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HanneleYki-Järvinen

Comprehensive Treatment and Follow-Up of Type 2 Diabetes

Essentials

  • The main objective is to prevent the development or worsening of arterial disease, retinopathy, nefropathy, neuropathy and a severe liver disease Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) through a treatment strategy targeted at correcting
    • hyperglycaemia
    • dyslipidaemia
    • hypertension
    • overweight and lack of physical exercise
    • increased blood coagulability
    • smoking.
  • The HbA1c target on pharmacological treatment is < 53 mmol/mol (7.0%) without episodes of hypoglycaemia, on non-pharmacological treatment a normal HbA1c (20-42 mmol/mol [4-6%]).
    • A less stringent target may be appropriate in patients with
      • limited life expectancy
      • severe vascular complications
      • severe systemic comorbidities
      • history of recurrent severe hypoglycaemias.
  • Treat hypertension aggressively (target level < 140/80 mmHg).
  • Target levels for lipids: HDL cholesterol > 1 in men, > 1.2 in women, triglycerides < 1.7
  • LDL cholesterol < 2.6 mmol/l but
    • in high risk patients < 1.8 mmol/l
    • in very high risk patients < 1.4 mmol/l (see Table T1)
  • Prescribe aspirin (100 mg) for all patients with arterial disease.
  • Even a slight decrease in body weight facilitates the management of risk factors.
  • Encourage smokers to stop smoking.

General aims

Aims of treatment of type 2 diabetes (T2D)

VariableGeneral aims to be adjusted individually
HbA1c<53 mmol/mol (< 7.0%)
Plasma glucose4-7 mmol/l before meals
<10 mmol/l after meals
Post-meal rise no more than 2-3 mmol/l
Plasma LDL cholesterol<2.6 mmol/l - patients with moderate risk:
  • Age < 40-50 yrs, no risk factors and history of T2D < 10 yrs
  • No high risk using a relevant risk score calculator (myocardial infarction, severe cerebrovascular disturbances)

<1.8 mmol/l - patients with high risk:
  • History of T2D > 10 yrs without target organ damage
  • T2D and even just one risk factor (such as smoking, hypertension, dyslipidaemia, obesity, insulin resistance, family history)

<1.4 mmol/l - patients with very high risk:
  • Coronary artery disease or other atherosclerotic arterial disease
  • T2D and target organ damage (albuminuria, renal failure, retinopathy)
  • T2D and 3 risk factors
Plasma HDL cholesterolMen > 1.0 mmol/l
Women > 1.2 mmol/l
Plasma triglycerides<1.7 mmol/l
FIB-4<1.3 in patients aged 35-65 yrs
<2.0 in patients aged > 65 yrs
Blood pressure<140/80 mmHg (< 135/80 mmHg measured at home)
  • No nephropathy or cardiovascular disease
  • No high risk using a relevant risk score calculator (myocardial infarction, severe cerebrovascular disturbances)

<130/80 mmHg (< 125/80 mmHg measured at home) in patients with diabetic kidney disease or high risk of disease and possibility of reaching the target without adverse effects
  • Diabetic nephropathy, eGFR < 60 ml/min
  • Diabetic nephropathy with albuminuria (U-Alb > 300 mg/day or U-AlbCrea > 30 mg/mmol)
  • High risk using a relevant risk score calculator (myocardial infarction, severe cerebrovascular disturbances)
WeightNormal (BMI < 25)
LifestyleDaily activity and regular physical activity, avoidance of sitting
Dietary choices promoting cardiac health and glucose control
Sufficient rest and sleep
No smoking
No more than moderate alcohol consumption

Treatment of hyperglycaemia Association of Glycaemic Control and Complications of Type 2 Diabetes, Exercise for Type 2 Diabetes Mellitus, Dietary Advice and Exercise for Type 2 Diabetes Mellitus, Low Glycaemic Index, or Low Glycaemic Load, Diets for Diabetes Mellitus, Glycaemic Control for Slowing the Progression of Microvascular Complications in Diabetes Mellitus

