Management Of Type 2 Diabetes PDF

MANAGEMENT OF DIABETES PROF. REEM KAYYALI  reduced insulin Keto stable bloodsugar 2 insulin resistant type  GLUCOSE METABOLISM Blood glucose levels are closely regulated. The principal organ of glucose homeostasis is the liver (gl...

MANAGEMENT OF DIABETES PROF. REEM KAYYALI  reduced insulin Keto stable bloodsugar 2 insulin resistant type  GLUCOSE METABOLISM Blood glucose levels are closely regulated. The principal organ of glucose homeostasis is the liver (glycogenesis, glycogenolysis & gluconeogenesis) Insulin is the principal hormone affecting blood glucose levels Insulin is a polypeptide synthesised in the beta cells of islets of langerhams of the pancreas. It plays a key role in the regulation of carbohydrate, fat and protein metabolism.  INSULIN FUNCTION Insulin is involved in the storage of nutrients in the form of glycogen in liver and muscle and triglycerides in fat During a meal, insulin is released to facilitate glucose uptake by fat and muscle In the fasting state , the main action of insulin is to regulate glucose release by the liver The effects of insulin are opposed by other hormones, e.g. glucagon, adrenaline (epinephrine), glucorticoids and growth hormone. Sometimes referred to as stress hormones. These cause greater production of glucose from the liver and less utilization of glucose in fat and muscle.  DIABETES MELLITUS (DM) DM is the name given to a group of disorders where the circulating levels of the hormone insulin are insufficient to maintain blood glucose concentrations within the normal range. The normal range is 4-5.6mmol/l  DIABETES MELLITUS (DM) Diabetes is usually primary but may be secondary to other conditions e.g. pancreatic disease, endocrine disease e.g. Cushing's syndrome, drug therapy, high growth hormone levels, etc Primary Diabetes is generally sub-classified into: Insulin dependent diabetes mellitus or Type 1 diabetes mellitus (IDDM, T1DM ) Non-insulin dependent diabetes mellitus or Type 2 diabetes mellitus (NIDDM, T2DM ) Other types?  TYPE 2 DIABETES There are an estimated 4.5 million people living with diabetes in the UK. Over three million people are living with diabetes in England and Five million people are at high risk of developing Type 2 diabetes If current trends persist, one in three people will be obese by 2034 and one in ten will develop Type 2 diabetes.  T2DM Accounts for approximately 90% of all diabetic patients. It is most common between 40 and 80 years. It is polygenic but with no HLA links No evidence of immune disturbance (the genetic causes include mutation of the insulin receptor and structural alteration of the insulin molecule). In this condition, there is resistance of peripheral tissues to the actions of insulin, so that insulin levels may be normal or even high. Hyperglycaemia can also be the result of reduced insulin secretion (inappropriately low for the glucose level) Obesity is the most commonly associated clinical feature. It appears to trigger the disease in genetically susceptible individuals – Read articles on Canvas. We see now T2DM in the young due to increased obesity CLINICAL FEATURES T2DM – present with the same symptoms as T1DM, thirst and polyurea, although less marked and extending over several months. They may also complain of lack of energy, visual problems and pruritis vulvae or balanitis due to Candida infection (recurrent infections).  