Diabetes mellitus is the leading cause of chronic kidney disease (CKD) and end stage renal disease (ESRD) globally. Around 20-40 per cent of diabetics develop diabetic kidney disease (DKD). This is a clinical syndrome characterised by progressive decline in estimated glomerular filtration rate (eGFR); elevated arterial blood pressure (BP); and persistent albuminuria (>300mg/d) on at least two visits, three to six months apart.

Structural changes include thickening of the glomerular basement membrane (GBM), mesangial expansion, podocyte injury, and glomerulosclerosis. Extraglomerular lesions are also involved in the progression of the disease, including tubular atrophy, interstitial inflammation, and tubulointerstitial fibrosis.

Functional changes encompass a paradoxically high eGFR in the early stages of the disease, termed glomerular hyperfiltration, caused by afferent arteriolar vasodilation and/or by efferent arteriolar vasoconstriction owing to activation of the renin-angiotensin-aldosterone system (RAS), leading to glomerular hypertension. Later, proteinuria, systemic hypertension, and loss of renal function develop.

Risk factors for DN

Non-modifiable risk factors for DN include increasing age, family history, and genetic factors, with genes such as ACE, APOC1, GREM1, UNC13B, ALR2, APOE associated with the disease. DN is also more common in black people, Mexican Americans, Pima Indians, and Hispanics compared to Caucasians, and female gender is associated with a reduced risk of progression from moderate albuminuria to severe albuminuria or ESRD.

Modifiable risk factors include smoking; longer durations of diabetes; obesity; hypertension; poor glycaemic control; and dyslipidaemia (abnormal lipoprotein metabolism is accelerated in DN that causes further renal injury, leading to ESRD).

Clinical features

The most common clinical abnormalities of DKD are persistently elevated urine albumin excretion and/or persistently declining eGFR. These manifestations tend to be asymptomatic, being detected through routine periodic testing. For this reason, type 2 diabetics should undergo testing at the time of diagnosis, and yearly thereafter.

On some occasions, patients can complain of fatigue, foamy urine, and pedal oedema due to hypoalbuminaemia and nephrotic syndrome. They may also have associated peripheral vascular disease, hypertension, cardiovascular disease (CVD), and diabetic retinopathy.

Investigations

1. Routine blood tests: Renal profile, full blood count, electrolytes.
2. Urine albumin excretion: Albuminuria can be established if two to three urine collections obtained over three to six months show elevated levels of albumin.
3. Urine culture to exclude infection and microscopy to examine for red cell casts in glomerulonephritis.
4. Anti-DNA antibodies, antinuclear antibody, extractable nuclear antigen, complement levels, anti-neutrophil cytoplasmic antibodies, antistreptolysin O titre, rheumatoid factor, and anti-glomerular membrane antibody to check for autoimmune disease.
5. Serum protein electrophoresis, immunoglobulins, urine protein electrophoresis for multiple myeloma.
6. Renal ultrasound.
7. Renal biopsy: The gold standard, but rarely used.

Classification

Tervaert classification provides a systematic approach with regards to the classification of the pathology of DN and gives a guide with regards to the prognosis of the disease. An important limitation of this classification scheme is that not all pathologic lesions are included, such as presence of mesangiolysis, capillary aneurysms, exudative lesions, and focal/segmental sclerosis.

Treatment

There is no definitive cure for DKD, with management focused on lifestyle interventions and optimal glucose and BP control.

Lifestyle interventions

Input from a dietitian is often indicated for this patient cohort. Patients with diabetes and CKD should generally consume a diet rich in vegetables, fruits, fibre, legumes, plant-based proteins, unsaturated fats, and nuts whilst avoiding processed meats, sweetened beverages, and refined carbohydrates. In advanced CKD, however, potassium in particular, needs to be restricted.

Nutrition therapy can reduce levels of Hba1c to similar or even better ones to those achieved with glucose-lowering medications. However, too much protein can lead to reduced carbohydrate intake with consequent weight loss, and such diets can cause harm to kidney function due to increased urinary excretion of amino acids, which can elevate acid load and precipitate metabolic acidosis, especially in patients with poor kidney function.

