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Pharmaceutical Interventions for Diabetes Prevention in Patients at Risk

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Abstract

With the rising incidence and prevalence rates of type 2 diabetes globally, it is imperative that diabetes prevention strategies are implemented to stem the flow of new cases. Successful interventions include both lifestyle modification and pharmaceutical agents, and large, multicentre, randomised, controlled studies in different populations have identified the benefits of both. However, translating positive trial outcomes to the real world is particularly challenging, as lifestyle interventions require regular reinforcement from healthcare professionals to be maintained. Pharmaceutical therapies may therefore play an adjunctive role in combination with lifestyle to prevent diabetes. Population-based strategies are also necessary to reduce sedentary behaviour and obesity. Well-established glucose-lowering therapies such as metformin, sulphonylureas, thiazolidinediones and insulin and newer agents such as incretin therapies and sodium glucose co-transporter 2 inhibitors have all been investigated in randomised controlled trials for diabetes prevention with varying success. Non-glucose-lowering therapies such as orlistat and renin angiotensin system blockers can prevent diabetes, whereas statins are associated with slightly increased risk. Diabetes prevention strategies should carefully consider the use of these agents according to individual patient circumstances and phenotypic profile.

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References

  1. International Diabetes F. IDF diabetes atlas; 2015.

  2. Hex N, Bartlett C, Wright D, Taylor M, Varley D. Estimating the current and future costs of type 1 and type 2 diabetes in the UK, including direct health costs and indirect societal and productivity costs. Diabet Med J Br Diabet Assoc. 2012;29(7):855–62.

    Article  CAS  Google Scholar 

  3. Harris MI, Klein R, Welborn TA, Knuiman MW. Onset of NIDDM occurs at least 4–7 yr before clinical diagnosis. Diabetes Care. 1992;15(7):815–9.

    Article  CAS  PubMed  Google Scholar 

  4. Morris DH, Khunti K, Achana F, Srinivasan B, Gray LJ, Davies MJ, et al. Progression rates from HbA1c 6.0-6.4% and other prediabetes definitions to type 2 diabetes: a meta-analysis. Diabetologia. 2013;56(7):1489–93.

    Article  CAS  PubMed  Google Scholar 

  5. Ferrannini E, Gastaldelli A, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA. beta-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis. J Clin Endocrinol Metab. 2005;90(1):493–500.

    Article  CAS  PubMed  Google Scholar 

  6. Stefan N, Fritsche A, Schick F, Haring HU. Phenotypes of prediabetes and stratification of cardiometabolic risk. Lancet Diabetes Endocrinol. 2016;4(9):789–98.

    Article  PubMed  Google Scholar 

  7. Patel SA, Shivashankar R, Ali MK, Anjana RM, Deepa M, Kapoor D, et al. Is the “South Asian phenotype” unique to South Asians? Comparing cardiometabolic risk factors in the CARRS and NHANES studies. Global Heart. 2016;11(1):89–96.e3.

  8. Stevens JW, Khunti K, Harvey R, Johnson M, Preston L, Woods HB, et al. Preventing the progression to type 2 diabetes mellitus in adults at high risk: a systematic review and network meta-analysis of lifestyle, pharmacological and surgical interventions. Diabetes Res Clin Pract. 2015;107(3):320–31.

    Article  CAS  PubMed  Google Scholar 

  9. Yuen A, Sugeng Y, Weiland TJ, Jelinek GA. Lifestyle and medication interventions for the prevention or delay of type 2 diabetes mellitus in prediabetes: a systematic review of randomised controlled trials. Aust N Z J Public Health. 2010;34(2):172–8.

    Article  PubMed  Google Scholar 

  10. Merlotti C, Morabito A, Pontiroli AE. Prevention of type 2 diabetes; a systematic review and meta-analysis of different intervention strategies. Diabetes Obes Metab. 2014;16(8):719–27.

    Article  CAS  PubMed  Google Scholar 

  11. Phung OJ, Sood NA, Sill BE, Coleman CI. Oral anti-diabetic drugs for the prevention of type 2 diabetes. Diabet Med J Br Diabet Assoc. 2011;28(8):948–64.