MECHANISM OF CLINICAL FEATURES Polyurea – is the result of osmotics diuresis when blood glucose levels exceed the renal tubular reabsorptive capacity. Thirst – is stimulated by fluid and electrolyte losses  INVESTIGATIONS The diagnoses of DM is made by demonstrating: Fasting (no calorie intake for last 8 hours) plasma glucose ≥ 7.0 mmol/L Random (without regard to time since last meal) plasma glucose ≥ 11.1 mmol/L One abnormal laboratory value is diagnostic in symptomatic individuals; two values are needed in asymptomatic people. Gold standard: Glycosylated haemoglobin (HbA1c) – measures control over a period of 2-3M. HbA1c concentration of 48 mmol/mol (6.5%) or above is diagnostic. MANAGEMENT OF T2 DM First line: Lifestyle modifications (such as weight loss, eating a healthy diet, smoking cessation, and regular exercise) - These factors should improve glycaemic control in T2DM DIET AND T2DM A balanced diet whereby main nutrients load should be spread throughout the day (three main meals with snacks in between times and at bedtime) which reduces swings in blood glucose. Emphasise advice on healthy balanced eating. Encourage high-fibre, low-glycaemic-index sources of carbohydrate in the diet (low glycaemic load), care with fruit, vegetables, wholegrains, wholemeal and pulses; include low-fat dairy products and oily fish; and control the intake of foods containing saturated and trans fatty acids. Glycaemic index and diabetes | Diabetes UK include other aspects of lifestyle modification, such as increasing physical activity and losing weight. For adults who are overweight, set an initial body weight loss target of 5–10%.  LIFESTYLE CHANGES They are key to prevent DM and its CV complications. Smoking cessation Reduced calorie intake is recommended to lower excessive body weight in patients with DM. A Mediterranean diet supplemented with olive oil and/or nuts reduces the incidence of major CV events. Moderate-to-vigorous physical activity of ≥150 min/week is recommended for the prevention and control of DM.  ORAL ANTIDIABETIC DRUGS - 1 Used for T2DM. They should be prescribed only if the patient fails to respond adequately to at least 3 months’ restriction of energy and carbohydrate intake and an increase in physical activity. They should be used to augment the effect of diet and exercise, and not to replace them.  ORAL ANTIDIABETIC DRUGS - 2 Main Classes: Biguanides (metformin) Sulphonylureas (glipizide, tolbutamide, glimepiride & gliclazide) DPP-4 inhibitors (gliptins) (alogliptin, linagliptin, sitagliptin, saxagliptin, and vildagliptin) Thiazolidinediones (pioglitazone) SGLT-2 sodium–glucose cotransporter 2 inhibitors (flozins) (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin) -Glucosidase inhibitors (acarbose) Post prandial regulators (repaglinide) CATEGORIES OF DRUGS Therapeutic agents can be broadly characterised as belonging to one of five groups: (i)insulin sensitizers (metformin and pioglitazone); (ii)insulin providers (insulin, sulfonylureas, and meglitinides); (iii)incretin-based therapies (GLP1-RAs, Long acting GIP and GLP1- RA (Tirzepatide) and DPP4 inhibitors); (iv)renal glucose reuptake inhibitors (SGLT2 inhibitors) (v)gastrointestinal glucose absorption inhibitor (acarbose)  ORAL ANTIDIABETIC DRUGS - 3 Biguanides (Metformin) exert their effect mainly by decreasing gluconeogenesis and by increasing peripheral utilisation of glucose; It is the first line treatment in diabetic patients (especially obese) as does not increase appetite It is also considered as the first line option in patients who are not overweight Side effects include anorexia, N&V and diarrhoea (check anaemia as side effect) Rarely, Lactic acidosis has occurred in patients with severe hepatic or renal impairment, review dose if GFR is < 45ml/min/1.73m2 and avoid if GFR is < 30ml/min/1.73m2). Advantage? In T1DM? How do you load? What alternative formulation? When is it used? ORAL ANTIDIABETIC DRUGS - 4 Sulphonylurea Act mainly by augmenting insulin secretion Are considered for patients who are not overweight, or in whom metformin is contra-indicated or not tolerated. Several are available and choice is determined by side-effects and the duration of action as well as the patient’s age and renal function. The most common side effect is hypoglycaemia (a shorter-acting sulfonylurea, such as gliclazide or tolbutamide is preferred)  ORAL ANTIDIABETIC DRUGS - 5 All sulphonylureas encourage weight gain and are not drugs of first choice in obese patients Sulphonylureas should be avoided where possible in severe hepatic and renal impairment and in porphyria. They