DIABETES, OBESTY AND TESTOSTERONE. Referent Prof. Thomas Hugh Jones

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1 DIABETES, OBESTY AND TESTOSTERONE Referent Prof. Thomas Hugh Jones

2 Transparenzinformation arztcme Die Bundesärztekammer und die Landesärztekammer Hessen fordern zur Schaffung von mehr Transparenz beim Sponsoring in der ärztlichen Fortbildung auf. Fortbildungsveranstalter sind gehalten, potenzielle Teilnehmer von Fortbildungen bereits im Vorfeld der Veranstaltung u ber Umfang und Bedingungen der Unterstu tzung der Arzneimittelindustrie zu informieren. Dieser Verpflichtung kommen wir nach und werden Sie hier u ber die Höhe des Sponsorings() der beteiligten Arzneimittelfirma sowie u ber mögliche Interessenkonflikte der Autoren informieren. Diese Fortbildung wurde fu r den aktuellen Zertifizierungszeitraum von 12 Monaten mit 1.950,- EUR durch die Jenapharm GmbH & Co. KG unterstu tzt. Mögliche Interessenkonflikte Prof. Thomas Hugh Jones erklärt: Bei der Erstellung dieses Beitrags fu r eine durch die Landesärztekammer Hessen anzuerkennende Fortbildung bestanden keine Interessenkonflikte im Sinne der Empfehlungen des International Committee of Medical Journal Editors ( Prof. Jones erhielt persönliche Zahlungen von Bayer während der Durchführung einer Studie. Die Produktneutralität dieser Fortbildung wurde durch ein Review mit zwei Gutachtern gepru ft. Diese Fortbildung ist auf online verfu gbar. Die Transparenzinformationen sind fu r den Arzt dort einsehbar. () Die Sponsoringbeiträge können je nach Art und Umfang der Fortbildung unterschiedlich sein.

3 DIABETES, OBESTY AND TESTOSTERONE T. Hugh Jones Centre for Diabetes & Endocrinology, Barnsley Hospital NHS Foundation Trust & Academic Unit of Diabetes, Endocrinology & Metabolism, University of Sheffield

4 Testosterone Deficiency and Mortality in Men with Type 2 Diabetes Total Testosterone Bioavailable Testosterone N=581 Mean f/u 5.8years Multivariate-adjusted survival curves BMI HbA1c Smoking Statin Therapy ACEI/ARB Rx Pre-existing CVD Cardiovascular Mortality Sub-Analysis TT<8.4nmol/l HR 2.5 (p=0.02) Muraleedharan V, Marsh HA, Kapoor D, Channer KS, Jones TH Eur J Endocrinol ;

5 Low Testosterone Predicts Increased Mortality and Testosterone Therapy Improves Survival in 587 Men with Type 2 Diabetes (mean Follow-up: 5.8 years) % Low T treated Mortality (%) % 8.6% Normal T Low T untreated 5 0 low T (<10.4 nm ol/l) normal T low T treated Muraleedharan V et al. Eur J Endocrinol 169;6 2013)

6 Mortality Data of Patients with Type 2 Diabetes mellitus not Receiving PDE5 Inhibitors Followed for Approximately 4 Years 30,0 eugonadal untreated hypogonadal untreated hypogonadal treated 25,0 22,8 25,2 20,0 19,7 15,0 13,3 10,0 10,3 10,4 5,0 3,6 4,2 4,0 2,6 2,3 5,3 0,0 total group years years years Hackett G et al. Int J Clin Pract 70(3): (2016)

