Diabetes mellitus Yvona Pospíšilová Department of Internal Medicine, Hematology and Oncology FN Brno and Masaryk University Brno pospisilova.yvona@fnbrno.cz 3.11.2022 • • •The most frequent metabolic disease • •Relative or absolute insufficiency of insulin • •Hyperglycaemia • • •The most frequent cause of blidness • •The most frequent cause of amputation of lower extremities • •40 % patients on chronic dialysis • • lZimmet,P.: Preventing type 2 diabetes and dysmetabolic syndrome in the real word: a realistic view, Diabetic Medicine, 20, 2003 Classification of Diabetes • • •Type 1 diabetes mellitus • •Type 2 diabetes mellitus • •Gestational diabetes mellitus • •Specific types of diabetes due to other causes Other specific types • • •Genetic defects •Disease of the exocrine pancreas •Endocrinopathies •Infections • • •Drug – or chemical – induced diabetes (glucocorticoids) •Uncomon forms •Type 1 DM •- an absolute insulin deficiency • •a) immune-mediated (95%) • •b) idiopathic (mostly African or Asian ancestry) •Type 2 DM •- a relative insulin deficiency • •a) predominantly insulin resistance (Latinos) • •b) predominantly an insulin secretory defect (East Asians) • Type 1 Diabetes mellitus •6 % of all diabetics •mostly immune-mediated (autimmune destruction of beta-cells - insulitis) – in 96% •presence of antibodies: anti-GAD (glutamic acid decarboxylase), anti IA-2 (tyrosine phosphatase), antibodies to islet cells •strong HLA associations with DQA and DQB genes • •low C-peptide levels •low genetic predisposition (probability: 5 % in DM1 women, 8 % in DM1 men) • • • • • • • • • • •C-peptid •part of proinsulin •its concentration tells us about the amount of production of insulin C:\Users\25624\Pictures\300px-Cpeptid.png Risk factors – Type 1 DM • • • •Respiratory viruses ? •Enteroviruses ? • •Casein of cow milk ? • • Type 2 Diabetes mellitus • •94 % of all diabetics • heterogenous and multigenous • monogenous only in a very small percent •+ changes in life-style („coca - colonization“, „pandemic“) •strong genetic predisposition (probability: one parent – 50 %, both parents – 100 %) Diabetes mellitus typ 2 •a) insulin resistance (muscle, liver, fat) •b) an insulin secretory defect •c) progressively declining of beta-cell mass - declining of function of pancreas) • •GIT: incretin deficiency and/or resistance •Pancreas: hyperglucagonemia •Kidneys: enhanced glucose reabsorption •CNS: insulin resistance • Risk Factors – Type 2 DM • • •strong familial aggregation •age •obesity •physical inactivity •racial and ethnic subgroups (Native American, Polynesian, Micronesian, Asian-Indian, Hispanic, Afro-American) Diagnosis of DM • • • •fasting plasma glucose level (FPG) - 7,0 mmol/l or more •2 – hour postload plasma glucose level or casual plasma glucose level - 11,1 mmol/l or more • •without clinical symptoms - 2x • •Oral Glucose Tolerance Test (oGTT) - Czech •75 g glucose load, usually dissolved in water • • • Glycosylated/glycated haemoglobin (HbA1C) • • • •fusion glucose + haemoglobin (….compensation of DM for last 6- 8 weeks..) • •in some countries – dg of DM (only adult populations, 6.5 % and more - by DCCT – US, Europe: 48 mmol/mol and more …) • •in all countries – compensation of DM Prediabetes….. • • • • • •microvascular complications - 7 mmol/l (fasting) •macrovascular complications - 6 mmol/l (fasting) Prediabetes („people with high risk of developing diabetes“) • • •1) Impaired glucose tolerance (IGT) • •7,8 – 11,0 mmol/l postprandial (2-hour postload) • • •independent risk factor for ischemic heart disease • • •2) Impaired fasting glucose (IFG) • •5,6 - 6,9 mmol/l fasting • • • • •3) Glyk. Hb 5.7-6.4 % (USA)…39-47 mmol/mol in Europe • Symptomatology of Type 1 Diabetes • • • • •beginning is quick (hours, dayes) •thirst, increasing urination, fatigue •hyperglycaemia, ketoacidosis, thirst, fatigue, coma…. Symptomatology of Type 2 Diabetes • • • •very often without any problems (many years…) •finding the complications (skin, kidney, eyes, neuropathy..) • •can be thirst, increasing urination, fatigue •hyperglycaemia, mostly without ketoacidosis Screening for Type 2 DM and prediabetes • • •In all adults who are overweight (BMI 25 kg/m2 or more) and have additional risk factors in any time: •physical inactivity, first-degree relative with diabetes, members of high-risk ethnic population, women with GDM or PCOS or who delivered a baby weighing more than 9 lb (?), subjects with IGT or/and IFG, subjects with hypertension, dyslipidemia or history of CVD Screening for Type 2 DM and prediabetes • • • •In the absence of these criteria, testing should begin at age 40 (30…35?) years • •Testing should be repeated at 1-3 years intervals GDM (Gestational diabetes mellitus) – in Czech • • •In the first three months • at every pregnant women – normal fasting plasma glucose level (FPG) - less than 5,0 mmol/l • fasting plasma glucose level (FPG) 5,1-6,9 mmol/l – GDM • fasting plasma glucose level (FPG) ≥ 7 mmol/l or HbA1c ≥ 48 mmol/mol - DM •- No clear result → oGTT • GDM (Gestational diabetes mellitus) • • •In 24-28 week of pregnancy •at every woman oGTT •(dg: •fasting plasma glucose level (FPG) •5,1 mmol/l and more •after 1. hour - 10,0 mmol/l and more •after 2. hour - 8,5 mmol/l and more) • GDM (Gestational diabetes mellitus) Treatment • • •80 % lifestyle intervention • •20 % - + metformin • - + insulin (does not cross placenta) • • ( - + glibenclamid in US ?) Long therapy with glucocorticoids - drug or chemical – induced diabetes (glucocorticoids) • • •there are problems with regulation of glucose in all patients • •almost 25 % (4-44 %) patients develop DM • •there is worsening of glucose in diabetics • • • • •level of glycaemia starts to increase 4-6 hours after application of glucocorticoids and lasts about 12 hours •the highest levels of glucose are in the afternoon and in the evening •the lowest levels of glucose are during the night and in the morning • • Drug – or chemical – induced diabetes (glucocorticoids) PS-PP IHOK glycemia 8.00 12.00 14.00 18.00 6.00 •Increasing of previous medications •Insulin – the highest levels at noon, the lowest at night (in the evening)….. • •Short acting insulin: 6 IU – 12 IU – 4 IU • • •The high levels of glucose should continue several dayes after termination of therapy with glucocorticoids • • • Treatment of patients with Diabetes Mellitus •Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach (Position Statement of ADA and EASD): Inzucchi, Bergenstal, Buse et all., in Diabetes Care, April 2012 • •„within the context of the needs, preferences, and tolerances of each patient, •individualization of treatment is the corneston of success“ •„the synthesis of best available evidence from the literature with the clinician´s expertise and patient´s own inclinations“ Treatment of Type 1 Diabetes • • •Insulin • •Insulin •(+ amylin agonist (pramlintid-inhibition of glucagon secretion and slowing gastric emtying) – in USA •p.o. antidiabetics – „do not work“ - Europe • •Transplantation (pancreas, pankreatic islets) Treatment of Type 2 Diabetes • • •1) Non – pharmacological ( life style intervention) • • •2) Pharmacological (drugs, insulin) • • •3) Surgery + metabolic intervention – gastric and intestine operation (gastric banding etc…) - metabolic surgery • Vasodilators Diuretics Central a-2 agonists ACEIs CCBs Peripheral a-1 blockers ß-blockers Adrenergic neuronal blockers ARBs 1 SUs Insulin Biguanides GLP-1 agonists Amylin analogues DPP-4 inhibitors Biguanides AGIs TZDs Meglitinides Adapted from: Inzucchi SE in Clinical Diabetes, Fonseca VA ed., 2006. SGLT2 inhibitors Antidiabetics 2 3 4 5 