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Triple Therapy

Definitions, application, and treating to target

From the Diabetes Program, King-Drew Medical Center, Los Angeles, California

Address correspondence to Mayer B. Davidson, MD, Clinical Trials Unit, Charles R. Drew University, 1731 East 120th St., Los Angeles, CA 90059. E-mail: madavids{at}cdrewu.edu

In this issue of Diabetes Care, Strowig, Avilés-Santa, and Raskin (1) evaluated the glycemic response to "triple therapy" in a small number of patients. Their study of triple therapy involved adding metformin to type 2 diabetic patients receiving >30 units of insulin plus troglitazone or adding troglitazone to similar patients receiving >30 units of insulin plus metformin. The added oral antidiabetes medications were titrated upward over 1 month to maximal doses and the patients followed for another 3 months without further changes in their doses. Insulin doses were not allowed to be increased but could be decreased in response to hypoglycemia. Although these patients were well controlled at baseline, their control improved even further with this triple therapy. A1C levels in patients in whom troglitazone was added fell from 7.0 ± 0.8% (mean ± SD) at baseline to 6.1 ± 0.4%. Corresponding changes in A1C levels in the group receiving metformin as the third medication were 6.2 ± 0.8 to 5.8 ± 0.6%.

There is no agreement on what constitutes triple therapy. The term has been used to describe oral medications from three classes of antidiabetes drugs, as well as various insulin regimens (mixed-split, basal-bolus, preprandial lispro) in combination with two oral medications (1–3). Although triple therapy has not been used to describe it, probably the most common combination is bedtime NPH (or glargine) insulin plus two oral medications. I would propose that we modify the term triple therapy in patients taking three medications to "triple oral therapy" or "triple therapy with insulin," depending on what the patient is taking. The specific components can then be added, e.g., triple oral therapy (metformin, glyburide, pioglitazone), triple therapy with insulin (bedtime glargine, glipizide, rosiglitazone), etc. If one wanted to be more specific, the doses of each could be placed next to the drug.

Regardless of terminology, one must put triple therapy in the therapeutic perspective. There is no one right way to treat type 2 diabetes. The goal is to achieve evidence-based targets. For a glycemic outcome, the American Diabetes Association’s goal is an A1C level <7%. This is based on the results of five studies in several thousand diabetic patients carried out over 6–9 years relating the average A1C level to the development and progression of the microvascular complications of diabetes (4–8). All five demonstrated that if the average A1C level was <1% above the upper limit of normal (ULN) for the assay used (e.g., <7% for the assay used in the Diabetes Control and Complications Trial [DCCT], in which the ULN was 6.0%), there was virtually no development or progression of diabetic retinopathy or nephropathy. If the average A1C levels were between 1 and 2% above the ULN (7–8% in a DCCT-standardized assay), there was a slight increase in the development and progression of these complications. Average values >2% above the ULN (>8% in a DCCT-standardized assay) were associated with much higher risks for the microvascular complications. Thus, lower goal values, e.g., <6.5%, are not evidence based, and the harm of increased hypoglycemia (4) would not seem balanced by any additional benefit.

Many studies have compared various therapeutic approaches in type 2 diabetic patients at specific points in the course of their disease progression, e.g., failing monotherapy, failing dual oral therapy. There have been no studies, and indeed there probably never will be, directly comparing different therapeutic approaches along the progressive continuum of type 2 diabetes. However, two studies (9,10), utilizing very similar therapeutic approaches that were driven by algorithms, demonstrated glycemic outcomes just slightly above the A1C target level of 7% after 1 year. That these results were achieved in poorly educated, minority populations strongly suggests that similar outcomes are attainable in general. Therapy was progressively increased from diet/exercise in asymptomatic patients to monotherapy with metformin or a sulfonylurea agent, and to dual oral therapy with both of these. An important factor in their success was the imperative to raise the doses of metformin or the sulfonylurea agent every 2 weeks until either the American Diabetes Association’s fasting plasma glucose goal was achieved or the maximal dose was reached, at which time the other medication was added. In this manner, patients did not remain out of control for long periods of time. Before glitazones became available, the next step was to add bedtime NPH insulin. If the cost of glitazones is a factor, this still remains an attractive option. In our institution (9), glitazones have been added to the formulary to be used for either triple oral therapy (metformin, glipizide or glyburide, glitazone) (11) (or if patients take >80 units insulin/day and remain in poor control). If triple oral therapy fails, bedtime insulin is substituted for the glitazone.

