Optimizing combination therapy for type 2 diabetes in adolescents and adults: A case-based approach

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Applied Evidence

Optimizing combination therapy for type 2 diabetes in adolescents and adults: A case-based approach

J Fam Pract. 2004 October;53(10):815-822

By

Tom A. Elasy, MD, MPH

Philip Levy, MD

Stephen N. Davis, MD, FRCP

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References

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24. Sonnenberg GE, Garg DC, Weidler DJ, et al. Short-term comparison of once- versus twice-daily administration of glimepiride in patients with non-insulin-dependent diabetes mellitus. Ann Pharmacother. 1997;31:671-676.

25. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care. 2004;27:256-263.

26. May LD, Lefkowitch JH, Kram MT, Rubin DE. Mixed hepatocellular-cholestatic liver injury after pioglitazone therapy. Ann Intern Med. 2002;136:449-452.

27. Pinto AG, Cummings OW, Chalasani N. Severe but reversible cholestatic liver injury after pioglitazone therapy. Ann Intern Med. 2002;137:857.-

28. Maeda K. Hepatocellular injury in a patient receiving pioglitazone. Ann Intern Med. 2001;135:306.-

29. Dhawan M, Agrawal R, Ravi J, et al. Rosiglitazone-induced granulomatous hepatitis. J Clin Gastroenterol. 2002;34:582-584.

30. Forman LM, Simmons DA, Diamond RH. Hepatic failure in a patient taking rosiglitazone. Ann Intern Med. 2000;132:118-121.

31. Al Salman J, Arjomand H, Kemp DG, Mittal M. Hepatocellular injury in a patient receiving rosiglitazone. A case report. Ann Intern Med. 2000;132:121-124.

32. Coniff RF, Shapiro JA, Robbins D, et al. Reduction of glycosylated hemoglobin and postprandial hyperglycemia by acarbose in patients with NIDDM. A placebo-controlled dose-comparison study. Diabetes Care. 1995;18:817-824.

33. Fritsche A, Schweitzer MA, Haring HU. Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. A randomized, controlled trial. Ann Intern Med. 2003;138:952-959.

34. Hirsch IB. Treatment of patients with severe insulin deficiency; what we have learned over the past 2 years. Am J Med. 2004;116(suppl 3A):17S-22S.

35. Hunt LM, Valenzuela MA, Pugh JA. NIDDM patients’ fears and hopes about insulin therapy. The basis of patient reluctance. Diabetes Care. 1997;20:292-298.

36. Frykberg RG. Diabetic foot ulcers: pathogenesis and management. Am Fam Physician. 2002;66:1655-1662.

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38. 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.

39. 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.

40. Rendell MS, Glazer NB, Ye Z. Combination therapy with pioglitazone plus metformin or sulfonylurea in patients with Type 2 diabetes: influence of prior antidiabetic drug regimen. J Diabetes Complications. 2003;17:211-217.

41. Fonseca V, Grunberger G, Gupta S, Shen S, Foley JE. Addition of nateglinide to rosiglitazone monotherapy suppresses mealtime hyperglycemia and improves overall glycemic control. Diabetes Care. 2003;26:1685-1690.

42. Raskin P, Klaff L, McGill J, et al. Efficacy and safety of combination therapy: repaglinide plus metformin versus nateglinide plus metformin. Diabetes Care. 2003;26:2063-2068.

43. Schwartz S, Sievers R, Strange P, Lyness WH, Hollander P. Insulin 70/30 mix plus metformin versus triple oral therapy in the treatment of type 2 diabetes after failure of two oral drugs: efficacy, safety, and cost analysis. Diabetes Care. 2003;26:2238-2243.

44. Wolffenbuttel BH, Gomis R, Squatrito S, Jones NP, Patwardhan RN. Addition of low-dose rosiglitazone to sulphonylurea therapy improves glycaemic control in type 2 diabetic patients. Diabet Med. 2000;17:40-47.

45. Fonseca V, Rosenstock J, Patwardhan R, Salzman A. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA. 2000;283:1695-1702.

46. Moses R, Slobodniuk R, Boyages S, et al. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 1999;22:119-124.

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49. Weitgasser R, Lechleitner M, Luger A, Klingler A. Effects of glimepiride on HbA(1c) and body weight in Type 2 diabetes: results of a 1.5-year follow-up study. Diabetes Res Clin Pract. 2003;61:13-19.