Principles of treating hyperglycaemia Metformin Monotherapy for Type 2 Diabetes Mellitus, Surgery for Morbid Obesity, Insulin Added on Metformin in Type 2 Diabetes, Glucagon-Like Peptide Analogues (GLP-1 Analogues) for Type 2 Diabetes, Pioglitazone for Type 2 Diabetes Mellitus, Incretin-Based Therapy with Dipeptidyl Peptidase 4 Inhibitors in Type 2 Diabetes, Sulphonylurea for Type 2 Diabetes

  • Inform the patient that it is possible to achieve remission of type 2 diabetes by permanent lifestyle changesIntensive Weight Management for Remission of Type 2 Diabetes.
  • Where possible, provide the patient with an opportunity to participate in an intensive lifestyle intervention organised individually or in a group.
  • The most important goal is to reach the HbA1c target (see Essentials). All the blood glucose-lowering drugs, alone or in combinations, can be used to treat hyperglycaemia Oral Antidiabetic Drugs and GLP-1 Analogues, unless their use is prevented by adverse effects or contraindications.
    • How well the therapeutic target is reached depends on the baseline HbA1c level: the maximum dose of one oral drug usually lowers HbA1c levels by no more than 21-22 mmol/mol (2 percentage units). If, for instance, the baseline level exceeds 86 mmol/mol (10%), one oral drug will not be enough to reach the target.
  • It is justified to use products for which long-term studies show a favourable effect on diabetic organ changes Oral Antidiabetic Drugs and GLP-1 Analogues.
  • Bariatric surgery should be considered when BMI is 30-35 kg/m2 Surgery for Morbid Obesity Bariatric Surgery (Obesity Surgery), if permanent lifestyle changes do not produce the desired result.

Beginning treatment

Treatment of hypertension Exercise for Type 2 Diabetes Mellitus, Choice of Antihypertensive Drug in the Diabetic Patient from Prognostic Point of View, ACE Inhibitors and Angiotensin II Receptor Blockers for Diabetics with Microalbuminuria, Dietary Advice and Exercise for Type 2 Diabetes Mellitus, Association of Systolic Blood Pressure and Complications of Type 2 Diabetes

Treatment of hypertension in a patient without nephropathy

  1. Lifestyle modification
    • Weight reduction in overweight patients, reduction of salt intake and excessive consumption of alcohol, increased proportion of vegetables, berries and fruits in the diet, regular exercise, smoking cessation
    • Provide patient education on healthy food symbols, if such symbols are locally available.
  2. Start with an ACE inhibitor or ARB , for example. Take into consideration other diseases and adverse effects when choosing the drug.
  3. If necessary, add another drug, e.g. a low-dose diuretic or a calcium-channel blocker.
  4. If necessary, add a third drug, e.g. a diuretic + ACE inhibitor + long-acting dihydropyridine group calcium-channel blocker or a diuretic + selective beta-blocker + calcium-channel blocker.
  • If no response is achieved with a particular drug, it should be stopped and another drug prescribed from a different drug group.
  • Before prescribing a new drug, check patient compliance and the dose that he/she has been taking.
  • Following parameters should be monitored after starting medication (see also Drug Treatment for Hypertension):
    • ACE inhibitors and ARBs: plasma creatinine and potassium should be checked 1-2 weeks after initiation of treatment. Avoidance of salt increases the effect.
    • Thiazides: plasma sodium, potassium, urate

Treatment of hypertension in a patient with nephropathy

  • The earliest sign of nephropathy is microalbuminuria: Albumin/creatinine ratio (mg/mmol) 2.5-25 in men, 3.5-35 in women, or 24 h albumin excretion in urine 30-300 mg/day or overnight albumin excretion in urine 20-200 µg/min. In macroalbuminuria, albumin excretion is > 300 mg, and in proteinuria, 24 h urinary protein excretion is > 1 g.
  • The target is < 130/80 mmHg (125/75 mmHg, when protein excretion into urine exceeds 1 g/24 h).
  1. ACE inhibitor (reduce the dose if creatinine is increased) or ARB. Measurement of plasma creatinine and potassium after 1-2 weeks. The ACE inhibitor or ARB should be discontinued if the plasma creatinine concentration increases more than 30% from the baseline value during the first 2 months or if the patient develops hyperkalaemia (plasma potassium > 5.6 mmol/l). Consultation with specialized care is warranted in this situation.
  2. If necessary, add a small dose of a thiazide diuretic. If eGFR is < 30 ml/min/1.73 m2 Gfr Calculator or plasma creatinine concentration is > 150 µmol/l replace the thiazide diuretic with a loop diuretic, e.g. furosemide.
  3. If necessary, add another antihypertensive drug, e.g. a calcium-channel blocker.
  4. Of blood glucose lowering drugs, the benefit of SGLT2 inhibitors and GLP-1 analogues has been shown.
  • Good glucose control hinders the development of nephropathy.