On the other hand, in very limited studies, protein restriction has been associated with a slower decline in eGFR in non-diabetics with CKD. Most type 2 diabetic CKD patients would have already been counselled on the appropriate carbohydrate and fat intake, and with protein restriction, malnutrition, reduced quality of life, and hypoglycaemia can develop.

In view of the lack of clinical trials, guidance for such patients is based on the World Health Organisation recommendations for protein intake of 0.8g/kg/day being associated with good outcomes. Patients on dialysis are recommended to consume 1.0-to-1.2g/kg/day as dialysis causes a catabolic response, with loss of amino acids. In addition, the presence of uraemia promotes decreased appetite, increased catabolism, and reduced muscle mass.

Low sodium intake is associated with lower BP and improved cardiovascular (CV) outcomes in the general population. Patients with CKD tend to be salt-sensitive and unable to regulate BP and extracellular fluid volume status when consuming high salt diets. Low salt intake is associated with improvement in volume status and reduced proteinuria, while high sodium intake is associated with increased mortality and morbidity. The guidelines advise that sodium intake should be restricted to <2g/day or <90mmol of sodium/day (<5g of sodium chloride/day).

Engaging in physical activity offers cardiometabolic, kidney, and cognitive benefits. Weight loss may reduce urinary albumin excretion and improve BP. Physical activity lowers inflammatory markers, improves insulin sensitivity and endothelial function, and is associated with slower decline in eGFR.

Therefore, it is recommended that CKD patients with diabetes perform at least 150 minutes of moderately intense physical activity per week. Nonetheless, such patients tend to be elderly with increased risk of falls, obese, and anaemic, with further limitations in their functional capacity, so care needs to be taken.

Use of tobacco is a leading cause of death and also promotes the development of CKD, with a higher incidence of CV events noted among current and former smokers in diabetics with CKD versus never smokers. Second hand exposure is also associated with CKD and kidney disease.

Therefore, diabetics with CKD, along with the general population, are advised to stop using tobacco products, with the help of pharmacotherapy and behavioural support. E-cigarettes are not recommended due to emerging links with lung cancer and CVD, and their impact on kidney disease is not fully known.

Pharmacological therapy

Angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB): It is recommended that patients with diabetes, hypertension, and albuminuria are started on ACEi or ARB, with dose titration as needed. Albuminuria is associated with increased risk of progression of CKD, and ultimately kidney failure, and with increased risk of CVD. Several trials have shown that through RAS (renin-angiotensin-system) blockade, ACEi, and ARBs were effective in reducing albuminuria and even reversal of moderately increased albuminuria, slowing the rate of kidney function loss.

Use of ACEi/ARBs in type 2 diabetes (T2D), albuminuria, and without hypertension are beneficial. However, their use is not beneficial for patients with neither albuminuria nor elevated BP. For CKD patients with T2D and hypertension, but normal urine albumin excretion, BP control with any anti-hypertensive class is important to prevent CVD.

Serum creatinine, eGFR, and potassium should be measured within two to four weeks of starting treatment or making a change in the dose of ACEi/ARBs. These drugs block the action of angiotensin II, leading to selective vasodilatation of the efferent arterioles, resulting in a decrease in the intraglomerular pressure with consequent rise in creatinine and decrease in eGFR, and block the action of aldosterone, potentially leading to hyperkalaemia. ACEi should not be combined with ARBs as this can lead to hyperkalaemia and acute kidney injury (AKI).

It is also important to advise contraception for women of child-bearing age or to discontinue treatment in women who are pregnant or planning to conceive, as ACEi/ARBs are associated with neonatal complications, especially when continued in the second/third trimester including:

• Impaired foetal or neonatal kidney function resulting in oligohydramnios during pregnancy and kidney failure after delivery;
• Pulmonary hypoplasia;
• Limb defects;
• Cerebral complications;
• Miscarriages or perinatal death.

ACEi can also cause dry cough and angioedema due to inhibition of bradykinin. Switching to ARBs is an option in such cases. Treatment should begin with the lowest possible dose and titrate to the maximum tolerated one, as with increasing dose, side-effect risks increase.

