Controlling hypoglycemia in type 2 diabetes: Which agent for which patient?

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Controlling hypoglycemia in type 2 diabetes: Which agent for which patient?

J Fam Pract. 2005 October;54(10):855-862

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References

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2. Cryer PE, ed. Hypoglycemia: Pathophysiology, Diagnosis, and Treatment. New York, NY: Oxford University Press; 1997.

3. McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. Diabet Med 2001;18:690-705.

4. Towler DA, Havlin CE, Craft S, Cryer P. Mechanism of awareness of hypoglycemia. Perception of neurogenic (predominantly cholinergic) rather than neuroglycopenic symptoms. Diabetes 1993;42:1791-1798.

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6. Miller CD, Phillips LS, Ziemer DC, Gallina DL, Cook CB, El-Kebbi IM. Hypoglycemia in patients with type 2 diabetes mellitus. Arch Intern Med 2001;161:1653-1659.

7. The DCCT Research Group. Epidemiology of severe hypoglycemia in the diabetes control and complications trial. Am J Med 1991;90:450-459.

8. UK Prospective Diabetes Study Group. Perspectives in diabetes. UK Prospective Diabetes Study 16: overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes 1995;44:1249-1258.

9. United Kingdom Prospective Diabetes Study Group. UKPDS 24: a 6-year, randomized, controlled trial comparing sulfonylurea, insulin, and metformin therapy in patients with newly diagnosed type 2 diabetes that could not be controlled with diet therapy. Ann Intern Med 1998;128:165-175.

10. MacLeod KM, Hepburn DA, Frier BM. Frequency and morbidity of severe hypoglycaemia in insulin-treated diabetic patients. Diabet Med 1993;10:238-245.

11. Vervoort G, Goldschmidt HM, van Doorn LG. Nocturnal blood glucose profiles in patients with type 1 diabetes mellitus on multiple (>or=4) daily insulin injection regimens. Diabet Med 1996;13:794-799.

12. Gale EA, Tattersall RB. Unrecognised nocturnal hypoglycaemia in insulin-treated diabetics. Lancet 1979;1:1049-1052.

13. Pramming S, Thorsteinsson B, Bendtson I, Ronn B, Binder C. Nocturnal hypoglycaemia in patients receiving conventional treatment with insulin. Br Med J (Clin Res Ed) 1985;291:376-379.

14. Goudswaard AN, Furlong NJ, Valk GD, Stolk RP, Rutten GEHM. Insulin monotherapy versus combinations of insulin with oral hypoglycaemic agents in patients with type 2 diabetes mellitus. Cochrane Database Syst Rev 2004;4:1-51.

15. Strowig SM, Avilés-Santa ML, Raskin P. Comparison of insulin monotherapy and combination therapy with insulin and metformin or insulin and troglitazone in type 2 diabetes. Diabetes Care 2002;25:1691-1698.

16. Campbell IW. Hypoglycaemia and type 2 diabetes: sulphonylureas. In: Frier BM, Fisher BM, eds. Hypoglycaemia and Diabetes: Clinical and Physiological Aspects. London, UK: Edward Arnold, 1993;387-392.

17. Shorr RI, Ray WA, Daugherty JR, Griffin MR. Individual sulfonylureas and serious hypoglycemia in older people. J Am Geriatr Soc 1996;44:751-755.

18. Holstein A, Egberts EH. Risk of hypoglycaemia with oral antidiabetic agents in patients with Type 2 diabetes. Exp Clin Endocrinol Diabetes 2003;111:405-414.

19. Holstein A, Plaschke A, Egberts E-H. Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide. Diabetes Metab Res Rev 2001;17:467-473.

20. Aljabri K, Kozak SE, Thompson DM. Addition of pioglitazone or bedtime insulin to maximal doses of sulfonylurea and metformin in type 2 diabetes patients with poor glucose control: a prospective, randomized trial. Am J Med 2004;116:230-235.

21. Wolffenbuttel BHR, Landgraf R. A 1-year multicenter randomized double-blind comparison of repaglinide and glyburide for the treatment of type 2 diabetes. Dutch and German Repaglinide Study Group. Diabetes Care 1999;22:463-467.

22. Raskin P, McGill J, Saad MF, et al. Combination therapy for type 2 diabetes: repaglinide plus rosiglitazone. Diabetes Med 2004;21:329-335.