should not be used while breast- feeding and insulin therapy should be substituted during pregnancy. Sulphonylureas are contra- indicated in the presence of ketoacidosis  ORAL ANTIDIABETIC DRUGS - 6 Thiazolidinediones (Pioglitazone) Enhance insulin receptor sensitivity, hence reducing peripheral insulin resistance, leading to a reduction of blood-glucose concentration They are contraindicated in patients with hepatic impairment – rare reports of liver toxicity – counsel patients on signs (what are they? DILI) Incidence of heart failure increased when pioglitazone is used with insulin Small increased risk of bladder cancer associated with pioglitazone use  ORAL ANTIDIABETIC DRUGS - 7 Do not offer or continue pioglitazone if patient has: heart failure or history of heart failure hepatic impairment diabetic ketoacidosis current or a history of bladder cancer uninvestigated macroscopic haematuria.  ORAL ANTIDIABETIC DRUGS - 8 Alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin inhibit dipeptidylpeptidase-4 to increase insulin secretion and lower glucagon secretion. Do not appear to be associated with weight gain and have less incidence of hypo. Available now as combination tablets of metformin and gliptins – compliance  ANTIDIABETIC DRUGS - 9 SGLT-2 sodium–glucose cotransporter 2 inhibitors (canagiflozin (what specific risk, not class risk?), dapagliflozin, empagliflozin, ertugliflozin) reversibly inhibit sodium-glucose co-transporter 2 (SGLT2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion. Again now available as combination preparation with metformin – compliance They are beneficial in patients with T2DM and established CVD (see later). Side effects? Caution?  ANTIDIABETIC DRUGS - 10 Serious and potentially life-threatening cases of diabetic ketoacidosis (DKA) have been reported in patients taking SGLT2 inhibitors for type 2 diabetes. The EMA has issued the following advice to minimise the risk: Test for raised ketones in patients presenting with symptoms of DKA, even if plasma glucose levels are near-normal; omitting this test could delay a diagnosis of DKA. Discontinue treatment if DKA is suspected. If DKA is confirmed, take appropriate measures to correct the DKA and monitor glucose levels. Patients should be advised on how to recognise the signs and symptoms of DKA such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness, and to seek prompt medical attention if symptoms of DKA develop. https://onlinelibrary.wiley.com/doi/pdf/10.1111/jdi.12401 ANTIDIABETIC DRUGS - 11 MHRA/CHM advice: SGLT2 inhibitors: reports of Fournier’s gangrene (necrotising fasciitis of the genitalia or perineum) (February 2019) Fournier’s gangrene, a rare but serious and potentially life- threatening infection, has been associated with the use of sodium- glucose co-transporter 2 (SGLT2) inhibitors. If Fournier's gangrene is suspected, stop the SGLT2 inhibitor and urgently start treatment (including antibiotics and surgical debridement). Patients should be advised to seek urgent medical attention if they experience severe pain, tenderness, erythema, or swelling in the genital or perineal area, accompanied by fever or malaise— urogenital infection or perineal abscess may precede necrotising fasciitis. ORAL ANTIDIABETIC DRUGS - 12 - Glucosidase inhibitors (Acarbose) – Hardly used Inhibits intestinal glucosidase, thus impairing carbohydrate digestion and slowing glucose absorption. Gasrointestinal side-effects e.g. flatulence, bloating and diarrhoea are common and limit the dose and acceptability of this treatment. ORAL ANTIDIABETIC DRUGS - 12 Post prandial regulators (Repaglinide) – hardly used Stimulate insulin release (rapid insulin secretagogues) It has a rapid onset of action and short duration of activity, and should be administered shortly before each main meal. Hence, lowering postprandial hyperglycaemia.  