Reducing the Burden of Diabetes Treatment: A Review of Low-cost Oral Hypoglycemic Medications

Author(s): Elizabeth M. Vaughan*, Jaime J. Rueda, Susan L. Samson, David J. Hyman

Journal Name: Current Diabetes Reviews

Volume 16 , Issue 8 , 2020

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Background: The vast majority of individuals diagnosed with diabetes are low/middle income and may have access to only three of the 11 oral hypoglycemic medications (OHMs) due to cost: metformin intermediate release (IR) or extended release (ER), sulfonylureas (glimepiride, glipizide, glyburide), and pioglitazone. Sulfonylureas and pioglitazone have had significant controversy related to potential adverse events, but it remains unclear whether these negative outcomes are class, drug, or dose-related.

Objective: We conducted a narrative review of low-cost OHMs.

Methods: We evaluated the maximum recommended (MAX) compared to the most effective (EFF) daily dose, time-to-peak change in HbA1c levels, and adverse events of low-cost oral hypoglycemic medications.

Results: We found that the MAX was often greater than the EFF: metformin IR/ER (MAX: 2,550/2,000 mg, EFF: 1,500–2,000/1,500–2,000 mg), glipizide IR/ER (MAX: 40/20 mg, EFF: 20/5 mg), glyburide (MAX: 20 mg, EFF: 2.5–5.0 mg), pioglitazone (MAX: 45 mg, EFF: 45 mg). Time-to-peak change in HbA1c levels occurred at weeks 12–20 (sulfonylureas), 25–39 (metformin), and 25 (pioglitazone). Glimepiride was not associated with weight gain, hypoglycemia, or negative cardiovascular events relative to other sulfonylureas. Cardiovascular event rates did not increase with lower glyburide doses (p<0.05). Glimepiride and pioglitazone have been successfully used in renal impairment.

Conclusion: Metformin, glimepiride, and pioglitazone are safe and efficacious OHMs. Prescribing at the EFF rather than the MAX may avoid negative dose-related outcomes. OHMs should be evaluated as individual drugs, not generalized as a class, due to different dosing and adverse-event profiles; Glimepiride is the preferred sulfonylurea since it is not associated with the adverse events as others in its class.

Keywords: Diabetes, medication, low-income or underserved, hypoglycemic medication, metformin, sulfonylurea, thiazolidinediones.