    Article  CAS  Google Scholar 

  12. Gillies CL, Abrams KR, Lambert PC, Cooper NJ, Sutton AJ, Hsu RT, et al. Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis. BMJ (Clinical research ed). 2007;334(7588):299.

    Article  PubMed Central  Google Scholar 

  13. Gillies CL, Lambert PC, Abrams KR, Sutton AJ, Cooper NJ, Hsu RT, et al. Different strategies for screening and prevention of type 2 diabetes in adults: cost effectiveness analysis. BMJ (Clinical research ed). 2008;336(7654):1180–5.

    Article  PubMed Central  Google Scholar 

  14. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm—2017 executive summary. Endocr Pract. 2017;23(2):207–38.

    Article  PubMed  Google Scholar 

  15. Pernicova I, Korbonits M. Metformin—mode of action and clinical implications for diabetes and cancer. Nature Rev Endocrinol. 2014;10(3):143–56.

    Article  CAS  Google Scholar 

  16. Wang L, Weinshilboum R. Metformin pharmacogenomics: biomarkers to mechanisms. Diabetes. 2014;63(8):2609–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403.

    Article  CAS  PubMed  Google Scholar 

  18. Diabetes Prevention Program Research G. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol. 2015;3(11):866–75.

  19. Diabetes Prevention Program Research G. The 10-year cost-effectiveness of lifestyle intervention or metformin for diabetes prevention: an intent-to-treat analysis of the DPP/DPPOS. Diabetes Care. 2012;35(4):723–30.

    Article  Google Scholar 

  20. Salpeter SR, Buckley NS, Kahn JA, Salpeter EE. Meta-analysis: metformin treatment in persons at risk for diabetes mellitus. Am J Med. 2008;121(2):149–57.e2.

  21. Ramachandran A, Snehalatha C, Shetty AS, Nanditha A. Trends in prevalence of diabetes in Asian countries. World J Diabetes. 2012;3(6):110–7.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V, et al. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia. 2006;49(2):289–97.

    Article  CAS  PubMed  Google Scholar 

  23. Weber MB, Ranjani H, Staimez LR, Anjana RM, Ali MK, Narayan KM, et al. The stepwise approach to diabetes prevention: results from the D-CLIP randomized controlled trial. Diabetes Care. 2016;39(10):1760–7.

    Article  PubMed  PubMed Central  Google Scholar 

  24. American Diabetes A. Prevention or delay of type 2 diabetes. Diabetes Care. 2015;38(suppl 1):S31–2.

    Article  Google Scholar 

  25. Lindblad U, Lindberg G, Mansson NO, Ranstam J, Tyrberg M, Jansson S, et al. Can sulphonylurea addition to lifestyle changes help to delay diabetes development in subjects with impaired fasting glucose? The Nepi ANtidiabetes StudY (NANSY). Diabetes Obes Metab. 2011;13(2):185–8.

    Article  CAS  PubMed  Google Scholar 

  26. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M, et al. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003;290(4):486–94.

  27. Kahn SE, Lachin JM, Zinman B, Haffner SM, Aftring RP, Paul G, et al. Effects of rosiglitazone, glyburide, and metformin on beta-cell function and insulin sensitivity in ADOPT. Diabetes. 2011;60(5):1552–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kohlroser J, Mathai J, Reichheld J, Banner BF, Bonkovsky HL. Hepatotoxicity due to troglitazone: report of two cases and review of adverse events reported to the United States Food and Drug Administration. Am J Gastroenterol. 2000;95(1):272–6.

    Article  CAS  PubMed  Google Scholar 

  29. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–71.

    Article  CAS  PubMed  Google Scholar 

  30. Kermode-Scott B. Meta-analysis confirms raised risk of bladder cancer from pioglitazone. BMJ (Clinical research ed). 2012;345:e4541.

    Google Scholar 

  31. 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.

  32. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374(14):1321–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes. 2002;51(9):2796–803.