Treatment of dyslipidaemias

  • Patients with type 2 diabetes have such a high risk of arterial disease that drug therapy for hyperlipidaemia often is necessary in order to achieve target levels even if the patient does not yet have a diagnosed arterial disease.
  • Target levels for lipids are shown in table T1.

Treatment strategy

  1. Lifestyle modifications are sufficient if they reduce the concentration of LDL cholesterol (program Ldl) to the target.
    • Weight reduction, diet (moderate fat content with a sufficient proportion of soft fat is essential), increased physical exercise and cessation of smoking
  2. Improving diabetic control
    • The effect of antihyperglycaemic medication on lipids depends on the product used. Usually, the treatment of hyperglycaemia affects plasma triglyceride and HDL cholesterol levels more than LDL cholesterol levels.
  3. Drug therapy Efficacy and Safety of Cholesterol Lowering by Statins, Statins for the Primary Prevention of Cardiovascular Disease
    • Should be started if lifestyle changes have not proved effective (see Table T1).
    • In very high risk patients, the aim should be to achieve the lowest possible LDL cholesterol levels (< 1.4 mmol/l). Statins are the first-line drugs. Ezetimibe or a PCSK9 inhibitor (alirocumab, evolocumab) can be added to the regimen, as necessary.
    • In diabetic dyslipidaemia with typically high plasma triglyceride concentration (usually 1.7-5.0 mmol/l) and low HDL cholesterol concentration, a statin is the drug of choice.
    • In severe diabetic dyslipidaemia (plasma triglyceride level > 5.0 mmol/l), adding fenofibrate to statin therapy can be considered. In such a case, it is usually advisable to consult a specialist.
    • Comparison of the efficacy of different statins: atorvastatin 10 mg = simvastatin 20 mg = rosuvastatin 5 mg = lovastatin 40 mg = pravastatin 40 mg = fluvastatin 80 mg

Antithrombotic therapy Low-Dose Aspirin for Prevention of Vascular Events in Type 2 Diabetes

  • Prescribe aspirin (100 mg) for all patients with arterial disease.
  • Patients with arterial disease and aspirin allergy: clopidogrel 75 mg/day

Interpretation and treatment of microalbuminuria

  • Definition: Albumin/creatinine ratio 2.5-25 in men, 3.5-35 in women or overnight albumin excretion in urine 20-200 µg/min or 24 h albumin excretion in urine 30-300 mg.
  • Microalbuminuria with concurrent retinopathy can be a sign of incipient nephropathy.
  • If the patient does not have retinopathy, microalbuminuria may reflect a high risk of cardiovascular disease. A patient with microalbuminuria can have either normal or elevated blood pressure.
  • Microalbuminuria may have a cause other than diabetic nephropathy (i.e. another type of nephropathy).
  • Treatment
    1. Tight blood pressure control (reduced salt intake and use of antihypertensive drugs; target < 130/80 mmHg)
    2. Cessation of smoking
    3. Tight blood glucose control
    4. Treatment of dyslipidaemia
  • If plasma creatinine is ≥ 150 µmol/l (eGFR < 30 ml/min/1.73 m2 Gfr Calculator), 50% of renal function is lost, in an elderly patient even more. The patient should be referred to a nephrologist.
  • The patient should also be referred to a specialist in internal medicine if 24 h protein excretion exceeds 1.5 g.

Examinations during routine visits

  • The frequency of visits should be individual but all patients should be seen at least annually.

