Starting insulin in type 2 diabetes: Continue oral hypoglycemic agents?

Discussion

In this practice-based study of insulin-naïve patients, HbA_1c improved ~1 percentage point with both insulin combination therapy and insulin monotherapy. However, with both strategies, around 40% of patients reached HbA_1c levels <7%, which forces us to be realistic regarding the glycemic target that can be achieved in the current family practice setting. Despite systematic titration of the insulin dosage, 24% of the patients in the IC group did not reach the titration targets. In addition, HbA_1c levels for those patients did not change from baseline, in contrast with patients in the IC group who did reach the targets (Figure 1). So it is doubtful if lower HbA_1c levels could have been achieved if the study design had allowed for increasing the daily insulin dose over 40 IU.

Treatment failure rate in this study was considerably lower compared with 66% failures reported in another trial in which insulin NPH or glargine was added to oral therapy.¹³ However, this difference could probably be explained by a difference in target for fasting blood glucose: ≤5.6 mmol/L vs ≤7.0 in our study. So it might be relevant in future research to seek factors that could predict failure on oral agent/insulin combinations.¹⁴

With insulin monotherapy, body weight increased significantly, and patients experienced more hypoglycemic events. Treatment satisfaction did not differ, whereas general well-being improved more with combination therapy. For most patients, the injection- and test-activities appeared to be well tolerated, with no differences between treatment groups.

Though several trials have been conducted to compare insulin combination therapies with insulin monotherapy in insulin-naïve patients,^6,15-17 studies with follow-up >6 months, and including patients taking maximum dosages of two oral agents, are sparse. Moreover, no studies have been conducted in a primary care setting. Chow et al compared a regimen of bedtime NPH insulin and 1 or 2 oral agents with a regimen of premixed insulin 30/70 in 53 mostly lean patients during 6 months.¹⁸ The effects on HbA_1c, body weight, and number of hypoglycemic events were comparable to our results, and a similar treatment failure rate in the combination group was found.

Yki-Järvinen et al studied the effects of 4 insulin regimens including the addition of bedtime NPH insulin to either morning NPH, glyburide, metformin, or glyburide plus metformin in patients previously treated with maximal dosage sulfonylurea.¹⁹ The greatest decrease in HbA_1c accompanied by the lowest number of hypoglycemic events was observed in the insulin/metformin group.

However, the impact of these results might be limited, since current guidelines recommend treatment with maximum doses of both sulfonylurea and metformin before introducing insulin therapy.^2,8 Nevertheless, the results underline the favorable influence on relevant outcomes of insulin combination therapy compared with insulin monotherapy, provided that at least metformin is used.

Patients in our study were recruited during regular appointments with their own care provider, and insulin treatment was established under “usual care” conditions. So it is likely that this study group represents the type 2 diabetes patients in primary care that, sooner or later, should start insulin therapy, and that the results of this study are highly applicable to them.

Our results suggest that an evening injection with NPH insulin in addition to an existing maximal therapy with sulfonylurea and metformin can be recommended as an effective, simple, and well-tolerated first-choice approach with patients who are willing to continue oral medication. Since both family physicians and patients are inclined to delay starting insulin,²⁰ such a strategy might encourage the timely use of insulin.¹⁴

Acknowledgments

We thank Rianne Maillé for her expert contribution concerning the questionnaires. In particular we would like to thank the patients, diabetes nurses, and family physicians for their participation.

Corresponding author
Alex N. Goudswaard, Koperslagersgilde 5, 3994 CH Houten, Netherlands. E-mail: lex@goudswaard.cx.