Standards of medical care in diabetes 2019. Diabetes Care 2019; 42(Suppl. 1): S1-2.
[] [PMID: 30559224]
International diabetes atlas-8th ed. Brussels, BE: International Diabetes Federation 2017; pp. 1-29. .
Beckles GL, Chou CF. Disparities in the Prevalence of Diagnosed Diabetes - United States, 1999-2002 and 2011-2014. MMWR Morb Mortal Wkly Rep 2016; 65(45): 1265-9.
[] [PMID: 27855140]
Abdelmoneim AS, Eurich DT, Senthilselvan A, Qiu W, Simpson SH. Dose-response relationship between sulfonylureas and major adverse cardiovascular events in elderly patients with type 2 diabetes. Pharmacoepidemiol Drug Saf 2016; 25(10): 1186-95.
[] [PMID: 27102581]
Abrahamson MJ. Should sulfonylureas remain an acceptable first-line add-on to metformin therapy in patients with type 2 diabetes? Yes, they continue to serve us well! Diabetes Care 2015; 38(1): 166-9.
[] [PMID: 25538313]
Davidson MB. Pioglitazone (Actos) and bladder cancer: Legal system triumphs over the evidence. J Diabetes Complications 2016; 30(6): 981-5.
[] [PMID: 27133452]
McEwen LN, Casagrande SS, Kuo S, Herman WH. Why Are Diabetes Medications So Expensive and What Can Be Done to Control Their Cost? Curr Diab Rep 2017; 17(9): 71.
[] [PMID: 28741264]
Guidelines on second- and third-line medicines and type of insulin for the control of blood glucose levels in non-pregnant adults with diabetes mellitus. Geneva: CH: World Health Organization. 2018.
Qaseem A, Barry MJ, Humphrey LL, Forciea MA. Oral pharmacologic treatment of type 2 diabetes mellitus: A clinical practice guideline update from the American college of physicians. Ann Intern Med 2017; 166(4): 279-90.
[] [PMID: 28055075]
Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American association of clinical endocrinologists and american college of endocrinology on the comprehensive type 2 diabetes management algorithm - 2019 executive summary. Endocr Pract 2019; 25(1): 69-100.
[] [PMID: 30742570]
Del Guerra S, Marselli L, Lupi R, et al. Effects of prolonged in vitro exposure to sulphonylureas on the function and survival of human islets. J Diabetes Complications 2005; 19(1): 60-4.
[] [PMID: 15642492]
Fickweiler F, Fickweiler W, Urbach E. Interactions between physicians and the pharmaceutical industry generally and sales representatives specifically and their association with physicians’ attitudes and prescribing habits: a systematic review. BMJ Open 2017; 7(9)e016408
[] [PMID: 28963287]
Loke YK, Singh S, Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ 2009; 180(1): 32-9.
[] [PMID: 19073651]
Zhu ZN, Jiang YF, Ding T. Risk of fracture with thiazolidinediones: an updated meta-analysis of randomized clinical trials. Bone 2014; 68: 115-23.
[] [PMID: 25173606]
Company B-MS Glucovance. Highlights of prescibing information. Princeton, NJ: US Food and Drug Administration 2018.
Takeda Pharmaceuticals Highlights of prescribing information: Actos. Deerfield, IL: US Food and Drug Administration, Takeda Pharmaceuticals 2011.
Institute of Medicine (US) Committee on Standards for Systematic Reviews of Comparative Effectiveness Research. Eden J, Levit L, Berg A, Eds. Finding What Works in Health Care: Standards for Systematic Reviews. Washington (DC) . 2011.
Chow CK, Ramasundarahettige C, Hu W, et al. Availability and affordability of essential medicines for diabetes across high-income, middle-income, and low-income countries: a prospective epidemiological study. Lancet Diabetes Endocrinol 2018; 6(10): 798-808.
[] [PMID: 30170949]
Yeaw J, Lee WC, Aagren M, Christensen T. Cost of self-monitoring of blood glucose in the United States among patients on an insulin regimen for diabetes. J Manag Care Pharm 2012; 18(1): 21-32.
[] [PMID: 22235952]
Essential medicines and health products surveying insulin availability and pricing: vital to treating diabetes. 2019.
Berkowitz SA, Karter AJ, Lyles CR, et al. Low socioeconomic status is associated with increased risk for hypoglycemia in diabetes patients: the Diabetes Study of Northern California (DISTANCE). J Health Care Poor Underserved 2014; 25(2): 478-90.
[] [PMID: 24858863]
Vaughan EM, Moreno JP, Hyman D, Chen TA, Foreyt JP. Efficacy of oral versus insulin therapy for newly diagnosed diabetes in low-income settings. Arch Gen Intern Med 2017; 1(2): 17-22.
[PMID: 29517061]
Geller AI, Shehab N, Lovegrove MC, et al. National estimates of insulin-related hypoglycemia and errors leading to emergency department visits and hospitalizations. JAMA Intern Med 2014; 174(5): 678-86.
[] [PMID: 24615164]
Rubin RR, Peyrot M, Kruger DF, Travis LB. Barriers to insulin injection therapy: patient and health care provider perspectives. Diabetes Educ 2009; 35(6): 1014-22.
[] [PMID: 19934459]
Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia 2017; 60(9): 1577-85.
[] [PMID: 28776086]
Aggarwal N, Singla A, Mathieu C, et al. Metformin extended-release versus immediate-release: An international, randomized, double-blind, head-to-head trial in pharmacotherapy-naïve patients with type 2 diabetes. Diabetes Obes Metab 2018; 20(2): 463-7.
[] [PMID: 28857388]
Schwartz S, Fonseca V, Berner B, Cramer M, Chiang YK, Lewin A. Efficacy, tolerability, and safety of a novel once-daily extended-release metformin in patients with type 2 diabetes. Diabetes Care 2006; 29(4): 759-64.
[] [PMID: 16567811]
Timmins P, Donahue S, Meeker J, Marathe P. Steady-state pharmacokinetics of a novel extended-release metformin formulation. Clin Pharmacokinet 2005; 44(7): 721-9.
[] [PMID: 15966755]
Donnelly LA, Morris AD, Pearson ER. Adherence in patients transferred from immediate release metformin to a sustained release formulation: a population-based study. Diabetes Obes Metab 2009; 11(4): 338-42.
[] [PMID: 19267712]
Jabbour S, Ziring B. Advantages of extended-release metformin in patients with type 2 diabetes mellitus. Postgrad Med 2011; 123(1): 15-23.
[] [PMID: 21293080]
Samson SL, Garber AJ. Metformin and Other Biguanides: Pharmacology and Therapeutic Usage, 4th edition of the International Textbook of Diabetes Mellitus. Wiley-Blackwell: Hoboken, NJ 2015.
Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med 1997; 103(6): 491-7.
[] [PMID: 9428832]
Sherifali D, Nerenberg K, Pullenayegum E, Cheng JE, Gerstein HC. The effect of oral antidiabetic agents on A1C levels: a systematic review and meta-analysis. Diabetes Care 2010; 33(8): 1859-64.
[] [PMID: 20484130]
Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346(6): 393-403.
[] [PMID: 11832527]
Aroda VR, Edelstein SL, Goldberg RB, et al. Long-term metformin use and vitamin B12 deficiency in the diabetes prevention program outcomes study. J Clin Endocrinol Metab 2016; 101(4): 1754-61.
[] [PMID: 26900641]
Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician 2003; 67(5): 979-86.
[PMID: 12643357]
Long AN, Atwell CL, Yoo W, Solomon SS. Vitamin B(12) deficiency associated with concomitant metformin and proton pump inhibitor use. Diabetes Care 2012; 35(12)e84
[] [PMID: 23173145]
Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care 2011; 34(6): 1431-7.
[] [PMID: 21617112]
Crowley MJ, Diamantidis CJ, McDuffie JR, et al. Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: A systematic review. Ann Intern Med 2017; 166(3): 191-200.
[] [PMID: 28055049]
Sola D, Rossi L, Schianca GP, et al. Sulfonylureas and their use in clinical practice. Arch Med Sci 2015; 11(4): 840-8.
[] [PMID: 26322096]
Rambiritch V, Maharaj B, Naidoo P. Glibenclamide in patients with poorly controlled type 2 diabetes: a 12-week, prospective, single-center, open-label, dose-escalation study. Clin Pharmacol 2014; 6: 63-9.
[PMID: 24741335]
Rambiritch V, Naidoo P, Pillai G. Glibenclamide population pharmacokinetic/pharmacodynamic modeling in South African type 2 diabetic subjects. Clin Pharmacol 2016; 8: 141-53.
[] [PMID: 27713650]
Hurren KM, Bartley EP, O’Neill JL, Ronis DL. Effect of sulfonylurea dose escalation on hemoglobin A1c in Veterans Affairs patients with type 2 diabetes. Acta Diabetol 2013; 50(2): 261-5.
[] [PMID: 20512383]
Dills DG, Schneider J. Clinical evaluation of glimepiride versus glyburide in NIDDM in a double-blind comparative study. Horm Metab Res 1996; 28(9): 426-9.
[] [PMID: 8911977]
Berelowitz M, Fischette C, Cefalu W, Schade DS, Sutfin T, Kourides IA. Comparative efficacy of a once-daily controlled-release formulation of glipizide and immediate-release glipizide in patients with NIDDM. Diabetes Care 1994; 17(12): 1460-4.
[] [PMID: 7882817]
Simonson DC, Kourides IA, Feinglos M, Shamoon H, Fischette CT. Efficacy, safety, and dose-response characteristics of glipizide gastrointestinal therapeutic system on glycemic control and insulin secretion in NIDDM. Results of two multicenter, randomized, placebo-controlled clinical trials. Diabetes Care 1997; 20(4): 597-606.
[] [PMID: 9096986]
Archer M, Oderda G, Richards K, Turpin S. Sulfonylurea agents & combination products: Drug class review. Salt Lake City, Utah: University of Utah 2013.
Rosenstock J, Samols E, Muchmore DB, Schneider J. Glimepiride, a new once-daily sulfonylurea. A double-blind placebo-controlled study of NIDDM patients. Diabetes Care 1996; 19(11): 1194-9.
[] [PMID: 8908379]
Goldberg RB, Holvey SM, Schneider J. A dose-response study of glimepiride in patients with NIDDM who have previously received sulfonylurea agents. The Glimepiride Protocol #201 Study Group. Diabetes Care 1996; 19(8): 849-56.
[] [PMID: 8842603]