At every visit

  • Symptoms
    • Physical performance: coronary heart disease/intermittent claudication?
    • Fatigue and poor treatment compliance may also result from poor glucose control.
    • Episodes of hypoglycaemia (rare in overweight patients)
  • Examinations
    • Record weight and height; calculate BMI Bmi
    • Blood pressure (target < 140/80 mmHg, in patients with nephropathy 130/80 mmHg)
    • The feet should be examined if the patient has the so called risk feet Treatment of the Diabetic Foot.
      • History of lesion or amputation
      • Peripheral neuropathy (impaired monofilament touch sensation, sense of vibration or Achilles tendon reflex; see Diabetic Neuropathy)
      • Arteriosclerosis of the lower limbs (claudication, absent pulses, skin lesions)
      • Deformities and calluses
    • HbA1c
      • Target on pharmacological treatment is < 53 mmol/mol (7.0%) or individually defined.
    • Fasting blood glucose (not indispensable; regular home measurements give a more reliable picture)
      • In tablet and diet treatment the target is < 6.7 mmol/l, with bedtime insulin treatment 4.0-5.5 mmol/l, in order to reach the HbA1c target 53 mmol/mol (7.0%).
  • Encourage the patient to adopt and maintain a healthy lifestyle.
  • Medication
    • Dose of drugs (blood pressure/glucose/lipids)
    • Is aspirin (100 mg) indicated?

Annual examinations

  • ECG; further testing should readily be performed if the patient has coronary symptoms Chronic Coronary Syndrome (Coronary Heart Disease).
  • Photograph of the fundi of the eyes (dilate pupils) at 1-3-year intervals. The photograph can be taken infrequently (every 3 years), if glucose control is good (HbA1c< 58 mmol/mol [7.5%]) and the photography findings are normal.
  • Blood pressure (target < 140/80 mmHg, in patients with nephropathy 130/80 mmHg)
  • Examination of the feet: temperature, interdigital spaces, pulses, ulcerations, monofilament test
  • Examination of injection sites in patients on insulin
  • LDL cholesterol, HDL cholesterol, triglycerides
  • Plasma sodium and potassium, if the patient has hypertension
  • Fibrosis-4 (FIB-4) Index
  • Chemical urinalysis, plasma creatinine, eGFR, urine albumin excretion: either a single specimen (albumin/creatinine ratio) or timed overnight excretion or 24 h albumin excretion; in patients with macroalbuminuria also 24 h protein excretion.

When to consult a specialist?

  • Indications for consultation are often regionally agreed. Consider consultation e.g. in the situations described below.
    • Refractory hyperglycaemia (HbA1c> 86 mmol/mol [10%] despite maximal medication with a combination of several tablets and insulin/GLP-1 analogue) or hypertension or dyslipidaemia (LDL cholesterol > 2.5 mmol/l despite statin therapy, triglycerides > 5 mmol/l despite antihyperglycaemic, statin and fibrate medication) or thrombotic tendency despite aspirin medication. Keep in mind the possibility of bariatric surgery in overweight patients.
    • Suspicion of coronary heart disease or other arterial disease
    • The patient should be referred to an ophthalmologist for examination and treatment if he/she has ocular or visual symptoms or if the periodic fundus photography of a symptomless patient shows
      • maculopathy, especially macular oedema (lipid exudates)
      • severe background retinopathy
      • proliferative retinopathy or changes caused by it (vitreous haemorrhage or tractional retinal detachment) Diabetic Retinopathy.
    • If the fundus photographs are assessed by the patient's own doctor, consultation with an ophthalmologist is recommended in the case of pictures that show more than mild retinopathy as well as pictures where media opacities or a small pupil prevent reliable assessment of the condition of the fundus Diabetic Retinopathy.
    • Moderate or severe infection of the foot, acute lower limb ischaemia, critical ischaemia, foot ulcer refractory to treatment, Charcot's arthropathy, foot deformities requiring treatment, osteomyelitis (see Treatment of the Diabetic Foot)
    • Diabetic nephropathy Diabetic Kidney Disease (Diabetic Nephropathy) (eGFR < 30 ml/min/1.73 m2 Gfr Calculator), significant proteinuria (24 h urinary protein excretion > 3.5 g) or increasing albuminuria or decreasing eGFR despite intensified treatment
    • Suspected advanced fibrosis associated with non-alcoholic fatty liver disease Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH)