23. Dailey GE, III, Noor MA, Park JS, Bruce S, Fiedorek FT. Glycemic control with glyburide/metformin tablets in combination with rosiglitazone in patients with type 2 diabetes: a randomized, double-blind trial. Am J Med 2004;116:223-229.

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28. Lepore M, Pampanelli S, Fanelli C, et al. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes 2000;49:2142-2148.

29. Riddle MC, Rosenstock J, Gerich J. The Treat-to-Target Trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003;26:3080-3086.

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31. Standl E, Maxeiner S, Raptis S, Karimi-Anderesi Z, Schweitzer MA. Good glycemic control with flexibility in timing of basal insulin supply: a 24-week comparison of insulin glargine given once daily in the morning or at bedtime in combination with morning glimepiride. Diabetes Care 2005;28:419-420.

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Thus, using insulin glargine as basal insulin allows patients to reach recommended targets with fewer episodes of hypoglycemia, and can help address patients’ fear that can be a barrier to initiating insulin therapy in type 2 diabetes. Two recent studies have reported that dosing of insulin glargine can be flexible—morning or bedtime administration yields comparable low rates of hypoglycemia.^30,31

FIGURE 3
Hourly hypoglycemia rate with glargine much less than with NPH

*P<.05 (between treatment).
Copyright © 2003 American Diabetes Association. From Diabetes Care 2003; 26:3080–3086.²⁹ Reprinted with permission from American Diabetes Association.

Basal insulin plus prandial insulin

For patients who cannot otherwise reach Hb A_1c goals, basal insulin therapy may be supplemented with prandial insulin. Newer, rapid-acting analogs used for the prandial component are insulin lispro, insulin glulisine, or insulin aspart. Although this approach is physiologically more rational than regimens using conventional insulins, data are limited for use in type 2 diabetes.

The incidence of nocturnal hypoglycemia was evaluated in a study of patients with type 1 diabetes and impaired hypoglycemic awareness who were treated with 1 of 2 regimens: insulin lispro in a basal-prandial combination with NPH insulin, or twice-daily, premixed NPH/regular insulin.³³ Results showed that the incidence of nocturnal hypoglycemia was lower in patients receiving the insulin lispro regimen.

Another study, comparing insulin aspart and regular insulin as the prandial component in a basal-prandial regimen with NPH, showed that postprandial glucose control and Hb A_1c levels were significantly better after 1 year of treatment in the insulin aspart group than in the group receiving regular insulin, without an increased risk for hypoglycemia.³⁴ These results suggest that treatment with rapidacting insulin analogs could be helpful in avoiding hypoglycemia in patients with type 2 diabetes when a basal-prandial insulin regimen is indicated.

Avoiding hypoglycemia in the elderly

Elderly patients may be at increased risk for iatrogenic hypoglycemia. A populationbased study of patients presenting to an emergency room with severe hypoglycemic symptoms reported that rates of such events among elderly patients with type 2 diabetes and multiple comorbidities approached the rates among patients with type 1 diabetes.³⁵

FAST TRACK

Rapid-acting insulin analogs may be preferred when basalprandial regimen indicated

Creatinine clearance is often decreased in elderly patients, slowing elimination of oral agents and insulin and potentially resulting in sustained pharmacological action and creating a greater risk for hypoglycemia.

Furthermore, there is evidence that the neurogenic symptoms of hypoglycemia are reduced in elderly patients, diminishing awareness of hypoglycemia.³⁶

In the demented elderly, malnutrition, weight loss, and anorexia may exacerbate the risk for hypoglycemia. For elderly patients with tertiary disease (eg, cerebrovascular accident, myocardial infarction, congestive heart failure, blindness, chronic renal failure), the risk for hypoglycemia and subsequent comorbidity may outweigh the benefits of strict glycemic control.^3,37 Elderly patients may have comorbid conditions that increase risk of falls (eg, poor vision, neurologic conditions), and hypoglycemic episodes may further increase the risk of falls and lead to morbidity (eg, fragility fracture in patients with osteopenia or osteoporosis).

Because the elderly are at a greater risk for hypoglycemia, a switch to a less restrictive diet, such as a “no concentrated sweets” diet, is an option, with control of glucose levels through the administration of oral agents or insulin.³⁶ This may also promote a better quality of life, considering that many of these patients already have secondary and tertiary complications of diabetes, prevention of which is not a realistic goal.

CORRESPONDING AUTHOR
William Cefalu, MD, Professor and Chief, Division of Nutrition and Chronic Diseases, Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808. Email: cefaluwt@pbrc.edu