    Article  CAS  PubMed  Google Scholar 

  34. Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, et al. Effect of pioglitazone on pancreatic beta-cell function and diabetes risk in Hispanic women with prior gestational diabetes. Diabetes. 2006;55(2):517–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Investigators DT, Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet (London, England). 2006;368(9541):1096–105.

  36. Investigators DT, Dagenais GR, Gerstein HC, Holman R, Budaj A, Escalante A, et al. Effects of ramipril and rosiglitazone on cardiovascular and renal outcomes in people with impaired glucose tolerance or impaired fasting glucose: results of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial. Diabetes Care. 2008;31(5):1007–14.

    Article  Google Scholar 

  37. Hanley AJ, Zinman B, Sheridan P, Yusuf S, Gerstein HC, Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM) Investigators. Effect of rosiglitazone and ramipril on {beta}-cell function in people with impaired glucose tolerance or impaired fasting glucose: the DREAM trial. Diabetes Care. 2010;33(3):608–13.

    Article  CAS  PubMed  Google Scholar 

  38. DeFronzo RA, Abdul-Ghani M. Type 2 diabetes can be prevented with early pharmacological intervention. Diabetes Care. 2011;34(Suppl 2):S202–9.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Group NS, Holman RR, Haffner SM, McMurray JJ, Bethel MA, Holzhauer B, et al. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010;362(16):1463–76.

  40. Nauck MA, Meier JJ. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol. 2016;4(6):525–36.

    Article  CAS  PubMed  Google Scholar 

  41. Uccellatore A, Genovese S, Dicembrini I, Mannucci E, Ceriello A. Comparison review of short-acting and long-acting glucagon-like peptide-1 receptor agonists. Diabetes Ther Res Treat Educ Diabetes Relat Disord. 2015;6(3):239–56.

    CAS  Google Scholar 

  42. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22.

  43. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373(1):11–22.

    Article  PubMed  Google Scholar 

  44. Kim SH, Abbasi F, Lamendola C, Liu A, Ariel D, Schaaf P, et al. Benefits of liraglutide treatment in overweight and obese older individuals with prediabetes. Diabetes Care. 2013;36(10):3276–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. le Roux CW, Astrup A, Fujioka K, Greenway F, Lau DC, Van Gaal L, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet. 2017;389(10077):1399–409.

    Article  PubMed  Google Scholar 

  46. Kalra S. Liraglutide and the rule of halves. Med Matt Diabetes. 2017. https://diabetes.medicinematters.com/editorial-board-comment/12087340

  47. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.

  48. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017. doi:10.1056/NEJMoa1611925.

  49. Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38(9):1687–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15(5):463–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Janssen R, Development LLC. CANVAS—Canagliflozin cardiovascular assessment study. 2015.

  52. Davies M, Chatterjee S, Khunti K. The treatment of type 2 diabetes in the presence of renal impairment: what we should know about newer therapies. Clin Pharmacol Adv Appl. 2016;8:61–81.

    Google Scholar 

  53. Investigators OT, Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4):319–28.

    Article  Google Scholar 

  54. Investigators Ot, Gilbert RE, Mann JF, Hanefeld M, Spinas G, Bosch J, et al. Basal insulin glargine and microvascular outcomes in dysglycaemic individuals: results of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial. Diabetologia. 2014;57(7):1325–31.

  55. Bray GA, Fruhbeck G, Ryan DH, Wilding JP. Management of obesity. Lancet (London, England). 2016;387(10031):1947–56.

  56. Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004;27(1):155–61.

    Article  CAS  PubMed  Google Scholar 

  57. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355(9200):253–9.

  58. Braunwald E, Domanski MJ, Fowler SE, Geller NL, Gersh BJ, Hsia J, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351(20):2058–68.

    Article  CAS  PubMed  Google Scholar 

  59. Dagenais GR, Pogue J, Fox K, Simoons ML, Yusuf S. Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials. Lancet (London, England). 2006;368(9535):581–8.

  60. Navigator study group, McMurray JJ, Holman RR, Haffner SM, Bethel MA, Holzhauer B, et al. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med.. 2010;362(16):1477–90.

  61. Abuissa H, Jones PG, Marso SP, O’Keefe JH Jr. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials. J Am Coll Cardiol. 2005;46(5):821–6.

