2017 Hot topics in cardiometabolism: an interactive update

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1 14-15 July, Bogotà, Colombia 2017 Hot topics in cardiometabolism: an interactive update IMPROVING THE PATIENT S LIFE THROUGH MEDICAL EDUCATION

2 Nicola Napoli Department of Medicine, Unit of Endocrinology and Diabetes University Campus Bio-Medico Rome, Italy Disclosure Declared receipt of grants and contracts from Bruno Farmaceutici; receipt of honoraria or consultation fees from MSD, AMGEN, Lilly; to be member of a compoany advisory board, board of directors or other similar groups of AMGEN, Lilly and MSD. 2

3 Metformin beyond diabetes: future perspectives of an old molecule (PCOS, obesity, etc.) Nicola Napoli Italy 3

4 Topics - Crucial role of insulin resistance in PCOS - Insulin resistance and bone health - Metformin benefits in women with PCOS - Insulin sensitizers and bone health: are they the same

5 Clinical case A 23-year-old woman with known polycystic ovary syndrome visits her family physician. She has taken oral contraceptive pills in the past but did not tolerate them and is not currently receiving any treatment. She has three or four menstrual periods per year and is not interested in becoming pregnant now, but she will be getting married in a year. She has heard that the polycystic ovary syndrome is associated with diabetes and is concerned because both her mother and father have type 2 diabetes. Her body-mass index is 32, her waist circumference is 38 in. (96.5 cm), her serum total testosterone level is elevated at 0.9 ng per milliliter (90 ng per deciliter, or 2.9 nmol per liter), her plasma HDL is 35 mg/dl (0.9 mmol per liter), and her triglyceride level is 190 mg/dl (2.1 mmol per liter). Her serum glucose level 2 hours after the ingestion of 75 g of glucose is 158 mg/dl(7.7 mmol per liter). The physician wonders whether treatment with metformin would be beneficial and refers the patient to an endocrinologist

6 Metabolic derangements in PCOS The prevalence of type 2 diabetes in the United States is 10 times higher among young women with PCOS than normal women Impaired glucose tolerance or overt type 2 diabetes develops by the age of 30 years in 30 to 50% of obese women with PCOS. The prevalence of the metabolic syndrome is two to three times higher in women with PCOS than normal women matched for age and body-mass index 20% of women with PCOS who are younger than 20 years of age have the metabolic syndrome.

7 The majority of women with PCOS, regardless of weight, have a form of insulin resistance that is intrinsic to the syndrome and is poorly understood. The insulin resistance that is characteristic of PCOS appears to be responsible of higher risk of type 2 diabetes. Insulin resistance underlies the association of PCOS with recognized cardiovascular risk factors such as dyslipidemia and hypertension, as well as with cardiovascular derangements.

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11 Human Reproduction Update, Vol.21, No.5 pp , 2015

12 Metabolic effects of metformi in PCOS insulin (20-30%) and testosterone (20%) SHBG Hirsutism: minimal/modest effect Acne: beneficial effect in one non-controlled study Menstrual regularity: restored in 25 to 70% of cases Pregnancy rates OR for metformin 1.7(CI )

13 Effects of metformin on inflamation and cardiovascolar parameters Improves endothelial dysfunction ( endothelin-1) Reduces intima-media thickness of carotid arteries (Orio2005)

14 Metformin and ovulation rate in PCOS

15 Metformin and ovulation rate in PCOS Metformin + clomiphene

16 Treating women with PCOS

17 Conclusions Women with PCOS, long-term treatment with metformin increase ovulation, improve menstrual cyclicity, and reduce serum androgen levels; Use of metformin may also improve hirsutism. Importantly, metformin prevents progression to glucose intolerance in affected women

18 Type 2 DM and hip fracture RR (95% CI) Heath, (0.6, 1.02) Meyer, (3.4, 24.9) Forsen, (1.1, 2.9) Ivers, (0.2, 2.2) Nicodemus and Folsom, (1.2, 2.4) Schwartz, (1.2, 2.7) Ottenbacher, (1.0, 2.3) de Liefde, (0.8, 2.3) Vestergaard, (1.2, 1.6) Holmberg, (1.7, 9.4) Ahmed, (1.02, 3.5) Janghorbani, (1.8, 2.7) All studies 1.7 (1.3, 2.2) RR any fracture 1.2 ( ) RR hip fracture 1.7 ( ) Test for heterogeneity: Q = 58.1; p < Relative risk RR=relative risk Janghorbani M et al. Am J Epidemiol 2007;166:

