Non-Insulin Therapy

What is diabetes?

A chronic metabolic condition. Characterised by persistent rise in blood glucose levels (hyperglycaemia). Can result in multiple complications (acute/chronic). Significant implications for life expectancy and quality of life

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What is diabetes caused by?

Insulin deficiency (reduced secretion) or insulin resistance (reduced effectiveness) or both

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What is type 1 diabetes?

Autoimmune destruction of pancreatic islet cells (beta)

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What is type 2 diabetes?

Insulin resistance and relative insulin deficiency

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What are the four types of diabetes? (1)

Type 1 (develop at a young age, autoimmune destruction of pancreatic beta cells, sudden onset/rapid weight loss). LADA (gradual autoimmune destruction, slower onset in 30+ yrs of age, not linked to insulin resistance)

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What are the four types of diabetes? (2)

MODY (hereditary condition, autosomal gene mutation, ineffective insulin production, commonly presents with slow onset in <30 yrs of age). Type 2 (affects 45+ yrs of age, insulin resistance/deficiency, slow onset, overweight)

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What are the principles of treatment for type 1 diabetes?

Exogenous replacement of the body's own insulin. Mirror natural insulin release profile. Prevent acute complications (hypo/hyper-glycaemia)

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What are the principles of treatment for type 2 diabetes?

Minimise metabolic risk with lifestyle modification. Improve insulin sensitivity. Prevent acute and chronic complications

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Describe features of pancreatic beta cell decline

Progressive loss of beta cell function in T2DM when hyperglycaemia is uncontrolled (treatments - lifestyle changes, monotherapy, dual therapy, insulin/oral drugs)

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Describe the natural history of T2DM

Before the diagnosis of diabetes, CV complications and microvascular complications develop in the body

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What are the blood glucose targets for type 2 diabetes? (1)

Check HbA1c (3-6 monthly until HbA1c stable, then 6 monthly once stable and on unchanging therapy). Involve patient in target decisions. Encourage them to achieve without adverse effects

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What are the blood glucose targets for type 2 diabetes? (2)

If diet and lifestyle modifications or on single antidiabetic drug with no hypoglycaemic risk, aim for 48 mmol/mol (6.5%). If on single antidiabetic drug associated with hypoglycaemic risk, aim for 53 mmol/mol (7%)

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What are the blood glucose targets for type 2 diabetes? (3)

If not achieved and HbA1c 58 mmol/mol (7.5%) - reinforce diet, lifestyle and adherence advice, intensify treatment. Aim for 53 mmol/mol (7%) or individual target if unachievable or will cause adverse effects

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What does a tighter individualised control of HbA1c indicate?

Lower HbA1c (patient is very motivated)

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What does a less tight individualised control of HbA1c indicate?

Higher HbA1c (risk of complications, hypos)

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Is the CBG checked at home routinely?

No. Unless - the patient is on insulin, evidence of hypoglycaemic episodes, on medication which increases risk of hypoglycaemia whilst driving, pregnant or planning to become pregnant

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Describe features of nutrition and diet (1)

Integrate dietary advice with personalised diabetes management plan. Includes increased physical activity (30 mins of moderate-intense exercise/day), and reduce weight. Healthy, balanced diet is essential for all diabetics

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Describe features of nutrition and diet (2)

Aims - maintain normal body weight, avoid hypo/hyper glycaemic episodes, reduce risk of CVD

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What is the dietary advice? (1)

Avoid high sugar foods and drinks. Eat plenty of fibre. Eat a low fat diet (mediterranean) - replace saturated fats with unsaturated fats. Eat at least 5 portions of fruit/veg a day. Try to eat at least 2 portions of oily fish a week

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What is the dietary advice? (2)

(Balanced diet - eat at least 5 servings of fruit/veg everyday, base meals and snacks on starchy foods, choose lean meat, poultry, fish, beans, choose lower fat dairy foods, cut down on fatty and sugary foods)

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Describe features of the Diabetes Remission Clinical Trial (1)

Investigated if early T2DM can be put into remission without diet control in primary care. Trial over 2 years, control group (current best practice T2DM management), intervention (structured weight management programme)

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Describe features of the Diabetes Remission Clinical Trial (2)

Inclusion criteria (T2DM for <6 yrs, BMI >27 - 45 kg.m^2). Remission (HbA1c <48 mmol/mol on no diabetic medications)

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Describe features of the Diabetes Remission Clinical Trial (3)

Results - 86% of patients who lost >15 kg. 57% of patients who lost 10-15 kg. 34% of patients who lost 5-10 kg. 7% of patients who lost 0-5 kg. 0% of patients who gained weight

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When are oral anti-diabetic medications initiated?

If diet/exercise measures fail to control blood glucose after 3 months

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What are the 4 main modes of actions for oral anti-diabetic drugs?