Sodium-glucose cotransporter-2 inhibitors (SGLTi): SGLTi are recommended for the treatment of patients with T2D, CKD, and eGFR ≥20ml/min per 1.73m². These drugs inhibit kidney tubular reabsorption of glucose leading to lower blood glucose. In view of this glycosuria, a diuretic effect is caused, leading to increased urine output. SGLTi also alter metabolism by shifting away from carbohydrate utilisation to ketogenesis, leading to lower HbA1c, BP, and weight. In addition, they lead to a reduction in intraglomerular pressure and subsequent preservation of kidney function.

SGLTi are associated with CV and heart failure (HF) benefits, with reduction in CV death, all-cause mortality, and HF hospitalisation compared to placebo. Kidney benefits include a slower decline in eGFR, reduction in albuminuria, and reduced risk of dialysis, kidney transplant, and death from renal causes.

With regards to initial therapy for patients not yet started on glucose-lowering drugs, different guidelines recommend different regimens, with some suggesting starting with metformin and others starting with SGLTi. Based on the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, it is recommended that most T2D CKD patients with an eGFR ≥30ml/min per 1.73m²:

• Start with a combination of metformin and SGLT2i;
• Once eGFR declines to 30-45ml/min/1.73m², maximum dose of metformin should be halved;
• Once eGFR <30ml/min/1.73m² or the patient is started on dialysis, metformin is stopped;
• Metformin can be administered to kidney transplant patients as long as eGFR is ≥30ml/min per 1.73m² ;
• Once eGFR <20ml/min/1.73m² one can continue treatment with SGLTi;
• Very little data is available once patients are started on dialysis or have received a kidney transplant, so discontinuation of SGLTi is recommended at this stage;
• SGLTi should not be started if eGFR is ≤20ml/min per 1.73m².

When used as monotherapy, the risk of hypoglycaemia with SGLTi is low as the drug-induced glycosuria decreases as blood glucose normalises. However, when used with other therapies that can cause hypoglycaemia, the dose of these pre-existing medications needs to be adjusted. Withhold SGLTi during times of prolonged fasting or surgery, when patients may be at a greater risk of ketosis.

In patients at risk of hypovolaemia, reduce thiazide or loop diuretic before starting treatment with SGLTi, as SGLTi are associated with an initial natriuresis. SGLTi can cause a reversible decrease in eGFR. An eGFR drop of ≤30 per cent should be tolerated and should not lead to discontinuation of treatment. If eGFR drops further, ensure the patient is not hypovolaemic, adjust diuretic dose, and seek other possible causes of the AKI. CKD or HF patients without T2D can be started on SGLTi, as they offer CV and kidney protection without conferring an increased risk of hypoglycaemia or diabetic ketoacidosis.

Diabetic ketoacidosis is a rare side-effect of SGLTi, as is an increased risk of genital mycotic infections.

Nonsteroidal mineralocorticoid receptor antagonist: Nonsteroidal mineralocorticoid receptor antagonist (MRA) are recommended for T2D patients with ≥eGFR 25ml/min/1.73m², normal serum potassium concentration, and albuminuria ≥30mg/g despite on maximum tolerated dose of ACEi/ARBs. Through the use of ACEi/ARBs, there is kidney and CV benefit via RAS blockade.

Nonetheless, data has shown that there is incomplete suppression of serum aldosterone levels, thereby suggesting the need for further treatment to reduce residual albuminuria. Steroidal MRA are used to treat primary hyperaldosteronism levels, HF, and to reduce albuminuria, but data is lacking with regards to their effect on kidney disease progression. Moreover, they can cause hyperkalaemia and AKI, and spironolactone is associated with gynaecomastia.

Novel nonsteroidal MRA such as finerenone are more selective for mineralocorticoid receptors, and confer CV and renal benefits with reduced albuminuria and slower decline in eGFR. They are also associated with a lower risk of hyperkalaemia compared to steroidal MRA.

