Therapeutic Effect of Quadruple Oral Hypoglycemic Agents in Patients with Type 2 Diabetes Mellitus Who Have Insulin Limitations

Won Sang Yoo; Do Hee Kim; Hee Jin Kim; Hyun Kyung Chung

doi:10.4093/jkd.2019.20.2.117

Journal List > J Korean Diabetes > v.20(2) > 1129402

Go to TopGo to Top Go to BottomGo to Bottom

TOOLS

Yoo, Kim, Kim, and Chung: Therapeutic Effect of Quadruple Oral Hypoglycemic Agents in Patients with Type 2 Diabetes Mellitus Who Have Insulin Limitations

Original Article

The Journal of Korean Diabetes 2019; 20(2): 117-126.

Published online: 30 June 2019

DOI: https://doi.org/10.4093/jkd.2019.20.2.117

Therapeutic Effect of Quadruple Oral Hypoglycemic Agents in Patients with Type 2 Diabetes Mellitus Who Have Insulin Limitations

Won Sang Yoo¹, Do Hee Kim^1,², Hee Jin Kim¹, Hyun Kyung Chung¹

¹Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea.

²Department of Kinesiologic Medical Science, Graduate School, Dankook University, Cheonan, Korea.

Corresponding author: Hyun Kyung Chung. Department of Internal Medicine, Dankook University College of Medicine, 119 Dandae-ro, Dongnam-gu, Cheonan 31116, Korea, chkendo@dankook.ac.kr

Received 13 September 2018 Revised 29 November 2018 Accepted 25 January 2019

Korean Diabetes Association

(open-access):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Insulin therapy is the treatment of choice in type 2 diabetes mellitus (T2DM) patients who are not achieving glycemic goals despite triple oral hypoglycemic agent (OHA) combination therapy. However, there is still no additional treatment option for patients who cannot afford insulin therapy or who have various clinical limitations. The purpose of this study was to evaluate the clinical efficacy and safety of four OHA combination therapy in poorly controlled T2DM patients who could not afford insulin therapy.

Methods

Forty-seven T2DM patients were enrolled according to the following criteria: 1) glycosylated hemoglobin [HbA1c] > 8.5%, 2) ongoing treatment with 3 OHA combination therapy (metformin, sulfonylurea, dipeptidyl peptidase-4 inhibitor), or 3) combined limitations for applying insulin therapy. Patients were given the fourth OHA (pioglitazone) in addition to their previous treatment for 12 months. We evaluated changes in HbA1c, body weight, hypoglycemic events, and side effects.

Results

At study completion, mean HbA1c and fasting plasma glucose were significantly reduced from 9.6% to 8.04% and from 198.4 mg/dL to 161.5 mg/dL, respectively (P < 0.001). Mean body weight was significantly increased from 66.7 kg to 69.3 kg. Hypoglycemia and side effects were observed 18 times and only 3 cases showed abnormal liver function tests or edema. In addition, subjects with higher initial HbA1c levels and HOMA-beta showed an independent association with a greater reduction in HbA1c.

Conclusion

The 4 OHA combination therapy is effective and safe when insulin is not feasible.

Keywords: Diabetes mellitus, type 2, Drug therapy, combination, Hypoglycemic agents

Figures and Tables

Fig. 1

Change in mean glycosylated hemoglobin (HbA1c) in patients with 4 oral hypoglycemic agent (OHA) therapy.

^aMean HbA1c was significantly decreased after 4 OHA therapy (P < 0.01).

Fig. 2

Change in mean fasting plasma glucose in patients with 4 oral hypoglycemic agent therapy.

^aMean fasting plasma glucose was significantly decreased after 4 OHA therapy (P < 0.01).

Fig. 3

Change of mean body weight in patients with 4 oral hypoglycemic agent therapy.

^aMean body weight was significantly increased after 4 OHA therapy (P < 0.01).

Table 1

Patient baseline clinical characteristics

Values are presented as mean±standard deviation or number (%).

HbA1c, glycosylated hemoglobin; HOMA-IR, homeostasis model assessment insulin resistance; HOMA-beta, homeostasis model assessment beta cell function; CVD, cardiovascular disease; DPP4, dipeptidyl peptidase-4.

Table 2

Comparison of clinical characteristics between good responders and non-responders in 4 drug combination treatment patients, defined as a decrease in HbA1c ≥1.0%

Values are presented as mean±standard deviation or number (%).

HbA1c, glycosylated hemoglobin; HOMA-IR, homeostasis model assessment insulin resistance; HOMA-beta, homeostasis model assessment beta cell function.

Table 3

Simple correlation analysis between reduction of HbA1c after 12 months and clinical variables

HbA1c, glycosylated hemoglobin; SE, standard error; HOMA-IR, homeostasis model assessment insulin resistance; HOMA-beta, homeostasis model assessment beta cell function.

