obesity are susceptible to insulin-associated weight gain. This can be due to continued dietary indiscretion, reduction in glycosuria with more physiologic glycemic control, conscious or subconscious snacking to support an insulin dose that is too high, overtreatment of hypoglycemia, overly tight glycemic targets, or a combination of these factors. The resulting weight gain worsens insulin resistance and may prompt insulin dose escalation, leading to a vicious cycle.

The magnitude of the weight gain depends upon the intensity of regimen (dose and frequency of insulin) and the dietary pattern [51]. In the United Kingdom Prospective Diabetes Study (UKPDS), the average weight gain after 10 years of insulin therapy was approximately 7 kg for patients with type 2 diabetes, with the most rapid weight gain occurring when insulin was first initiated [52]. Less intensive therapy with either insulin or a sulfonylurea (which increases endogenous insulin secretion) was associated with a 3.5 to 4.8 kg weight gain at three years versus no change with metformin monotherapy [47]. In a subsequent trial, weight gain was greater with prandial than basal insulin (4.8 versus 3.1 kg) [18]; however, patients receiving prandial insulin also received a greater insulin dose, which could account for the small difference in weight gain. In other trials, pre-mixed rapid-acting preparations were more often associated with weight gain than long-acting insulin or oral agents [44].

It is not clear if the weight gain is important for diabetes complications, as microvascular complications were reduced with insulin monotherapy in the UKPDS despite weight gain [52]. Whether weight gain with insulin might adversely affect risk for cardiovascular disease (CVD) in type 2 diabetes is not clear; however, in type 1 diabetes, intensive insulin therapy in Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) resulted in weight gain but a major reduction in CVD [53]. A subsequent analysis of the DCCT data revealed that the CVD benefit of intensive therapy was attenuated by weight gain [54]. (See "Initial management of blood glucose in adults with type 2 diabetes mellitus", section on 'Diabetes education'.)