Patients with T2D, CKD, and albuminuria on SGLTi and ACEi/ARBs can also start taking finerenone, provided that they have a normal serum potassium and albumin to creatinine ratio is ≥30mg/g. Use of SGLTi also reduces the risk of hyperkalaemia in patients already on ACEi/ARBs and finerenone. Moreover, finerenone can be added to patients on ACEi/ARBs only, despite not being on SGLTi.

A steroidal MRA is used in the treatment of HF, hyperaldosteronism, and refractory hypertension. Clinical evidence is lacking whether switching from a steroidal to nonsteroidal is associated with an improvement in clinical outcome. When the patient is treated with neither and has T2D, HF, and albuminuria and is already on ACEi/ARBs and SGLTi, treatment should be based on the most concerning clinical indication. At present, a nonsteroidal MRA cannot replace a steroidal MRA for HF and hyperaldosteronism.

Finerenone can cause hyperkalaemia, and monitoring of this electrolyte is important. Treatment with finerenone should not be started if serum potassium is >5mmol/l. Finerenone has a short half-life, therefore stopping the drug for 72 hours will lead to resolution of the elevated potassium.

Steroidal and nonsteroidal MRA should not be combined due to risk of hyperkalaemia. Steroidal MRA are currently contraindicated in pregnancy, and in view of the lack of clinical data of the use of nonsteroidal MRA in pregnancy, this drug should be stopped.

Other anti-hypertensive treatment: KDIGO guidelines recommend that patients with albuminuria, T2D, CKD, and hypertension are started on ACEi/ARBs until maximum tolerated dose. If patients have normal serum potassium and albumin to creatinine ratio is ≥30mg/g, finerenone can be added. If this is not the case and BP is still high, dihydropyridine calcium channel blocker and/or diuretic can be added. Should BP still remain high and eGFR ≥45, steroidal MRA can be added.

Glucagon-like peptide-1 receptor agonists: In T2D CKD patients who have not achieved the desirable glycaemic targets despite lifestyle interventions, treatment with metformin and  SGLT2i, or in whom the latter two medications are not tolerated, guidelines recommend prioritising glucagon-like peptide-1 receptor agonists(GLP-1 RA) over other glucose lowering therapies.

GLP-1 RA have been shown to improve glycaemic control, confer weight loss and CV benefit, reduce albuminuria, and slow the rate of eGFR decline. In view of their proven CV benefit, GLP-RA are preferred over other glucose-lowering therapies (Dipeptidyl peptidase-4 inhibitor (DPP-4) inhibitors, thiazolidinediones, sulfonylureas, insulin). The risk of hypoglycaemia is generally low when GLP-1 RA are used alone. When used with other medications, the risk is increased, so the dose of sulfonylurea and/or insulin may need to be reduced.

GLP-1 RA may be preferentially used in patients with obesity, T2D, and CKD to promote intentional weight loss. Further studies are required regarding the use of GLP-1RA in patients with very advanced CKD, patients on dialysis, and in kidney transplant recipients. Side-effects of GLP-1 RA include nausea/vomiting, diarrhoea, and increased heart rate. Also, since most of them are given as a subcutaneous injection, they are associated with pain over the injection site. These medications are contraindicated in patients with a history of medullary thyroid carcinoma, multiple endocrine neoplasia 2, and patients with a history of acute pancreatitis.

Other glycaemic treatment: If the glycaemic target is still not achieved despite lifestyle interventions, metformin, SGLTi, and GLP-1 RA, then other glucose-lowering agents can started, such as DPP-4 inhibitors, thiazolidinediones, sulfonylureas, and insulin.

Monitoring of blood glucose in T2D CKD patients

HbA1c is recommended to monitor glycaemic control in these patients, measured twice a year, or up to four times/year should glycaemic targets not be met. However, inflammation, oxidative stress, and metabolic acidosis associated with CKD, as well as anaemia, transfusions, and use of iron replacement therapies and erythropoiesis-stimulating agents, affect HbA1c level. These effects become more pronounced as the CKD advances or patients are treated with dialysis. Once HbA1c levels are not concordant with blood glucose levels, continuous glucose monitoring and self-monitoring of blood glucose can be used, as these are not influenced by CKD, dialysis, or other treatments. One should aim for target HbA1c of <6.5-to-8.0 per cent, with levels ≤6.0 per cent associated with greater risk of hypoglycaemia and increased mortality.

