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Diabetes inducing drugs – who is next on the list?

13th May 2019, Dr Chee L Khoo

The list of drugs that increase the risk of type 2 diabetes (T2D) is increasing. We know statins (1,2), anti-psychotics (3) and many of the anti-retroviral (4) and immunosuppressant agents (5) have been shown to increase the risk of T2D. We also heard last year about the ACE inhibitors. Recent studies have implicated the 5α-reductase inhibitors, the drugs that we use to treat benign prostatic hypertrophy (BPH) as well. How significant is the effect in clinical practice? This week we investigate the link between these agents and diabetes.

5α-reductases (5αRs) are a family of isozymes expressed in a wide host of tissues including the central nervous system and play a pivotal role in male sexual differentiation, development and physiology. 5αRs convert testosterone, progesterone, deoxycorticosterone, aldosterone and corticosterone into their respective 5α-dihydro-derivatives. These are further transformed into neuroactive steroid hormones which modulate a multitude of functions in human physiology encompassing regulation of sexual differentiation, neuroprotection, memory enhancement, anxiety, sleep and stress, among others. 5αRs is known to most of us for converting testosterone, the male sex hormone, into the more potent  dihydrotestosterone. There are 3 iso-enzymes of 5αRs: steroid 5α-reductase 1, 2 and 3. Finasteride inhibits isoenzymes 1 and 2 while dutasteride not only inhibits all three isoenzymes but it also inhibits isoenzymes 1 and 2 better than finasteride.

In addition to sex hormone metabolism, 5αRs also irreversibly catalyse A-ring reduction of other steroids, including glucocorticoids. Genetic disruption of 5α-reductase 1 in male mice impairs glucocorticoid clearance and predisposes to glucose intolerance and hepatic steatosis upon metabolic challenge. Given the potent effects of both glucocorticoids and androgens on metabolic homeostasis, there has been recent interest in the consequences of inhibition of 5αRs on metabolic health. This has implications for men receiving 5αR inhibitors for chronic treatment of prostatic disease or women receiving these drugs for hirsutism. Furthermore, 5α-reduction of steroid hormones is increased in obesity (6, 7) and polycystic ovarian syndrome (PCOS) (8).

However, it is unclear whether the effect on metabolic homeostasis is driven by changes in androgen and/or glucocorticoid action. When female mice without 5αR1 (5αR1 knockout mice) were studied, gluco-corticosteroid clearance were reduced. These mice are considered to be in a low androgen state. These mice when fed normal chow demonstrated insulin resistance upon glucose tolerance testing and hepatic steatosis. They progressed to obesity (~12% increased body weight) and sustained insulin resistance (~38% increased insulin) by age 12 months. What about humans?

In a recent population-based cohort study using data from the UK Clinical Practice Research Datalink (CPRD), men aged > 40 years with a recorded diagnosis of BPH and who were prescribed dutasteride, finasteride or tamsulosin were studied (9). Patients who were registered from 2003 were followed up till December 2014. Patients who had received prescriptions for finasteride or tamsulosin before 2003 or had a history of cancer, diabetes, or oral glucose lowering or insulin treatment before the index date were excluded. The study was replicated using the Taiwanese National Health Insurance Research Database (NHIRD), which is a validated database with more than 99%of the population registered. They used the same criteria for cohorts, participants, and outcome as described for the CPRD database.

The primary outcome was the incidence of new onset T2D during the follow-up period or prescription of oral glucose lowering drugs or insulin. They compared the incidence of new onset T2D in the dutasteride and finasteride cohorts versus the tamsulosin cohort, and the incidence in the dutasteride cohort versus the finasteride cohort.

In the UK CPRD , of the 55 275 eligible participants, 39 005 patients were prescribed a 5α-reductase inhibitors (8231 dutasteride and 30 774 finasteride) and 16 270 receiving tamsulosin. At baseline, patients receiving dutasteride or finasteride were older, had more comorbidities, except for dyslipidaemia, and used more oral corticosteroids and cardiovascular drugs than those receiving tamsulosin.

There were 2081 new onset type 2 diabetes events (368, 1207, and 506 for the dutasteride, finasteride and tamsulosin groups, respectively) during a mean follow-up of 5.2 (SD 3.1) years. After adding patients receiving dutasteride or finasteride with tamsulosin, there were 395 and 1289 events in the “total” cohorts for dutasteride and finasteride, respectively.

