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

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Original Research

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

J Fam Pract. 2004 May;53(5):393-399

By

Alex N. Goudswaard, MD

A randomized trial in primary care

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References

1. Burgers JS, Bailey JV, Klazinga NS, Van der Bij AK, Grol R, Feder G. Inside guidelines: comparative analysis of recommendations and evidence in diabetes guidelines from 13 countries. Diabetes Care 2002;25:1933-1939.

2. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care 2002;25:S33-S49.

3. Garber AJ. Benefits of combination therapy of insulin and oral hypoglycemic agents. Arch Intern Med 2003;163:1781-1782.

4. Westphal SA, Palumbo PJ. Insulin and oral hypoglycemic agents should not be used in combination in the treatment of type 2 diabetes. Arch Intern Med 2003;163:1783-1785.

5. Rutten GEHM, Verhoeven S, Heine RJ, et al. Diabetes mellitus type 2. NHG-standaard (eerste herziening) (in Dutch). Huisarts Wet 1999;42:67-84.

6. Yki-Järvinen H. Combination therapies with insulin in type 2 diabetes. Diabetes Care 2001;24:758-767.

7. De Sonnaville JJ, Snoek FJ, Colly LP, Deville W, Wijkel D, Heine RJ. Well-being and symptoms in relation to insulin therapy in type 2 diabetes. Diabetes Care 1998;21:919-924.

8. De Grauw WJ, Van de Lisdonk EH, Van Gerwen WH, Van Den Hoogen HJ, Van Weel C. Insulin therapy in poorly controlled type 2 diabetic patients: does it affect quality of life? Br J Gen Pract 2001;51:527-532.

9. Bradley C. Handbook of Psychology and Diabetes. A Guide to Psychological Measurement in Diabetes Research and Practice. Amsterdam: Harwood Academic Publishers; 1994.

10. Pouwer F, Snoek FJ, Van der Ploeg HM, Ader HJ, Heine RJ. The well-being questionnaire: evidence for a three-factor structure with 12 items (W-BQ12). Psychol Med 2000;30:455-462.

11. Mollema ED, Snoek FJ, Pouwer F, Heine RJ, Van der Ploeg HM. Diabetes Fear of Injecting and Self-Testing Questionnaire: a psychometric evaluation. Diabetes Care 2000;23:765-769.

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Practice recommendations

Consider adding bedtime NPH insulin to maximal oral therapy—a simple, safe, and well-tolerated regimen that lowers HbA_1c on average by 1 percentage point.
Expect this regimen to fail for about 25% of patients within 1 year.

ABSTRACT

Objective: To evaluate the effects of insulin 30/70 twice daily or bedtime isophane (NPH) insulin plus continued sulfonylurea and metformin in patients with type 2 diabetes in primary care.

Study Design: Open-label, randomized trial.

Population: Persons younger than 76 years with type 2 diabetes whose disease had not been controlled with oral hypoglycemic agents alone. A total of 64 insulinnaïve patients treated with maximal feasible dosages of sulfonylurea and metformin (baseline glycosylated hemoglobin [HbA_1c]=8.5%) were randomly assigned to insulin monotherapy (IM group; n=31) or insulin in addition to unchanged oral hypoglycemic medication (IC group; n=33) for 12 months. Insulin doses were adjusted to obtain fasting glucose <7.0 mmol/L and postprandial glucose <10.0 mmol/L.

Outcomes Measured: Outcome measures included HbA_1c, treatment failure, weight, hypoglycemic events and symptoms, satisfaction with treatment, general well-being, and fear of injecting insulin and testing.

Results: HbA_1c improved from 8.3% to 7.6% in the IC group, and from 8.8% to 7.6% in the IM group (P=NS). The IC group had 24% treatment failures, compared with 2% in the IM group (P=.09). Patients in the IC group had less weight gain than those in the IM group (1.3 vs 4.2 kg; P=.01), and they reported fewer hypoglycemic events (2.7 vs 4.3; P=.02). Increased satisfaction with treatment was equal in the 2 groups, and general well-being improved by 3.0 points more in the IC group (P=.05). Fear of self-injecting and self-testing did not differ.

Conclusions: Bedtime NPH insulin added to maximal therapy with sulfonylurea and metformin is an effective, simple, well-tolerated approach for patients with uncontrolled type 2 diabetes.

The goal for glycemic control in current guidelines on type 2 diabetes is a glycosylated hemoglobin (HbA_1c) value of <7.0%.¹ If this target is not achieved or maintained with sulfonylurea and metformin at maximally tolerated dosages, insulin therapy is recommended as the next step for patients without advanced diabetes complications and with a reasonably long life expectancy.²

There is little doubt that exogenous insulin aids in glycemic control at this stage of disease. It is still debated, though, whether insulin should be used as monotherapy or be added to a regimen of 1 or 2 oral agents (combination therapy).^{3, 4}

Guidelines on type 2 diabetes conflict with one another about indications for treatment and preferred regimens, and most recommendations are based on less-than-sufficient evidence.¹ For example, it is unclear in the case of combination therapy whether sulfonylurea or metformin or both should be continued. Moreover, the Dutch guideline on type 2 diabetes recommends that in combination therapy, the dose of isophane (neutral protamine Hagedorn or NPH) insulin be taken to a maximum of 40 IU, after which one should switch to a regimen of twice-daily insulin only. This recommendation is not based on published evidence.⁵

A number of randomized controlled trials have investigated the efficacy of different insulin regimens in patients whose diabetes was not controlled with oral agents. Few studies, though, have included patients using both sulfonylurea and metformin.⁶ In addition, studies that have measured treatment satisfaction, general wellbeing, fear of injections, and hypoglycemic complaints are sparse. Although we know from observational studies that insulin therapy is usually well accepted,^7,8 little is known as to what extent patient satisfaction and quality of life are influenced by either treatment schemes.

The purpose of this study was to compare insulin monotherapy with insulin combination therapy in patients whose diabetes was inadequately controlled (HbA_1c ≥7.0%) despite maximally tolerated dosages of sulfonylurea and metformin. Endpoints included glycemic control, insulin dosage, body weight, number of treatment failures, number of hypoglycemic events and symptoms, treatment satisfaction, general well-being, and fear of injections and self testing.

Methods

Design

This was an open-label, parallel group trial of 12 months duration. Patients were randomly assigned to receive NPH insulin at bedtime (Insulatard; Novo Nordisk, Copenhagen, Denmark) in addition to current treatment with sulfonylurea and metformin (insulin combination [IC] group) or to receive a mixture of 30% soluble and 70% NPH insulin (Mixtard 30/70; Novo Nordisk, Copenhagen, Denmark), twice daily before breakfast and dinner (insulin monotherapy [IM] group). Randomization was performed by a telephone call to an independent trial center that used a computer-generated random assignment.

The medical ethics committee of the University Medical Centre of Utrecht approved the study. All patients gave written informed consent.

Patients

Patients were recruited from family practices in and around the city of Utrecht, the Netherlands. Patients were asked to participate if they were younger than 76 years, had HbA_1c ≥7.0% despite treatment with both sulfonylurea and metformin in maximally tolerated dosages, were willing to start insulin therapy, and were deemed by their family physician to be candidates for more tight glycemic control.