Douros A, Dell’Aniello S, Yu OHY, Filion KB, Azoulay L, Suissa S. Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycaemic events: population based cohort study. BMJ 2018; 362: k2693.
[] [PMID: 30021781]
Riddle MC. Modern Sulfonylureas: Dangerous or Wrongly Accused? Diabetes Care 2017; 40(5): 629-31.
[] [PMID: 28428320]
Cheng V, Kashyap SR. Weight considerations in pharmacotherapy for type 2 diabetes. J Obes 2011 2011.
Lee TM, Chou TF. Impairment of myocardial protection in type 2 diabetic patients. J Clin Endocrinol Metab 2003; 88(2): 531-7.
[] [PMID: 12574175]
Varvaki Rados D, Catani Pinto L, Reck Remonti L, Bauermann Leitão C, Gross JL. The association between sulfonylurea use and all-cause and cardiovascular mortality: A meta-analysis with trial sequential analysis of randomized clinical trials. PLoS Med 2016; 13(4)e1001992
[] [PMID: 27071029]
Basit A, Riaz M, Fawwad A. Glimepiride: evidence-based facts, trends, and observations (GIFTS)[corrected]. Vasc Health Risk Manag 2012; 8: 463-72. [corrected]
[] [PMID: 23028231]
Szoke E, Gosmanov NR, Sinkin JC, et al. Effects of glimepiride and glyburide on glucose counterregulation and recovery from hypoglycemia. Metabolism 2006; 55(1): 78-83.
[] [PMID: 16324923]
Kim JM, Kim SS, Kim JH, et al. Efficacy and safety of pioglitazone versus glimepiride after metformin and alogliptin combination therapy: A randomized, open-label, multicenter, parallel-controlled study. Diabetes Metab J 2019; (Jul): 11.
[] [PMID: 31339011]
Aronoff S, Rosenblatt S, Braithwaite S, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care 2000; 23(11): 1605-11.
[] [PMID: 11092281]
Ryder RE. Pioglitazone has a dubious bladder cancer risk but an undoubted cardiovascular benefit. Diabet Med 2015; 32(3): 305-13.
[] [PMID: 25472014]
Erdmann E, Harding S, Lam H, Perez A. Ten-year observational follow-up of PROactive: a randomized cardiovascular outcomes trial evaluating pioglitazone in type 2 diabetes. Diabetes Obes Metab 2016; 18(3): 266-73.
[] [PMID: 26592506]
Lewis JD, Habel LA, Quesenberry CP, et al. Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes. JAMA 2015; 314(3): 265-77.
[] [PMID: 26197187]
Korhonen P, Heintjes EM, Williams R, et al. Pioglitazone use and risk of bladder cancer in patients with type 2 diabetes: retrospective cohort study using datasets from four European countries. BMJ 2016; 354: i3903.
[] [PMID: 27530399]
Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 2007; 298(10): 1180-8.
[] [PMID: 17848652]
Liao HW, Saver JL, Wu YL, Chen TH, Lee M, Ovbiagele B. Pioglitazone and cardiovascular outcomes in patients with insulin resistance, pre-diabetes and type 2 diabetes: a systematic review and meta-analysis. BMJ Open 2017; 7(1)e013927
[] [PMID: 28057658]
Lee M, Saver JL, Liao HW, Lin CH, Ovbiagele B. Pioglitazone for Secondary Stroke Prevention: A Systematic Review and Meta-Analysis. Stroke 2017; 48(2): 388-93.
[] [PMID: 27999139]
Smith SR, De Jonge L, Volaufova J, Li Y, Xie H, Bray GA. Effect of pioglitazone on body composition and energy expenditure: a randomized controlled trial. Metabolism 2005; 54(1): 24-32.
[] [PMID: 15562376]
Després JP. Cardiovascular disease under the influence of excess visceral fat. Crit Pathw Cardiol 2007; 6(2): 51-9.
[] [PMID: 17667865]
Finelli C, Sommella L, Gioia S, La Sala N, Tarantino G. Should visceral fat be reduced to increase longevity? Ageing Res Rev 2013; 12(4): 996-1004.
[] [PMID: 23764746]
Pavlova V, Filipova E, Uzunova K, Kalinov K, Vekov T. Pioglitazone therapy and fractures: systematic review and meta- analysis. Endocr Metab Immune Disord Drug Targets 2018; 18(5): 502-7.
[] [PMID: 29683100]
Viscoli CM, Inzucchi SE, Young LH, et al. Pioglitazone and risk for bone fracture: safety data from a randomized clinical trial. J Clin Endocrinol Metab 2017; 102(3): 914-22.
[PMID: 27935736]
Hu M, Tomlinson B. Current Perspectives on rosuvastatin. Integr Blood Press Control 2013; 6: 15-25.
[PMID: 23637557]
Tayal U, Carroll R. Should anyone still be taking simvastatin 80 mg? BMJ Case Rep 2013; 2013: 2013
[] [PMID: 23929614]
Rodriguez-Gutierrez R, Gonzalez-Gonzalez JG, Zuñiga-Hernandez JA, McCoy RG. Benefits and harms of intensive glycemic control in patients with type 2 diabetes. BMJ 2019; 367: l5887.
[] [PMID: 31690574]
Peng Y, Chen SH, Liu XN, Sun QY. Efficacy of different antidiabetic drugs based on metformin in the treatment of type 2 diabetes mellitus: A network meta-analysis involving eight eligible randomized-controlled trials. J Cell Physiol 2019; 234(3): 2795-806.
[] [PMID: 30145806]

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Year: 2020
Page: [851 - 858]
Pages: 8
DOI: 10.2174/1573399816666200206112318
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