Increase insulin secretion. Increase peripheral utilisation of glucose. Alterations in dietary absorption. Excreting glucose via the kidneys

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Describe features of oral anti-diabetic medications

Very few patients achieve target for more than a few months with lifestyle changes alone. Stepwise approach as progressive failure of insulin secretion, different MOA.

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Choice, order and combination should reflect evidence of what?

Efficacy (metabolic response), safety/tolerability, individual circumstances (co-morbidities, polypharmacy), individual preferences and needs, licensed indications and available combinations, cost, (National Guidance, NICE, GSST guidelines - diagram)

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Describe features of metformin (1)

Standard release (1st line). Reduces gluconeogenesis, increases peripheral utilisation of glucose, reduce insulin resistance. Introduce gradually to reduce risk of GI S/E. Use MR if GI S/E are intolerable. Caution if eGFR <45 L/min/1.73 m^2

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Describe features of metformin (2)

Stop if eGFR <30 L/min/1.73 m^2. 1st line choice for most individuals. No associated weight gain (small weight loss). No hypoglycaemic risk, trials demonstrated reduce incidence of MI/stroke/mortality. Long term outcome data, inexpensive

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Describe features of metformin (3)

HbA1c reduction by 1-2% (high efficacy). Most common adverse effects - GI effects upon initiation (nausea, vomiting, diarrhoea, abdominal pain), metallic taste, lactic acidosis (caution renal function). Initial dose of 500 mg OD with food

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Describe features of metformin (4)

Maintenance - titrate gradually to max 2-3g/daily (in divided doses)

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Describe features of sulfonylureas (1)

MOA (increase insulin secretion - bind to SU receptor on pancreatic beta cell). Needs residual pancreatic function to be effective. Often used in non-overweight patients or if metformin is CI

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Describe features of sulfonylureas (2)

Choice of drug. All drugs in this class have different PK profiles, choice often dictated by patient factors e.g. compliance and drug factors e.g. S/E. HbA1C effectiveness - high efficacy. Inexpensive. Most commonly used sulphonylurea - gliclazide

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What are the side effects of sulphonylureas?

Hypoglycaemia, weight gain, GI disturbances, changes in liver function and blood disorders (rare)

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Describe features of DPP-4 inhibitors

Gliptins/dipeptidyl peptidase. MOA (blocks glucose dependent DPP-4 enzyme which increases levels of GLP-1, increase pancreatic insulin secretion, reduce glucose release from liver

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What are the 5 currently licensed DPP-4 inhibitors?

Sitagliptin, Saxagliptin, Linagliptin, Alogliptin & Vildagliptin (don't cause hypoglycaemia, weight neutral, HbA1c effectiveness - intermediate)

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What are the side effects of DPP-4 inhibitors?

GI disturbances, pain, URTI, peripheral oedema, nasopharyngitis (don't use saxagliptin/alogliptin if PMH or at risk of HF)

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Describe features of glitazones (1)

Thiazolidinediones. MOA (reduce gluconeogenesis, increase peripheral utilisation of glucose, reduce free fatty acids, reduce insulin resistance). Pioglitazone used. HbA1c efficacy - high. No hypoglycaemia, reduced ASCVD events, inexpensive

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Describe features of glitazones (2)

Cause weight gain via fluid retention. Used as monotherapy if metformin CI. Used in combination therapy with metformin or a sulfonylurea. Used in triple therapy with metformin and sulfonylurea

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Describe features of glitazones (3)

Not used if current, PMH or at risk of HF, hepatic impairment, bladder cancer, uninvestigated macroscopic haematuria, risk of bone fracture

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Describe features of rosiglitazone

Reports of heart problems - increased risk of MI for patients in rosiglitazone, increased fluid retention - increased risk of HF. Withdrawn from UK market in 2010

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Describe features of SLGT-2 inhibitors (1)

Dapagliflozin, Canagliflozin, Empagliflozin, Ertugliflozin. MOA (block reabsorption of glucose in the kidneys, promote excretion of excess glucose in urine (up to 180g/day). No hypoglycaemia, reduced weight, reduced BP, CVD/renal benefits

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Describe features of SGLT-2 inhibitors (2)

HbA1c efficacy - intermediate. Not to be initiated if CrCl <60 mL/min

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What are the side effects of SGLT-2 inhibitors?

Hypovolaemia, polyuria, UTI, thrush, DKA, Fouriner's gangrene. (MHRA warning - ketoacidosis can occur but with normoglycaemia). CV/CKD risk reduction seen in some SGLT-2 inhibitors (Dapagliflozin, Canagliflozin, Empagliflozin)

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Describe features of GLP-1 analogues (1)

Non-insulin injectable class for T2DM. MOA (mimic anti-hyperglycaemic effects of natural GLP-1, enhance glucose dependent insulin secretion, promote satiety, increase fullness, suppress post-prandial glucagon secretion, reduce hepatic glucose output)

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Describe features of GLP-1 analogues (2)

(Slows gastric emptying)

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Which GLP-1 analogues are currently licensed in the UK?