Dyslipidemia treatment

Managing dyslipidaemia, according to KDIGO recommendations, includes:

• CKD patients are at increased risk of adverse events when statins and fibrates are combined. Since statins confer a greater clinical benefit compared to fibrates, statins are preferred.
• Statin or statin/ezetimibe combination in adults aged ≥50 with eGFR ≤60ml/min/1.72m², not on dialysis and without kidney transplant. Ezetimibe monotherapy is not recommended.
• Statin in adults aged ≥50 with eGFR  ≥60ml/min/1.72m².
• Statin in adults aged 18 to 49 with CKD, but not on dialysis and without kidney transplant if they have coronary disease (myocardial infarction or coronary revascularisation); diabetes mellitus; prior ischaemic stroke; estimated 10-year incidence of coronary death or non-fatal myocardial infarction >10 per cent.
• If at the time of dialysis initiation, patients are already on statin or statin/ezetimibe combination, this can be continued.
• Do not start statin or statin/ezetimibe combination in dialysis patients.
• In adult kidney transplant recipients, treatment with a statin is recommended.
• Statins are contraindicated in pregnant or breastfeeding females, patients with active liver disease or in patients in whom transaminase levels are three times or more the upper limit of normal.

For additional risk-based therapy, aspirin can be used lifelong for secondary prevention among those with established CVD. Ezetimibe or proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) can be added to a statin. PCSK9i can be used in statin-intolerant patients, with these medications showing an improvement in lipid profile and CV risk. Nonetheless, further studies are needed to ascertain their safety in patients with eGFR ≤20ml/min/1.73m², those on dialysis, and/or renal transplant patients.

Conclusion

DKD is a constantly evolving subject with new guidelines issued very frequently. Nonetheless, a patient-centred approach with involvement of relatives and multidisciplinary team is required to achieve the best care possible, including involvement of nutritionist, physiotherapist, personal trainer, smoking cessation support,  endocrinologist, cardiologist, GP, and various other medical disciplines.

KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease provides evidence-based recommendations and can be accessed at: www.kdigo.org/wp-content/uploads/2022/10/KDIGO-2022-Clinical-Practice-Guideline-for-Diabetes-Management-in-CKD.pdf. 

References available on request

Type 2 diabetes is characterised by hyperglycaemia, insulin resistance, and impairment in insulin secretion. Diagnosis is made based on measures that show evidence of elevated glycaemia due to both issues with insulin secretion (beta-cell dysfunction) and insulin action, or resistance. Resistance to insulin may contribute to further physiological abnormalities in type 2 diabetes such as inflammation, lipoprotein abnormalities, hypertension, and further metabolic issues. Metabolic syndrome refers to type 2 diabetes when accompanied by additional clinical conditions like hypertension, dyslipidaemia, and central obesity; issues that may be caused at least in part due to insulin resistance.

Pathophysiology of type 2 diabetes

The cause of insulin resistance is commonly attributed to environmental factors related to increased food intake and a sedentary lifestyle, which causes overweight and obesity. Genetics and ageing also contribute. Issues with insulin secretion result from genetics and how pancreatic beta-cells are made and programmed in utero. The presence of hyperglycaemia can itself also impair beta-cell function, further exacerbating the problem.

Studies have shown that defects in beta-cell function can occur early in disease pathogenesis, even before the development of obesity and insulin resistance. Substances released by adipocytes [adipokines, eg, leptin, adiponectin, tumour necrosis factor (TNF) alpha, resistin] may, at least in part, cause insulin resistance. Insulin release involves the cleavage of proinsulin to insulin.

In type 2 diabetes, there is an increase in proinsulin secretion, suggesting that this processing is somehow impaired in the beta-cells in type 2 diabetes. Insulin resistance becomes more pronounced with increasing age and weight, revealing any underlying defect in beta-cell function in affected individuals.