7 Odds Ratio for Major Adverse Cardiovascular Events (MACE) According to Baseline Characteristics in Subjects Treated with Testosterone or Placebo MACE: cardiovascular death, non-fatal myocardial infarction, stroke, acute coronary syndromes, and/or heart failure Source Trials MH-OR LL UL p Odds ratio for MACE TRT Placebo Events Patients Events Patients Associated diseases Elderly men 10 1,22 0,49 3,03 0,67 Men with CVD 2 2,48 0,35 17,45 0,36 Frail men 5 2,25 0,72 7,08 0,17 Men with metabolic diseases 4 0,19 0,04 0,85 0, Hypogonadism status Mixed population 14 1,26 0,58 2,73 0,56 TT < 12 nm 12 0,84 0,32 2,23 0, Type of support Drug company not supported 12 0,94 0,39 2,24 0,88 Drug company supported 14 1,07 0,51 2,24 0, Trial duration 12 weeks 4 1,02 0,20 5,29 0,98 >12 weeks 22 1,01 0,55 1,84 0, CVD: Cardiovascular diseases; LL: Lower limit; UL: Upper limit; MH-OR: Mantel-Haenszel odds ratio; TT: Total testosterone Placebo TS Corona G et al. Expert Opin Drug Saf, 2014:13;

8 Consequence or Cause? Is low testosterone just a biomarker of illness? Is it an adaptation to the clinical state? Does the low Testosterone state promote disease progression? Does Testosterone replacement ameliorate the disease process and improve clinical outcomes? Does testosterone replacement improve QOL as well?

9 Percentage of type 2 diabetic men with positive symptom score with low testosterone by decades of age (ADAM questionnaire) Percentage of men with low TT TT < 8 nmol/l TT < 12 nmol/l < >69 Age (years) Percentage of men with low BT, cft BT < 2.5 nmol/l BT < 4 nmol/l cft < nmol/l < >69 Age (years) Total testosterone (TT) Bioavailable testosterone (BT) and calculated free testosterone (cft) Kapoor D et al. Diabetes Care 30: (2007)

10 Macrovascular disease at diagnosis in Type 2 diabetes 50% of all deaths in people with Type 2 diabetes are due to cardiovascular disease Cerebrovascular disease Abnormal ECG Hypertension 1% 18% 35% 57% Hepatic Steatosis 7% Microalbuminuria Absent foot pulses 13% 70% ED Intermittent claudication 3% UKPDS Group. Diabetes Res 1990; 13: 1 11.

11 Insulin resistance is an independent predictor of cardiovascular disease 2.5 Odds ratio (95% CI) for incident cardiovascular disease Insulin resistance Smoking (yes vs no) TC:HDL-C (per unit) Age (per year) TC = total cholesterol Measured by log HOMA-IR (per unit) HDL-C = HDL cholesterol Bonora E et al. Diabetes Care 2002; 25:

12 Insulin resistance syndrome and cardiovascular risk Genetic Hyperglycaemia 1 Obesity Lack of exercise Insulin resistance Hypertension 1 Dyslipidaemia 1 Thrombotic risk 2 Cardiovascular risk Microalbuminuria 3 1. Haffner SM, Miettinen H. Am J Med 1997; 103: Reaven GM. J Int Med 1994; 236: (Suppl 736): Abuaisha B. Diabet Res Clin Pract 1998; 39:

13 HOMA INDEX p=0.02 HbA1c (%) 7,8 7,6 7,4 7,2 7 n=14p= Placebo Testosterone 6,8 Placebo Testosterone n=14 n=24

14 Percentage mean change from baseline in HOMA-IR for patients with T2D (with or without MS) (LOCF) Jones et al. Diabetes Care 2011; 34:

15 EFFECT of TRT on HOMA-ir and HbA1c In Hyogonadal Men with the Metabolic Syndrome and/or Type 2 Diabetes over 12 months (n=220) TIMES2 Study Jones TH et al Diabetes Care 2011;34:

16 HOMA-IR and Serum INSULIN Hackett G et al. J Sex Med 2014;11:840-56

17 Insulin Sensitivity Clamp Trial - Glucose Infusion Rate (GIR) mg/kg fat free mass/min 10 9 p= p=0.004 p= baseline 24 weeks TRT baseline 24 weeks Placebo Dhindsa et al Diabetes Care :1-10