The event rate was 76.2 per 10,000 person-years for dutasteride and 76.6 for finasteride compared with 60.3 for tamsulosin. There was a modest increased risk of type 2 diabetes for dutasteride (adjusted hazard ratio 1.32) and finasteride (adjusted hazard ratio 1.26) compared with tamsulosin. Similar event rates were observed in the “combination” cohorts: 76.6 for total dutasteride and 76.1 for total finasteride.  The increase in risk of type 2 diabetes did not differ among patients receiving dutasteride or finasteride alone or when they included patients receiving these drugs in combination with tamsulosin.

The Taiwanese cohort of patients were younger than UK patients and took fewer drugs for cardiovascular indications, but more oral corticosteroids. Similar to the UK patients, Taiwanese patients receiving tamsulosin were slightly younger than those receiving dutasteride or finasteride. More patients had dyslipidaemia in the dutasteride group. The event rate per 10 000 person years was 152.8 (95% confidence interval 144.5 to 161.5) for dutasteride and 109.1 (105.9 to 112.5) for finasteride compared with 74.7 (74.2 to 75.2) for tamsulosin. Results for the NHIRD were consistent with the findings for the CPRD (adjusted hazard ratio 1.34, 95% confidence interval 1.17 to 1.54 for dutasteride, and 1.49, 1.38 to 1.61 for finasteride compared with tamsulosin).

The risk of developing T2D is increased in patients exposed to dutasteride or finasteride. There is biochemical basis for the increased risk although the precise mechanism of this increased risk is unclear. 5α-reductases are highly expressed in the liver, but also in other tissues critical for insulin sensitivity—for example adipose tissue and skeletal muscle. The increased susceptibility to type 2 diabetes might reflect changes in these hormones, most plausibly androgens or glucocorticoids. Low circulating levels of testosterone are associated with an increased risk of type 2 diabetes (10) and perhaps, inhibiting 5αRs at the local tissues (including liver and adipose tissues) may increased insulin resistance. Prevention of inactivation of cortisol by 5α-reductases leading to accumulation of glucocorticoid in metabolic tissues and promoting insulin resistance.

Up to 50% older men suffer from BPH to some degree but these patients are also likely to have glucose dysmetabolism. The decision to prescribe a 5αR inhibitors for men with metabolic disease should be made in the context of other risk factors for type 2 diabetes. Additional monitoring might be required for men starting these drugs, particularly in those with other risk factors for type 2 diabetes.

Access the abstract here.

References:

  1. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735-42. doi:10.1016/S0140-6736(09)61965-6
  2. Preiss D, Seshasai SRK, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a metaanalysis. JAMA 2011;305:2556-64. doi:10.1001/jama.2011.860
  3. Holt RIG, Peveler RC. Association between antipsychotic drugs and diabetes. Diabetes Obes Metab 2006;8:125-35. doi:10.1111/j.1463-1326.2005.00495.x
  4. Brown TT, Cole SR, Li X, et al. Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Arch Intern Med 2005;165:1179-84. doi:10.1001/archinte.165.10.1179
  5. Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and meta-analysis. Am J Transplant 2004;4:583-95. doi:10.1046/j.1600-6143.2003.00372.x
  6. Andrew R, Phillips DIW, Walker BR. 1998. Obesity and gender influence cortisol secretion and metabolism in man. Journal of Clinical Endocrinology and Metabolism83 1806–1809
  7. Fraser R, Ingram MC, Anderson NH, Morrison C, Davies E, Connell JMC. 1999. Cortisol effects on body mass, blood pressure, and cholesterol in the general population. Hypertension33 1364–1368
  8. Stewart PM, Shackleton CHL, Beastall GH, Edwards CRW. 1990. 5α-Reductase activity in polycystic ovarian syndrome. Lancet335 431–433
  9. Li Wei, Edward Chia-Cheng Lai, Yea-Huei Kao-Yang, Brian R Walker, Thomas M MacDonald, Ruth Andrew. Incidence of type 2 diabetes mellitus in men receiving steroid 5α-reductase inhibitors: population based cohort study BMJ 2019;365:l1204 http://dx.doi.org/10.1136/bmj.l1204
  10. Hackett G. Type 2 Diabetes and testosterone therapy. World J Mens Health 2019;37:31-44. doi:10.5534/wjmh.180027

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