    Article  CAS  PubMed  Google Scholar 

  62. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet (London, England). 2010;375(9716):735–42.

  63. Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011;305(24):2556–64.

    Article  CAS  PubMed  Google Scholar 

  64. Sapkota S, Brien JA, Greenfield JR, Aslani P. A systematic review of interventions addressing adherence to anti-diabetic medications in patients with type 2 diabetes—components of interventions. PLoS One. 2015;10(6):e0128581.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell. 2012;150(6):1223–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. El Ouaamari A, Kawamori D, Dirice E, Liew CW, Shadrach JL, Hu J, et al. Liver-derived systemic factors drive beta cell hyperplasia in insulin-resistant states. Cell Rep. 2013;3(2):401–10.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Khunti K, Chatterjee S, Carey M, Daly H, Batista-Ferrer H, Davies MJ. New drug treatments versus structured education programmes for type 2 diabetes: comparing cost-effectiveness. Lancet Diabetes Endocrinol. 2016;4(7):557–9.

    Article  PubMed  Google Scholar 

  68. Khunti K, Nikolajsen A, Thorsted BL, Andersen M, Davies MJ, Paul SK. Clinical inertia in intensifying therapy among people with type 2 diabetes treated with basal insulin. Diabetes Obes Metab. 2016;18(4):401–9.

  69. Pillinger T, Beck K, Gobjila C, Donocik JG, Jauhar S, Howes OD. Impaired glucose homeostasis in first-episode schizophrenia: a systematic review and meta-analysis. JAMA Psychiatry. 2017;74(3):261–9.

  70. Willig AL, Overton ET. Metabolic complications and glucose metabolism in HIV infection: a review of the evidence. Curr HIV/AIDS Rep. 2016;13(5):289–96.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Yudkin JS, Montori VM. The epidemic of pre-diabetes: the medicine and the politics. BMJ (Clinical research ed). 2014;349:g4485.

    PubMed Central  Google Scholar 

  72. Collaboration NCDRF. Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet (London, England). 2016;387(10027):1513–30.

  73. DeFronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, et al. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med. 2011;364(12):1104–15.

    Article  CAS  PubMed  Google Scholar 

  74. Investigators DT, Bosch J, Yusuf S, Gerstein HC, Pogue J, Sheridan P, et al. Effect of ramipril on the incidence of diabetes. N Engl J Med. 2006;355(15):1551–62.

    Article  Google Scholar 

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Acknowledgments

The authors acknowledge support from the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care—East Midlands (NIHR CLAHRC—EM), the Leicester Clinical Trials Unit, and the NIHR Leicester-Loughborough Diet, Lifestyle and Physical Activity Biomedical Research Centre, which is a partnership between the University Hospitals of Leicester NHS Trust, Loughborough University and the University of Leicester.

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  1. Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, Leicestershire, UK

    Sudesna Chatterjee, Melanie Davies & Kamlesh Khunti

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  1. Sudesna Chatterjee
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Correspondence to Kamlesh Khunti.

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Dr Chatterjee has received speaker fees, educational funding, or both from Janssen, Eli Lilly, Novo Nordisk, Astra Zeneca, and Boehringer Ingelheim, and grants in support of investigator-initiated trials from Boehringer Ingelheim and Janssen. Professor Davies reports personal fees from Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca, Janssen, Mitsubishi Tanabe Pharma Corporation, and Takeda Pharmaceuticals International Inc. and grants from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim and Janssen. Professor Khunti has acted as a consultant and speaker for Astra Zeneca, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Janssen, and Boehringer Ingelheim. He has received grants in support of investigator and investigator-initiated trials from Astra Zeneca, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, Merck Sharp & Dohme, and Roche. Professor Khunti has also served on advisory boards for Astra Zeneca, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Janssen, and Boehringer Ingelheim.

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Chatterjee, S., Davies, M. & Khunti, K. Pharmaceutical Interventions for Diabetes Prevention in Patients at Risk. Am J Cardiovasc Drugs 18, 13–24 (2018). https://doi.org/10.1007/s40256-017-0239-y

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