18 Insulin Resistance HOMA-IR 4,5 4 p=0.03 3,5 3 2,5 2 1,5 1 p=0.03 p=0.90 0,5 0 baseline 24 weeks TRT baseline 24 weeks Placebo Dhindsa et al Diabetes Care :1-10

19 Testosterone Therapy Increases Lean Body Mass and Reduces Total Body Fat Mass in Men with Testosterone Deficiency Study Testosterone formulation Treatment period Lean body mass Fat mass Marin et al. [27] Gel 9 months Snyder et al. [28] Patch 36 months Kenny et al. [29] Patch 12 months Crawford et al. [30] Mixed esters 12 months Ferrando et al. [31] TE 6 months Steidle et al. [32] Gel 3 months Wittert et al. [33] Oral TU 12 months Casaburi et al. [34] TE 3 months Page et al. [35] TE 36 months Kapoor et al. [20] Mixed esters 3 months Bhasin et al. [36] TE 5 months Kapoor et al. [37] Mixed esters 3 months Bhasin et al. [38] Gel 6 months Svartberg et al. [39] Injectable TU 12 months Allan et al. [40] Patch 12 months Srinivas-Shankar et al. [41] Gel 6 months Aversa et al. [42] Injectable TU 24 months Aversa et al. [43] Injectable TU 12 months Behre et al. [44] Gel 6 months Finkelstein et al. [45] Gel 4 months Francomano et al. [46] Injectable TU 60 months Bouloux et al. [47] Oral TU 12 months Pexman-Fieth et al. [48] Gel 6 months Juang et al. [49] Gel 3 months Rodriguez-Tolra et al. [50] Gel/Injectable TU 24 months Frederiksen et al. [51] Gel 6 months Emmelot-Vonk et al. [52] Oral TU 6 months Borst et al. [53] TE 12 months TE, testosterone enanthate; TU, testosterone undecanoate Traish AM Curr Opin Endocrinol Diabet Obes 21: (2014)

20 Effects of Testosterone Therapy on Weight, Waist Circumference and BMI Study Testosterone Treatment Weight Waist Body mass formulation period circumference index Marin et al. [27] Gel 9 months ND ND Kapoor et al. [20,37] Mixed esters 3 months ND ND Svartberg et al. [39] Injectable TU 12 months ND ND Heufelder et al. [54] Gel 12 months ND ND Aversa et al. [42] Injectable TU 24 months ND ND Aversa et al. [43] Injectable TU 12 months ND ND Kalinchenko et al. [55] Injectable TU 7 months Aversa et al. [56] Injectable TU 36 months ND ND Zitzmann et al. [57] Injectable TU 9 12 months ND ND Francomano et al. [46] Injectable TU 60 months Francomano et al. [58] Injectable TU 12 months Haider et al. [59] Injectable TU months Haider et al. [60] Injectable TU months Saad et al. [23] Injectable TU months Yassin and Doros [61] Injectable TU months Pexman-Fieth et al. [48] Gel 6 months Hackett et al. [62,63] Injectable TU 7 and 20 months Bhattacharya et al. [64,65] Gel 12 months ND ND Garcia et al. [66] Injectable TU 24 months ND ND Zitzmann et al. [72] Injectable TU months ND, no data; TU, testosterone undecanoate Traish AM Curr Opin Endocrinol Diabet Obes 21: (2014)

21 Corona, Maggi, Zitzmann et al EJE 2016; 174: R99-R116 Meta-Analysis of 59 randomized controlled trials of T substitution in hypogonadism 3029 men (treated) vs 2049 (controls)

22 Meta-Analysis of 59 randomized controlled trials of T substitution in hypogonadism 3029 men (treated) vs 2049 (controls) Testosterone + - Corona, Maggi, Zitzmann et al EJE 2016; 174: R99-R116