6 7 8 9 Treatment of Type 2 Diabetes • •Biguanides (metformin) • • - the main drug for treatment Type 2 DM • - reduces hepatic glucose output and reduces hepatic insulin resistance • - rarely if ever causes hypoglycemia • • Prediabetes and metformin • • • •BMI > 35 kg/m2 •Aged < 60 years •Women with prior GDM Metformin – systemic effects •decreasing of cancers •pozitive cardiovascular effect •stimulation of immunity response •anabolic effect on bone •pozitive effect on ovulation (PCOSy) •reduction of weight and waist circumferrence •pozitive effect on steatosis hepatis •decreasing of chronnic inflammatory process in a body •increasing activity of GLP-1 •hypolipidemic acivity •decreasing aggregability of trombocytes Treatment of Type 2 Diabetes • •Sulphonylureas • • - stimulate insulin secretion from beta cells of pankreas – exhaustion of pancreas • - can cause severe hypoglycemia • •There are not often used now…. • • • Treatment of Type 2 Diabetes • •Thiazolidinediones • • - reduce peripheral insulin resistance • - preserve residual function of beta-cells • - can cause heart insufficiency (rosiglitazon) • (only pioglitazon is used….) • • „Incretin effect“… •…the insulin response to oral glucose is greater than for i.v. glucose • •Incretins (intestinal hormones) - GLP-1 (glucagon-like peptid): •stimulates insulin release from beta-cells •without hypoglycaemia •slowes gastric emptying (decreases glucose excursion and feeling of hunger) •centrally reduces food intake •promotes beta cell survival and their regeneration • • Treatment of Type 2 Diabetes • • •Incretin mimetics and enhancers: • •GLP-1 (glucagon-like peptid - 1) – receptor agonists • usually s.c. aplication (twice…once daily) • •DPP-4 inhibitors (inhibitors of dipeptidyl peptidase-4 – inhibition of enzyme which degrades GLP-1) • p.o. use • • • Treatment of Type 2 Diabetes • •Gliflozins – inhibition of reabsorbtion of glucose from kidney (SGLT2-inhibitors) • • - decreasing of increase reabsorbtion of glucose from kidney – DM Type 2 • - decreasing of glycaemia, blood pressure and weight • •New information: improvement of kidney and heart insufficiency also in non–diabetic people!! • - Insulin • •essential in Type 1 DM (and GDM?) • •Type 2 DM: •- glucose plasma level more than 15 mmol/l - decompensation of DM •- acidosis •- other serious diseases •- poor compensation of diabetes •- as a second step Type of insulin • • •Short (acting) human insulin (Regular) • •Rapid (acting) insulin analogues • •Intermediate (acting) human insulin (NPH) • •Long (acting) insulin analogues C:\Documents and Settings\25624\Dokumenty\Obrázky\350px-Insulin_short-intermediate-long_acting_svg.png Compensation • • •FPG („fasting“ plasma glucose) • •PPG („postprandial“ plasma glucose) • •Glycosylated/glycated haemoglobin (HBA1C) • New information in the past years…. • • •1) good compensation of diabetes at the beginning of the disease leads to less complications afterwards („glycemic memory“) • •2) there are more deaths when we try to have a good compensation of diabetes in patients with long duration of diabetes Glycemic targets • • • •Glycosylated/glycated haemoglobin (HbA1C) up to 45 mmol/mol at the beginning of the disease, long life expectancy, no CVD • •Glycosylated/glycated haemoglobin (HbA1C) up to 60 mmol/mol in people with complications of diabetes, e. g. severe hypoglycemia • •(Glycosylated/glycated haemoglobin more than 53 mmol/mol (7 % DCCT) – revise therapy) • • • •Blood pressure •Lipids •Antiplatelet treatment (??) •Retinopathy screening •Micro and macroalbuminuria and function of kidney screening •Neuropathy screening •Foot care Parametr Kompenzace výborná Kompenzace uspokojivá Kompenzace u pac. s vysokým KV rizikem Glykémie nalačno (mmol/l ) 4,0-6,0 6,0-7,0 < 7,0-8,0 Glykémie za 1-2 hod po jídle ( mmol/l ) 