NON-ORAL ANTIDIABETIC DRUGS Exenatide, liraglutide, semaglutide, dulaglutide & lixisenatide, a synthetic form of exendin-4, is an incretin mimetic (binds and activates GLP-1 receptor) which increases insulin secretion, suppresses glucagon secretion, and slows gastric emptying (have value in obese patients, see slides below) They are given by sc injection for the treatment of type 2 diabetes. Modified release (once weekly) Oral semaglutide 14 mg once daily is comparable to subcutaneous semaglutide 0.5 mg once weekly. Liraglutide has proven cardiovascular benefit and should be considered in T2DM patients with established CVD. TIRZEPATIDE A long-acting GIP (gastric inhibitory polypeptide - glucose-dependent insulinotropic polypeptide) receptor and GLP-1- RA, that increases insulin sensitivity and secretion, suppresses glucagon secretion, and slows gastric emptying. NON-ORAL ANTIDIABETIC DRUGS MHRA/CHM advice: GLP-1 receptor agonists: reports of diabetic ketoacidosis when concomitant insulin was rapidly reduced or discontinued (June 2019) Serious and life-threatening cases of diabetic ketoacidosis have been reported in patients with type 2 diabetes mellitus on a combination of a glucagon-like peptide-1 (GLP-1) receptor agonist and insulin, particularly after discontinuation or rapid dose reduction of concomitant insulin. Healthcare professionals are advised that any dose reduction of insulin should be done in a stepwise manner with careful blood glucose self-monitoring, particularly when GLP-1 receptor agonist therapy is initiated. Patients should be informed of the risk factors for and signs and symptoms of diabetic ketoacidosis, and advised to seek immediate medical attention if these develop. STEP WISE MANAGEMENT NG28 VISUAL SUMMARY ON CHOOSING MEDICINES FOR TYPE 2 DIABETES IN ADULTS (NICE.ORG.UK) STEP WISE MANAGEMENT In adults with T2DM, if HbA1c levels are not adequately controlled by a single drug and rise to 58 mmol/mol (7.5%) or higher: reinforce advice about diet, lifestyle and adherence to drug treatment and support the person to aim for an HbA1c level of 53 mmol/mol (7.0%) and intensify drug treatment STEP WISE MANAGEMENT If initial drug treatment with metformin has not continued to control HbA1c to below the person's individually agreed threshold for intensification, consider dual therapy with: metformin and a DPP-4 inhibitor or metformin and pioglitazone or metformin and a sulfonylurea SGLTs can also be an option in duel or triple therapy but behind above STEP WISE MANAGEMENT If metformin is contraindicated or not tolerated, the intensification will be through dual therapy as such: a DPP-4 inhibitor and pioglitazone or a DPP-4 inhibitor and a sulfonylurea or pioglitazone and a sulfonylurea  STEP WISE MANAGEMENT If dual therapy with metformin and another oral drug has not continued to control HbA1c to below the person's individually agreed threshold consider either: triple therapy with: metformin, a DPP-4 inhibitor and a sulfonylurea or metformin, pioglitazone and a sulfonylurea or metformin, sulfonylurea and SGLT2, metformin, pioglitazone and canagliflozin or empagliflozin or metformin and a DDP-4 inhibitor and ertugliflozin (only if a sulfonylurea or pioglitazone is not appropriate). consider starting insulin-based treatment  INSULIN IN T2DM (WILL BECOME CLEARER AFTER NEXT WEEK LECTURE) Intermediate Intermediate in combination with SA (in same formulation - biphasic) The first two particularly in highly uncontrolled T2DM, Long acting (start at night and check level in morning and amend) Monitor and amend  LONG ACTING INSULIN IN T2DM NICE (May 2009) has recommended that, if insulin is required in patients T2DM, insulin detemir or insulin glargine may be considered for those: who require assistance with injecting insulin or whose lifestyle is significantly restricted by recurrent symptomatic hypoglycaemia or who would otherwise need twice-daily basal insulin injections in combination with oral antidiabetic drugs or who cannot use the device needed to inject isophane insulin.  