23 HYPOGONADAL-OBESITY-ADIPOCYTOKINE HYPOTHESIS Rao P et al.nature Reviews Endocrinol 2013;9:

24 Effect of Weight Loss on Testosterone Levels Bariatric Surgery Dietary and exercise Grossman M JCEM 2011;96:

25 Weight (kg) in 362 Hypogonadal Men with Different Grades of Obesity Receiving Long-Term Treatment with Testosterone Undecanoate Injections kg kg kg p< vs baseline p< vs previous year p= p= p= p= NI= NII= NIII= Traish AM Curr Opin Endocrinol Diabet Obes 21: (2014)

26 Waist Circumference (cm) in 362 Hypogonadal Men with Different Grades of Obesity Receiving Long-Term Treatment with Testosterone Undecanoate Injections cm cm cm p< vs baseline p< vs previous year p= p= p= p=ns NI = NII = NIII = Traish AM Curr Opin Endocrinol Diabet Obes 21: (2014)

27 IPASS: intramuscular testosterone undecanoate in hypogonadal Men with Type 2 Diabetes mellitus Treatment of symptomatic hypogonadal men Baseline 7.9 % 0,0 Baseline 6.2 % Change (%) -0,4-0,3%...Reduction of HbA1c t-test: p=0.01-1,1% -0,8 t-test: p< ,2 n=293 n=60 Total population Zitzmann M et al. JSM 2013

28 HbA 1c (%) in 156 Obese Hypogonadal Men with Type 2 Diabetes mellitus Treated with Testosterone Undecanoate Injections for up to 6 Years HbA1c (%) p vs baseline; p vs previous year p= p= Years Patients, n Haider A et al. Int J Endocrol, Vol 2014, Article ID

29 Fasting Glucose (mg/dl or mmol/l) in 156 Obese Hypogonadal Men with Type 2 Diabetes mellitus Treated with Testosterone Undecanoate Injections for up to 6 Years Fasting Glucose (mmol/l) p= p=ns p vs baseline; p vs previous year p=ns p= p=ns Fasting Glucose (mg/dl) Patients, n Years Haider A et al. Int J Endocrol, Vol 2014, Article ID

30 Changes in HbA 1c in Total Testosterone-Treated and Untreated Groups Yellow bars show the estimated mean difference between groups, adjusted for baseline age, weight, waist circumference, fasting glucose, lipids, blood pressure, and quality of life (measured by AMS) Traish A et al. J Cardiovasc Pharmacol Therapeut 22, published online Feb 09, 2017

31 HbA 1c relationship with CV risk Glycaemia increase Associated risk increase 1% 21% increase in increase in HbA 1c diabetes-related deaths p< % increase in myocardial infarction p< % increase in peripheral vascular disease p< Stratton IM et al. BMJ 2000; 321:

32 Audit Patients by Disease Category N=505 Mean F/U 4.94yrs TRT patient yrs

33 Effect of TRT on HbA1c in Uncontrolled Type 2 Diabetes in Routine Clinical Practise HbA1c >7% at baseline n=104 HbA1c >6.5% at baseline n=140

34 BASELINE COHORT DATA Total Cohort T2DM CVD Patients No Comorbidities n=505 Patients n=232 n=167 n=196 Mean Standard Deviation Mean Standard Deviation Mean Standard Deviation Mean Standard Deviation Age (years) Testosterone (nmol/l) SHBG (nmol/l) Estrogen (nmol/l) LH (nmol/l) FSH (nmol/l) PSA (ng/ml) Hb (g/dl) HCT (%) HbA1c (%) Total Cholesterol (mmol/l) Triglycerides (mmol/l) LDL (mmol/l) HDL (mmol/l) AST (U/L) ALT (U/L) Albumin (g/l) Weight (kg) Waist Circumference (cm) Systolic BP (mmhg) Diastolic BP (mmhg) BMI (kg/m 2 )