5,0-7,5 7,5-9,0 < 9,0 HbA1c - glykovaný hemoglobin mmol/mol < 45 45 - 54 54-60 Celkový cholesterol ( mmol/l ) do 4,5? HDL - cholesterol ( mmol/l) >1,1 LDL - cholesterol ( mmol/l ) 2,5 – 1,8 1,4 - 1,8 Triglyceridy ( mmol/l ) < 1,7 Krevní tlak ( mm Hg) < 130/80 < do 140/90 Hmotnostní index BMI ( body mass index ) (kg/ m2 ) muži 21 - 25 25 - 27 Hmotnostní index BMI ( body mass index ) (kg/ m2 ) ženy 20 - 24 24 - 26 Acute complications •acute life threatening - coma • •HYPOGLYCAEMIA • •HYPERGLYCAEMIA: 1.Hyperglycaemic ketoacidotic coma 2.Hyperglycaemic hyperosmolary coma 3.Laktacidotic coma • Glukagon GlukaGen Hypo KIT Glukagon BAQSIMI – glukagon powder (talc) – Elli-Lilly – from 7/2020 v ČR 640x0_0_3e28218b-baqsimi-photo-768x719 Powder…talc…. Specific chronic complications • 1. 1. 1.Diabetic nephropathy 2.Diabetic retinopathy 3.Diabetic polyneuropathy 4.„Diabetic foot“ (neuropathy + vascular disease) 5.Diabetic osteoartropathy Measurement of blood glucose • • •SMBG (Self Monitoring Blood Glucose) • •CGM (Continual Glucose Monitoring) • •FGM (Flash Glucose Monitoring) SMBG CGM FGM C:\Users\25624\Desktop\how-to-use%20-1.png C:\Users\25624\Desktop\how-to-use%20-2.png C:\Users\25624\Desktop\how-to-use%20-3.png Treatment of DM type 2 (ADA + EASD from 2015) • • • •1) life style intervention + metformin (only highly motivated patients with glyk. Hb near target at diagnosis could be without farmacotherapy for 3-6 month) • •2) + insulin • + sulphonylureas • + thiazolidindiones • + incretins • + SGLT2-inhibitor •3) combinations of the above • Antihyperglycemic therapy in type 2 diabetes: general recommendations. Silvio E. Inzucchi et al. Dia Care 2015;38:140-149 ©2015 by American Diabetes Association Antihyperglycemic therapy in type 2 diabetes: general recommendations. Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, the usual transition being vertical, from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis, unless there are contraindications. If the HbA[1c] target is not achieved after ∼3 months, consider one of the six treatment options combined with metformin: a sulfonylurea, TZD, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, or basal insulin. (The order in the chart, not meant to denote any specific preference, was determined by the historical availability of the class and route of administration, with injectables to the right and insulin to the far right.) Drug choice is based on patient preferences as well as various patient, disease, and drug characteristics, with the goal being to reduce glucose concentrations while minimizing side effects, especially hypoglycemia. The figure emphasizes drugs in common use in the U.S. and/or Europe. Rapid-acting secretagogues (meglitinides) may be used in place of sulfonylureas in patients with irregular meal schedules or who develop late postprandial hypoglycemia on a sulfonylurea. Other drugs not shown (α-glucosidase inhibitors, colesevelam, bromocriptine, pramlintide) may be tried in specific situations (where available), but are generally not favored because of their modest efficacy, the frequency of administration, and/or limiting side effects. In patients intolerant of, or with contraindications for, metformin, consider initial drug from other classes depicted under “Dual therapy” and proceed accordingly. In this circumstance, while published trials are generally lacking, it is reasonable to consider three-drug combinations that do not include metformin. Consider initiating therapy with a dual combination when HbA[1c] is ≥9% (≥75 mmol/mol) to more expeditiously achieve target. Insulin has the advantage of being effective where other agents may not be and should be considered a part of any combination regimen when hyperglycemia is severe, especially if the patient is symptomatic or if any catabolic