Since triple oral therapy (metformin 2,000 mg/day, glyburide 20 mg/day, pioglitazone 45 mg/day) was as effective as triple therapy with insulin (metformin 2,000 mg/day, glyburide 20 mg/day, bedtime NPH) (12), cost and lifestyle considerations may be the deciding factors when dual therapy fails. Of course, the bottom line is to treat to target, regardless of how one gets there. The approach described above is a cost-effective way to do just that.

References

1. Strowig SM, Avilés-Santa ML, Raskin P: Improved glycemic control without weight gain using triple therapy in type 2 diabetes. Diabetes Care 27:1577–1583, 2004[Abstract/Free Full Text]
   
2. Poulsen MK, Henriksen JE, Hother-Nielsen O, Beck-Nielsen H: The combined effect of triple therapy with rosiglitazone, metformin, and insulin aspart in type 2 diabetic patients. Diabetes Care 26:3273–3279, 2003[Abstract/Free Full Text]
   
3. Hsia SH, Davidson MB: Combination therapy in type 2 diabetes. In Diabetes Mellitus: A Fundamental and Clinical Text. 3rd ed. LeRoith D, Taylor S, Olefsky J, Eds. Philadelphia, Lippincott, Williams & Wilkins, 2004, p. 1177–1190
   
4. DCCT Research Group: The effect of intensive diabetes treatment on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986, 1993[Abstract/Free Full Text]
   
5. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami I, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randmized prospective 6-year study. Diabetes Res Clin Pract 28:103–117, 1995[Medline]
   
6. Krolewski AS, Laffel LMB, Krolewski M, Quinn M, Warram JH: Glycosylated hemoglobin and the risk of microalbuminuria in patients with insulin-dependent diabetes mellitus. N Engl J Med 332:1251–1255, 1995[Abstract/Free Full Text]
   
7. Tanaka Y, Atsumi Y, Matsuoka K, Onuma T, Tohjima T, Kawamori R: Role of glycemic control and blood pressure in the development and progression of nephropathy in elderly Japanese NIDDM patients. Diabetes Care 21:116–120, 1998[Abstract]
   
8. Warram JH, Scott LJ, Hanna LS, Wantman M, Cohen SE, Laffel LM, Ryan L, Krolewski AS: Progression of microalbuminuria to proteinuria in type 1 diabetes: nonlinear relationship with hyperglycemia. Diabetes 49:94–100, 2000[Abstract]
   
9. Davidson MB: Effect of nurse-directed diabetes care in a minority population. Diabetes Care 26:2281–2287, 2003[Abstract/Free Full Text]
   
10. Fanning EL, Selwyn BJ, Larme AC, DeFronzo RA: Improving efficacy of diabetes management using treatment algorithms in a mainly Hispanic population Diabetes Care 27:1638–1646, 2004[Abstract/Free Full Text]
    
11. Roy R, Navar M, Palomeno G, Davidson MB: Real world effectiveness of rosiglitazone added to maximal (tolerated) doses of metformin and a sulfonylurea agent: a systematic evaluation of triple oral therapy in a minority population. Diabetes Care 27:1741–1742, 2004[Free Full Text]
    
12. 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 116:230–235, 2004[Medline]
    

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				J. Rosenstock, D. Sugimoto, P. Strange, J. A. Stewart, E. Soltes-Rak, G. Dailey, and on behalf of the Insulin Glargine 4014 Study Inves Triple Therapy in Type 2 Diabetes: Insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naive patients. Diabetes Care, March 1, 2006; 29(3): 554 - 559. [Abstract] [Full Text] [PDF]

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