35 DIFFERENTIAL EFFECT OF TRT BETWEEN PATIENTS WITH TYPE 2 DIABETES, CARDIOVASCULAR DISEASE and NO-COMORBIDITIES T2DM n=232 CVD n=167 No co-morbidities n=196 Sig Sig Sig Mean Std. Error Mean Mean Std. Error Mean Mean Std. Error Mean Testosterone (nmol/l) SHBG (nmol/l) Oestrogen (nmol/l) PSA (ng/ml) Haemoglobin (g/dl) Haematocrit (%) Total Cholesterol (mmol/l) Triglycerides (mmol/l) LDL (mmol/l) HDL(mmol/L) AST (U/L) ALT (U/L) Albumin (g/l) Weight (Kg) Waist (cm) BMI (kg/m 2 ) Systolic BP (mmhg) Diastolic BP (mmhg) HbA1c (%)

36 XY littermate Tfm Tfm High Cholesterol Diet High Cholesterol Diet High Cholesterol Diet Placebo Placebo Physiological Testosterone Replacement Normal Testosterone + Functional AR Low Testosterone + Non-functional AR Normal Testosterone + Non-functional AR

37 XY Placebo Tfm Placebo Tfm Testosterone Aortic Root Liver Normal Testosterone + Functional AR Low Testosterone + Non-functional AR Normal Testosterone + Non-functional AR

38 EFFECT OF TESTOSTERONE ON GLUCOSE UPTAKE IN HEPG2 INSULIN RESISTANT HUMAN LIVER CELLS M=Metformin F=Flutamide Unpublished

39 Effect of Testosterone on Rate of Glycolysis in HepG2 Liver Cells

40 GLUT4 G6P Dehydrogenase HK PFK

41 Kelly DM & Jones TH Endocrine 2016;54:

42 Kelly DM & Jones TH Endocrine 2016;54:

43 Abdominal Subcutaneous Adipose Visceral Adipose Kelly DM & Jones TH Endocrine 2016;54:

44 Functional background: Genetic changes induced by TRT Percent change in mrna expression or protein levels of insulin signaling mediators in adipose tissue after 24 weeks of testosterone or placebo treatment Dhindsa et al Diabetes Care :1-10

45 Subcutaneous Adipose TESTOSTERONE DEFICIENCY Glucose metabolism Triglyceride storage Glucose uptake Lypolysis Insulin sensitivity FAT spillover Glucose Glucose metabolism Lipogenesis Insulin sensitivity Reverse cholesterol transport Insulin sensitivity Glucose uptake Glucose metabolism Liver Visceral Adipose Muscle Artery

46 Testosterone may have tissue-specific metabolic effects to improve glucose utilisation and insulin sensitivity in liver, subcutaneous adipose and muscle tissue. Testosterone may improve lipid metabolism in liver and subcutaneous adipose tissue. Some of these effects are, at least in part, androgen receptor independent. Testosterone may increase the buffering capacity of subcutaneous adipose to protect against energy imbalance and fat overspill into liver and arterial vessels. This study adds mechanistic insight to the observed cardiometabolic clinical benefit of testosterone in men with T2D and metabolic syndrome.

47 Subcutaneous Adipose TESTOSTERONE REPLETE STATE Glucose metabolism Lipogenesis Insulin sensitivity Reverse cholesterol transport Glucose metabolism Triglyceride storage Glucose uptake Lypolysis Insulin sensitivity FAT No spillover Insulin sensitivity Glucose Increased Metabolism and reduced storage Glucose uptake Glucose metabolism Liver Visceral Adipose Muscle Artery

48 Summary Type 2 Diabetes is a terrible and serious disease associated with reduced QOL, major complications and premature death. High prevalence of Male Hypogonadism Low Testosterone is associated with an CV Risk Profile And all-cause and CV mortality and CV events TRT to the normal range reduces body fat, waist circumference, BMI and increases lean mass TRT Insulin Sensitivity, HbA1c, Total and LDL cholesterol, TNFα & may improve fatty liver TRT improves mortality and may reduce CV events