features (weight loss, any ketosis) are evident. Consider initiating combination injectable therapy with insulin when blood glucose is ≥300–350 mg/dL (≥16.7–19.4 mmol/L) and/or HbA[1c] ≥10–12% (≥86–108 mmol/mol). Potentially, as the patient’s glucose toxicity resolves, the regimen can be subsequently simplified. DPP-4-i, DPP-4 inhibitor; fxs, fractures; GI, gastrointestinal; GLP-1-RA, GLP-1 receptor agonist; GU, genitourinary; HF, heart failure; Hypo, hypoglycemia; SGLT2-i, SGLT2 inhibitor; SU, sulfonylurea. *See Supplementary Data for description of efficacy categorization. †Consider initial therapy at this stage when HbA[1c] is ≥9% (≥75 mmol/mol). ‡Consider initial therapy at this stage when blood glucose is ≥300–350 mg/dL (≥16.7–19.4 mmol/L) and/or HbA[1c] ≥10–12% (≥86–108 mmol/mol), especially if patient is symptomatic or if catabolic features (weight loss, ketosis) are present, in which case basal insulin + mealtime insulin is the preferred initial regimen. §Usually a basal insulin (e.g., NPH, glargine, detemir, degludec). ADA/EASD (from 2019) •New information: SGLT-2 inhibitors can lead to improvement kidney and heart insufficiency also in non–diabetic people!! • • •+ GLP-1-rp agonists (liraglutid) or SGLT-2 inhibitors (empagliflozin, canagliflozin, dapagliflozin) in people with CVD or with great risk of development CVD or in people with CKD • • F1 ADA + EASD – 2022 •Individualization of treatment •Preference of life style-intervention + metabolic surgery •Preference of using GLP-1-rp analogs or SGLT-2-inhibitors • • •Metformin as a first step, but from 2022 we can use as a first step also SGLT2- inhibitor (presence or risk of CVD or CKD), • or GLP-1-rp analog– liraglutid in people with obesity) • •If we use metformin as a first step, it is recommended to use as a second step GLP-1-rp agonist (liraglutid) or SGLT-2 inhibitor (gliflozin) Date of Download: 9/28/2022 Copyright © 2022 American Diabetes Association. All rights reserved. From: Standards of Medical Care in Diabetes—2022 Abridged for Primary Care Providers Clin Diabetes. 2022;40(1):10-38. doi:10.2337/cd22-as01 Pharmacologic treatment of hyperglycemia in adults with type 2 diabetes. 2022 ADA Professional Practice Committee (PPC) adaptation of Davies MJ, D’Alessio DA, Fradkin J, et al. Diabetes Care 2018;41:2669–2701 and Buse JB, Wexler DJ, Tsapas A, et al. Diabetes Care 2020;43:487–493. For appropriate context, see Figure 4.1. The 2022 ADA PPC adaptation emphasizes incorporation of therapy rather than sequential add-on, which may require adjustment of current therapies. Therapeutic regimen should be tailored to comorbidities, patient-centered treatment factors, and management needs. Refer to sections 10 and 11 in the complete 2022 Standards of Care for detailed discussions of CVD and CKD risk management. CVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase 4 inhibitor; GLP-1 RA, glucagon-like peptide 1 receptor agonist; SGLT2i, sodium–glucose cotransporter 2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione. Figure Legend: American Diabetes Association Prevention of Type 1 DM • • • •Insulin •Nikotinamid •Imunosupresive therapy (cyclosporin) • •But none of these exactly works…….. • • • Prevention of Type 2 DM • • •Life style intervention • • •Alfa-glucosidase inhibitors -acarbose •Metformin •Thiazolidinediones •Orlistat DM and coffee…. • •increasing of insulin sensitivity •includes potassium, magnesium, fibre •includes antioxidants •includes polyfenols – Chlorogen- acid – antioxidant + antiinflamatory efect •includes niacin, B - vitamins B Prevention/delay of type 2 DM lPrisant, L.M.:Preventing Type II Diabetes Mellitus. J. Clin. Pharmacol, 44, 2004 FINDRISC (FINnish Diabetes RIsk SCore) 1.JPG 2.JPG C:\Users\25624\Desktop\Fota na papír 2016\IMG_6655.JPG Děkuji vám za pozornost