Table 4

Multiple linear regression analysis of variables for HbA1c reduction after 12 months in 4 oral hypoglycemic agent therapy

Dependent variable: reduction of HbA1c after 48 weeks; independent variable: age, BMI, duration of diabetes, initial HbA1c, creatinine, HOMA-IR, HOMA-beta.

HbA1c, glycosylated hemoglobin; SE, standard error; BMI, body mass index; HOMA-beta, homeostasis model assessment beta cell function; HOMA-IR, homeostasis model assessment insulin resistance.

Notes

^{CONFLICTS OF INTEREST} No potential conflicts of interest relevant to this article were reported.

References

1. American Diabetes Association. 7. Obesity management for the treatment of type 2 diabetes: standards of medical care in diabetes—2018. Diabetes Care. 2018; 41:Suppl 1. S65–S72.

2. Korean Diabetes Association. 2015 Treatment guidelines for diabetes (5th edition). updated 2016 Mar 23. Available from: http://www.diabetes.or.kr/pro/publish/guide.php?code=guide&number=638&mode=view.

3. Kim SS, Kim IJ, Kim YK, Yoon KH, Son HY, Park SW, Sung YA, Baek HS. Insulin initiation in insulin-naïve Korean type 2 diabetic patients inadequately controlled on oral antidiabetic drugs in real-world practice: The Modality of Insulin Treatment Evaluation Study. Diabetes Metab J. 2015; 39:481–488.

4. University of Oxford. HOMA2 calculator. updated 2016 Mar 31. Available from:https://www.dtu.ox.ac.uk/homacalculator/.

5. Igarashi M, Jimbu Y, Kimura M, Hirata A, Yamaguchi H, Tominaga M. Effect of pioglitazone on atherogenic outcomes in type 2 diabetic patients: a comparison of responders and non-responders. Diabetes Res Clin Pract. 2007; 77:389–398.

6. Davies MJ, Gagliardino JJ, Gray LJ, Khunti K, Mohan V, Hughes R. Real-world factors affecting adherence to insulin therapy in patients with Type 1 or Type 2 diabetes mellitus: a systematic review. Diabet Med. 2013; 30:512–524.

7. Zinman B. Initial combination therapy for type 2 diabetes mellitus: is it ready for prime time? Am J Med. 2011; 124:1 Suppl. S19–S34.

8. Turner RC, Cull CA, Frighi V, Holman RR. UK Prospective Diabetes Study (UKPDS) Group. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA. 1999; 281:2005–2012.

9. Satoh N, Ogawa Y, Usui T, Tagami T, Kono S, Uesugi H, Sugiyama H, Sugawara A, Yamada K, Shimatsu A, Kuzuya H, Nakao K. Antiatherogenic effect of pioglitazone in type 2 diabetic patients irrespective of the responsiveness to its antidiabetic effect. Diabetes Care. 2003; 26:2493–2499.

10. Moon JH, Kim HJ, Kim SK, Shim WS, Kang ES, Rhee Y, Ahn CW, Lim SK, Kim KR, Lee HC, Cha BS. Long-term effect of pioglitazone treatment in patients with type 2 diabetes. J Korean Diabetes Assoc. 2006; 30:264–276.

11. Seufert J, Urquhart R. 2-year effects of pioglitazone addon to sulfonylurea or metformin on oral glucose tolerance in patients with type 2 diabetes. Diabetes Res Clin Pract. 2008; 79:453–460.

12. Triplitt C, Glass L, Miyazaki Y, Wajcberg E, Gastaldelli A, De Filippis E, Cersosimo E, DeFronzo RA. Comparison of glargine insulin versus rosiglitazone addition in poorly controlled type 2 diabetic patients on metformin plus sulfonylurea. Diabetes Care. 2006; 29:2371–2377.

13. Rosenstock J, Einhorn D, Hershon K, Glazer NB, Yu S;. Efficacy and safety of pioglitazone in type 2 diabetes: a randomised, placebocontrolled study in patients receiving stable insulin therapy. Int J Clin Pract. 2002; 56:251–257.

14. Charbonnel B, Schernthaner G, Brunetti P, Matthews DR, Urquhart R, Tan MH, Hanefeld M. Long-term efficacy and tolerability of add-on pioglitazone therapy to failing monotherapy compared with addition of gliclazide or metformin in patients with type 2 diabetes. Diabetologia. 2005; 48:1093–1104.

15. Campbell IW. Long-term glycaemic control with pioglitazone in patients with type 2 diabetes. Int J Clin Pract. 2004; 58:192–200.

16. Blüher M, Lübben G, Paschke R. Analysis of the relationship between the Pro12Ala variant in the PPARgamma2 gene and the response rate to therapy with pioglitazone in patients with type 2 diabetes. Diabetes Care. 2003; 26:825–831.

TOOLS

Similar articles