19 NAPOLI ET AL, NATURE ENDOCRINOLOGY

20 Negative correlation between glucose control and bone formation Vestergaard,oi 2014 and Bone 2016

21 % % % So why more fractures? Bone turnover? Histomorphometry shows reduced mineralizing surface, osteoid surface, and osteoblast surface (pilot study) Osteoid Surface * T2DM Rubin MR. Curr Osteoporos Rep 2015;13: Control Mineralizing Surface * T2DM Control Osteoblast Surface * T2DM Control *p<.05

22 Low Bone Formation in Diabetics Rubin et al. JCEM, 2012

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24 Utilising data from the Osteoporotic Fractures in Men (MrOS) study, a large multicentre prospective observational study examining the incidence and predictors of fractures in older men

25 Men using insulin had a higher risk of all non-vertebral fractures Model Diabetes, all a IFG b Diabetes, insulin use HR (95% CI) HR (95% CI) HR (95% CI) Unadjusted model 1.08 (0.91, 1.28) 0.93 (0.79, 1.08) 1.94 (1.35, 2.80) 2. Adjusted for age, race, clinic 1.12 (0.94, 1.34) 0.95 (0.81, 1.10) 2.24 (1.53, 3.27) 3. Adjusted for Model 1 plus total hip BMD 1.30 (1.09, 1.54) 1.04 (0.89, 1.21) 2.46 (1.69, 3.59) 4. Adjusted for Model 1 plus falls in the year before baseline 1.08 (0.91, 1.29) 0.95 (0.82, 1.11) 1.98 (1.34, 2.15) 5. Multivariable 1.00 model c (0.85, 1.18) 1.74 (1.13, 2.69) Napoli & Schwartz, Diabetologia, 2014

26 Risk factors for non-vertebral fracture in older men with diabetes Napoli & Schwartz, Diabetologia, 2014

27 SULFONYLUREAs result in significantly more hypoglycaemic events than other treatments Meta-analysis of head-to-head studies 1 Authors Type of therapy RR (95% CI) % weight Hypoglycaemic events* Burant et al 2 Monotherapy 5.37 (1.26, 22.85) 8.30 Simonson et al 3 Monotherapy 4.20 (0.25, 71.96) 3.03 DeFronzo and Goodman 4 Combination 9.37 (3.40, 25.78) Feinglos et al 5 Combination 4.50 (1.01, 19.98) 8.01 Horton et al 6 Combination 6.03 (0.73, 49.67) 4.92 Kabadi et al 7 Insulin 0.50 (0.05, 4.67) 4.50 Riddle et al 8 Insulin 1.36 (0.28, 6.56) 7.49 Riddle and Schneider 9 Insulin 1.39 (0.96, 2.02) Stenman et al 10 Insulin 1.63 (0.94, 2.80) Stuart et al 11 Insulin 1.67 (0.77, 3.61) Subtotal (I 2 =61.0%, p=0.006) 2.41 (1.41, 4.10) Favours sulfonylurea Favours comparator *Defined as either patient-reported symptoms or blood glucose levels below a threshold of mmol/l [55 60 mg/dl] 1. Hirst JA, et al. Diabetologia 2013;56: Burant CF, et al. Lancet 2012;379: Simonson DC, et al. Diabetes Care 1997;20: DeFronzo RA, Goodman AM. N Engl J Med 1995;333: Feinglos M, et al. Diabetes Res Clin Pract 2005;68: Horton ES, et al. Diabetes Care 1998;21: Kabadi UM, et al. Diab Med J Brit Diabet Assoc 1995: Riddle M, et al. Am J Med Sci 1992;303: Riddle MC, Schneider J. Diabetes Care 1998;21: Stenman S, et al. Diabetologia 1988;31: Stuart CA, et al. Endocr Pract 1997;3:

28 Palermo A, Napoli et al. Osteoporos Int 2015;26: Drugs for T2DM may affect fracture risk Bone biomarkers Bone formation Bone resorption BMD Fracture Metformin Sulphonylureas Thiazolidinediones Incretin GLP-1 analogue DPP-4 inhibitor b a SGLT2 inhibitor a The latest evidence of Bone and colleagues showed no effects of pioglitazone on BMD (Bone HG et al. J Clin Endocrinol Metab 2013;98: ) b GLP-2 administration. BMD=bone mineral density; DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; GLP-2=glucagon-like peptide-2; SGLT2=sodium glucose cotransporter 2

29 Skeletal effects of pharmacological treatments for T2DM Metformin increases the differentiation of osteoblasts through its actions on RUNX2. Glitazones simultaneously suppress RUNX2 and activate PPARγ, which drives differentiation of MSCs into adipocytes, thereby reducing osteogenesis. Bone, sweet bone - Osteoporotic fractures in diabetes mellitus Nature Reviews Endocrinology 2012