Liraglutide*, Dulaglutide*, Semaglutide*, Exenatide, Lixisenatide (*CV risk reduction seen with some GLP-1 analogues). HbA1c efficacy - high, reduced weight

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GLP-1 analogues are indicated for which patients? (1)

BMI of 35 kg/m^2 or higher (adjust according to minority ethnic groups) and specific psychological or other medical problems associated with obesity. BMI <35 kg/m^2 where insulin therapy has implications

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GLP-1 analogues are indicated for which patients? (2)

Or weight loss would benefit other obesity-related co-morbidities. Can be used along with insulin if under specialist care

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What are the adverse effects of GLP-1 analogues?

GI disturbances/IBS, decreased appetite, headaches and dizziness, occasional hypoglycaemia (in combination with SU or insulin), pancreatitis (CSM warning)

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Describe features of acarbose

MOA (slows absorption of glucose form intestine. Inhibition of alpha-glucosidase delays digestion of starch. Adverse effects - GI upset, flatulence. Take dose with first mouthful of meal. Rarely used

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Describe features of meglitinides (1)

MOA (increase insulin secretion). Currently licensed - repaglinide, nateglinide. Very rapid onset, short DOA. Rarely used currently, compliance issues. Rapaglinide can be used as monotherapy

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Describe features of meglitinides (2)

Combination therapy with metformin used if sulphonylurea is CI. No licensed non-metformin based combination containing repaglinide offered at first intensification

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What are the adverse effects of meglitinides?

Hypoglycaemia, visual disturbances, weight gain, GI upset, elevated LFTs (average absolute HbA1c reduction - diagram)

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Describe the aspects of stepping up therapy (1)

Initial drug treatment (treatment with single non-insulin blood glucose lowering therapy, monotherapy). First intensification (treatment with 2x non-insulin blood glucose lowering therapies in combination, dual therapy)

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Describe the aspects of stepping up therapy (2)

Second intensification (treat with either 3x non-insulin blood glucose lowering therapies in combination/triple therapy or any treatment combination containing insulin)

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What are the self-management programmes for T2DM?

NICE, DESMOND (Diabetes Education and Self-Management for Ongoing and Newly Diagnosed - Type 2). XPERT (for patients with long standing T2DM). National targets to ensure patients attend structured education programmes

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What is the BP treatment pathway for T2DM? (1)

ACE-I (used ARB for Afro-Caribbean patients or due to not being tolerated e.g. cough). Discuss adherence. Offer CCB/TLD. Review medication, optimise doses, offer CCD/TLD depending on previous step

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What is the BP treatment pathway for T2DM? (2)

If BP not controlled despite taking 3 medications at optimal doses, regard as resistant HTN). Confirmed resistant HTN - low dose spironolactone (if K+ <4.5 mmol/L, caution eGFR) or beta/alpha blocker (if K+ >4.5 mmol/L) - see specialist advice

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What is the BP treatment pathway for non-diabetes? (1)

T2DM, <55 yrs and not of Afro-Caribbean origin - use ACE-I. Use ARB for Afro-Caribbean patients, 55+ yrs or due to not being tolerated e.g. cough. If no T2DM, 55+ yrs, Afro-Caribbean origin - offer CCB (use TLD if CCB not tolerated)

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What is the BP treatment pathway for non-diabetes? (2)

Discuss adherence. If step 1 was ACE-I/ARB offer CCB/TLD. If step 1 was CCB, offer ACE-I/ARB/TLD. In Afro-Caribbean patients with no T2DM, consider ARB instead of ACE-I

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What is the BP treatment pathway for non-diabetes? (3)

Review medication to ensure taking at optimal doses, discuss adherence. Offer combination of ACE-I (or ARB for Afro-Caribbean patients), CCB and TLD. If BP not controlled despite taking optimal doses of 3 medications, regard as resistant HTN

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What is the BP treatment pathway for non-diabetes? (4)

Confirmed resistant HTN - consider low dose spironolactone (if K+ <4.5 mmol/L, caution eGFR) or beta/alpha blocker (if K+ >4.5 mmol/L) - see specialist advice

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What is the BP management for T2DM adults? (1)

Lifestyle (provide information on potential to improve BP, offer assistance in achieving their aims). Medication (start trial of renin-angiotensin system blocking drugs as first line for HTN)

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What is the BP management for T2DM adults? (2)

Don't allow concerns over potential S/E to inhibit advising and offering necessary use of any class of drugs unless S/E become symptomatic or clinically significant

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What is the BP management for T2DM adults? (3)

Selective beta-adrenergic blockers (don't avoid where indicated in adults on insulin). Low dose thiazides (may be combined with beta blockers). CCBs (use only long acting preparations)

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Non-Insulin Therapy

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