STEP WISE MANAGEMENT If triple therapy with metformin and 2 other oral drugs (is not effective, not tolerated or contraindicated), consider: combination therapy with metformin, a sulfonylurea and a glucagon-like peptide-1 (GLP-1) mimetic for adults with type 2 diabetes who: have a BMI of 35 Kg/m2 or higher (adjust accordingly for people from black, Asian and other minority ethnic groups) and specific psychological or other medical problems associated with obesity or have a BMI lower than 35 Kg/m2 and: for whom insulin therapy would have significant occupational implications or weight loss would benefit other significant obesity-related comorbidities After 6 months, only continue if a reduction of at least 11 mmol/mol (1.0%) in HbA1c and a weight loss of at least 3% of initial body-weight. STEP WISE MANAGEMENT  STEP WISE MANAGEMENT High risk of CVD QRISK2 of 10% or higher in those above 40 or elevated lifetime risk*: Offer standard-release metformin (monotherapy) If GI disturbance switch to metformin MR Once metformin tolerability is confirmed, offer SGLT2 inhibitor (flozin) If metformin is contraindicated, offer SGLTs inhibitor on its own *an elevated lifetime risk of cardiovascular disease is defined as the presence of 1 or more cardiovascular risk factors in someone under 40. Cardiovascular disease risk factors: hypertension, dyslipidaemia, smoking, obesity, and family history (in a first-degree relative) of premature cardiovascular disease MONITORING Patients with type 2 diabetes should be monitored every 3 to 6 months until HbA1c and medication are stable when monitoring can be reduced to every 6 months.  MONITORING Monitoring essentially the same for T1DM and T2DM. However: Routine self-monitoring of blood glucose levels for T2DM not required unless: the person is on insulin or there is evidence of hypoglycaemic episodes or the person is on oral medication that may increase their risk of hypoglycaemia while driving or operating machinery or the person is pregnant, or is planning to become pregnant. European Society of Cardiology 2019 indicates self-monitoring of blood glucose in T2DM to be considered for minimising glucose variability and to reduce heart disease risk MONITORING Targets for HbA1c for Type 2 diabetes: A target HbA1c concentration of 48 mmol/mol (6.5%) is recommended when managed by diet and lifestyle alone or with a single antidiabetic drug not associated with hypoglycaemia A target HbA1c concentration of 53 mmol/mol (7.0%) is recommended in adults prescribed a single drug associated with hypoglycaemia (such as a sulphonylurea), or two or more antidiabetic drugs.  DIABETES AS CVD RISK FACTOR Diabetes is a strong risk factor for cardiovascular disease. Other risk factors for cardiovascular disease such as smoking, hypertension, obesity and hyperlipidaemia should be addressed. Cardiovascular risk in patient with diabetes can be further reduced by the use of an ACE inhibitor (ARB, when?) and a lipid regulating drug (which one?) Regular checks of metabolic control (glycosylated haemoglobin) and physical examination for evidence of diabetic complications (BP, Body weight, visual acquity, plasma lipids, proteinurea, renal function, condition of feet, etc) is required Those with diabetes above 12 should have annual eye and foot check  BLOOD PRESSURE AND DIABETES - NICE Targets in patients living with T2DM with hypertension: A clinic BP below 140/90 mmHg in those aged under 80 years, and below 150/90 mmHg in those aged 80 years and over Ideally, monitor blood pressure every 1–2 months STEP WISE MANAGEMENT  REFERENCES BNF – latest edition NG28 Visual summary on choosing medicines for type 2 diabetes in adults (nice.org.uk) Diabetes UK – State of the Nation 2016. https://onlinelibrary.wiley.com/doi/pdf/10.1111/jdi.12401 European Society of cardiology guidelines 2019 https://academic.oup.com/eurheartj/advance- article/doi/10.1093/eurheartj/ehz486/5556890 https://www.nice.org.uk/guidance/ng136/resources/visual- summary-pdf-6899919517 NG19 Visual summary (nice.org.uk) https://www.nice.org.uk/guidance/ng136/resources/visual- summary-pdf-6899919517