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Practice recommendations

Children and adolescents who are overweight and have additional risk factors (ie, high-risk ethnic group or signs of insulin resistance) should be screened for diabetes every 2 years (SOR: C).
Management of type 2 diabetes in all age groups requires a multifactorial approach that addresses not only glycemic control (A1C <7%) but also other cardiovascular risk factors such as hypertension, dyslipidemia, and obesity (SOR: A).¹
Most patients with type 2 diabetes will eventually require combination therapy with 2 or more agents to attain and maintain glycemic control (SOR: A).^2,3
Combining an insulin secretagogue (ie, sulfonylurea or meglitinide) and an insulin sensitizer (ie, metformin or a glitazone) capitalizes on unique mechanisms of action and results in Significant A1C lowering (SOR: C).
If a patient is unable to achieve glycemic control on 2 oral agents, insulin therapy is an appropriate consideration and should be added to oral agents (rather than substituted) (SOR: B).⁴

Diabetes affects 18.2 million people in the United States.⁵ It is a leading cause of morbidity and mortality.⁵ Diabetes is associated with more than $90 billion in direct medical costs and with an estimated $40 billion in indirect costs (ie, disability, work loss, and premature mortality).⁵ Type 2 diabetes accounts for 90% to 95% of total cases. It disproportionately affects certain minority populations, and it is increasingly being identified in children and adolescents.^5-7

The obesity epidemic has received tremendous media and public attention and has sobering implications for the development of metabolic syndrome, which is often the precursor to diabetes, and cardiovascular disease (CVD).^8,9 In 1 study, the hazard ratio for development of diabetes was 3.85 for individuals who gained 20 kg or more over approximately 10 years, as compared with individuals whose weight remained relatively stable over the same period.¹⁰ Obesity is associated with elevations in free fatty acid levels and in other compounds which contribute to insulin resistance¹¹ —a key underlying defect in metabolic syndrome and type 2 diabetes. Thus, particularly in genetically predisposed individuals, obesity (through elevated fatty acids) may be the factor that drives insulin resistance to clinical diabetes. In addition, elevated free fatty acid levels also may contribute to the other key underlying defect in type 2 diabetes: progressive pancreatic β-cell loss which results in insulin deficiency.¹² Similar to the trend in adults, childhood obesity has now reached epidemic proportions and has been associated with the increased prevalence of glucose intolerance, metabolic syndrome, and biomarkers of increased CVD risk in this young population.^13-15

Type 2 diabetes in adolescents

CASE 1 Suspected new-onset type 2 diabetes

A 16-year-old Hispanic boy presents for treatment of weight loss. He is a defensive tackle on the high school football team and has a strong appetite. His height is 6 ft 1 in and he weighs 250 lb; his body mass index (BMI) is 32 kg/m², and most of the fat is abdominally distributed (waist circumference, 42 in). Both of his parents are obese, and a grandfather and aunt have type 2 diabetes. Further examination reveals a blood pressure (BP) level of 135/87 mm Hg and acanthosis nigricans. A random fingerstick test shows a blood glucose level of 240 mg/dL.

Until recently, type 2 diabetes rarely was observed in children, occurring in only 1% to 2% of children with new-onset diabetes.¹⁶ However, depending on the sampling strategy, race or ethnicity of the population, and the region of the country sampled, it now has been estimated that type 2 diabetes accounts for anywhere from 8% to 45% of all diabetes reported among children and adolescents.^6,16 Prevalence estimates of pediatric type 2 diabetes in population-based studies range from 4.1 per 1,000 in the National Health and Nutrition Survey (NHANES III) to 50.9 per 1,000 among Pima Indians in Arizona.¹⁷ Unlike the trends of increasing incidence and prevalence of type 2 diabetes in the pediatric population, a similar trend in type 1 diabetes has not been observed.⁷

The diagnosis and treatment of type 2 diabetes in pediatric patients can be challenging. Type 2 diabetes is associated with an increased BMI and is more common in adolescents than in younger children.⁶ Puberty is associated with relative insulin resistance and, along with the time-related effects of obesity, resistance may play a role in the subsequent onset of type 2 diabetes in pediatric patients. However, as an increasing number of children become obese at an earlier age, the onset of disease may occur earlier.

Other risk factors for type 2 diabetes in childhood include having a first- or second-degree relative with the disease or non-European ancestry (Americans of African, Hispanic, Asian, Pacific Islander, or Native American descent). In addition, acanthosis nigricans is a skin condition that serves as a specific, though insensitive, marker of insulin resistance. Among adolescent females, polycystic ovary syndrome has been associated with insulin resistance irrespective of excess weight or frank obesity¹⁸ and may be associated with an increased risk of type 2 diabetes.⁶