Home monitoring Computer-Based Diabetes Self-Management Interventions for Adults with Type 2 Diabetes Mellitus., Quality Improvement Strategies for Diabetes Care, Group Based Training for Self-Management Strategies in People with Type 2 Diabetes Mellitus, Self-Monitoring of Blood Glucose in Patients with Type 2 Diabetes Mellitus Who are Not Using Insulin

  • Weight
  • Blood pressure (it is recommended that the patient has his own device)
  • Self-monitoring of blood glucose. Think about the purpose of monitoring as it varies depending on the type of treatment..
    • Patients on diet treatment learn to identify the factors which affect the blood glucose level and how.
    • In patients on pharmacological treatment, there is the additional purpose of documenting the occurrence of hypoglycaemias, if the patient's medication has the propensity to cause these (metformin, GLP-1 analogues, SGLT2 inhibitors, glitazones and gliptins do not cause hypoglycaemias).
    • Patients on insulin treatment are the most important group to use self-monitoring. The particular aim is to learn self-adjustment of the insulin dose; see below (see also Insulin Therapy in Type 2 Diabetes). It is sufficient to determine the fasting blood glucose level when the patient is on basal insulin.
    • If the HbA1c has remained on target (such as 42-46 mmol/mol) for a long time, no regular self-monitoring will be necessary between visits.

Simple initiation of basal insulin therapy

  • If HbA1c target is not reached with oral medication, basal insulin therapy, often using bedtime insulin, should be added to the treatment.
  • Motivate the patient for instance by explaining that early initiation of basal insulin therapy prevents associated diseases in both small and large vessels, and that it is not necessary to change exercise habits or diet because of starting the basal insulin treatment.
  • Add insulin on tablet medication. The starting dose of basal insulin for all patients is 10 units (basal insulin once daily usually in the evening - may also be administered at some other time, provided that the administration always takes place at the same time of the day). Write dosage instruction on the prescription, such as. ”according to self-adjustment 10-200 units per day subcutaneously”.
  • Instructions for self-adjustment
    • The patient measures fasting blood glucose every morning.
    • If the fasting blood glucose concentration exceeds 6.0 mmol/l on 3 successive mornings the dose is increased by 2 units.
    • The average requirement is 70 units if the patient is taking one oral drug, e.g. metformin, and 50 units if the patient takes 2 oral drugs.

    References

    • Holman RR, Paul SK, Bethel MA et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359(15):1577-89. [PubMed]
    • Zinman B, Wanner C, Lachin JM et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015;373(22):2117-28. [PubMed]
    • Sjöström L, Peltonen M, Jacobson P et al. Association of bariatric surgery with long-term remission of type 2 diabetes and with microvascular and macrovascular complications. JAMA 2014;311(22):2297-304. [PubMed]
    • Wanner C, Inzucchi SE, Lachin JM et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med 2016;375(4):323-34. [PubMed]
    • Kernan WN, Viscoli CM, Furie KL et al. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med 2016;374(14):1321-31. [PubMed]
    • Marso SP, Daniels GH, Brown-Frandsen K et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016;375(4):311-22. [PubMed]
    • Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352(9131):854-65. [PubMed]
    • Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352(9131):837-53. [PubMed]
    • Scirica BM, Bhatt DL, Braunwald E ym. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369(14):1317-26. [PubMed]
    • Green JB, Bethel MA, Armstrong PW ym. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2015;373(3):232-42. [PubMed]
    • Zannad F, Cannon CP, Cushman WC ym. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet 2015;385(9982):2067-76. [PubMed]
    • Rosenstock J, Perkovic V, Alexander JH ym. Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA® ): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk. Cardiovasc Diabetol 2018;17(1):39. [PubMed]
    • Kernan WN, Viscoli CM, Furie KL ym. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med 2016;374(14):1321-31. [PubMed]
    • Dormandy JA, Charbonnel B, Eckland DJ ym. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366(9493):1279-89. [PubMed]
    • Zinman B, Wanner C, Lachin JM ym. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015;373(22):2117-28. [PubMed]
    • Marso SP, Daniels GH, Brown-Frandsen K ym. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016;375(4):311-22. [PubMed]
    • Marso SP, Bain SC, Consoli A ym. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016;375(19):1834-1844. [PubMed]
    • Pfeffer MA, Claggett B, Diaz R ym. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med 2015;373(23):2247-57. [PubMed]

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