The mechanism through which obesity causes insulin resistance, however, is poorly understood. Some studies have investigated the role of inflammation in the development of type 2 diabetes (and also atherosclerosis), the incidence of which is correlated with increased levels of inflammatory markers such as C-reactive protein, interleukin (IL)-6, TNF alpha, chemokines, and adipokines. These inflammatory markers can be reduced by intensive lifestyle interventions.

Interestingly, the anti-inflammatory effects of medications, like statins, may provide a greater therapeutic benefit beyond their intended effect. Use of anti inflammatory medications even in other diseases such as rheumatoid arthritis and psoriasis is linked with a lower incidence of type 2 diabetes.

Drug-induced hyperglycaemia

Certain drugs impair glucose tolerance through reducing insulin secretion, increasing hepatic glucose production, or causing insulin resistance (Table 1). Where appropriate, patients should be informed about these risks (especially with prolonged steroid use), as with all clinically-relevant side-effects.

Treatment

Lifestyle interventions are a mainstay of weight management, but used alone are associated only with moderate weight loss. Maintenance of weight loss is intrinsically difficult due to counter-regulatory neuroendocrine pathways that increase hunger and reduce satiety, promoting weight gain, and possibly reducing energy expenditure.

Metformin, the most common antidiabetic drug, decreases hepatic glucose production and intestinal glucose absorption, and increases peripheral glucose uptake. It does not affect insulin secretion.

Dipeptidyl peptidase (DPP) 4 Inhibitors (eg, sitagliptin, saxagliptin, linagliptin) inhibit DPP-4, which deactivates glucagon-like peptide (GLP)-1 and also the glucose-dependent insulinotropic polypeptide (GIP). These are oral GLP-1 based therapies that increase levels of GLP-1, but are not as effective as GLP-1 agonists at glucose or weight reduction.

Thiazolidinediones (eg, pioglitazone) increase insulin sensitivity by acting on adipose tissue and muscle to increase glucose use. They also reduce glucose production by the liver. Their mechanism of action is not fully understood, although they bind to and activate peroxisome proliferator-activated receptors (PPARs), mostly PPAR-gamma, which alters the transcription of multiple genes involved in glucose and lipid metabolism. Use of thiazolidinediones has decreased in recent years because of concerns about safety and side-effects such as heart failure and increased risk of fractures.

Sulfonylureas (eg, gliclazide) only benefit patients with some residual beta cell function. These drugs bind to specific receptors, with the ultimate effect of insulin release and stimulation of new insulin granules.

Sodium glucose co-transporter (SGLT) 2 inhibitors inhibit SGLT2 receptors in the kidneys’ proximal convoluted tubule, resulting in the prevention of glucose reabsorption. Glucose is then excreted in the urine, helping with weight loss, but also increasing UTI risk.

GLP 1 agonists (eg, exenatide, liraglutide, dulaglutide, semaglutide) are injectable medications that enhance the effect of GLP-1. GLP-1 is a gastrointestinal peptide contributing to the regulation of glucose levels when released after food consumption, when it stimulates insulin formation and release. It also slows gastric emptying and inhibits excess postprandial glucagon release. These drugs promote weight loss by reducing energy intake, increasing satiety, reducing hunger, and improving glycaemic control. Semaglutide is a long-acting GLP-1 analogue.

Type 2 diabetes is associated with an increased risk of cardiovascular and kidney disease and corresponding impaired quality-of-life and increased mortality. In recent years, it has been suggested that cardiovascular and kidney disease markers in type 2 diabetes are at least, if not more, clinically important for long-term outcomes than measures of glycaemia. Two classes of antidiabetic drugs in particular have been shown to help mitigate these risks: SGLT-2 inhibitors and GLP-1 receptor agonists.

Future care

Two new drugs are now available to treat type 2 diabetes: Finerenone (a non-steroidal mineralocorticoid receptor antagonist), and tirzepatide (a dual GIP/GLP-1 receptor agonist). The National Centre for Pharmacoeconomics (NCPE) in Ireland recently recommended that the HSE should consider funding finerenone if its cost-effectiveness can be improved relative to existing treatments, while a full health technology assessment was recommended by the NCPE for tirzepatide to assess its clinical and cost effectiveness compared with the current standard of care.

In trials investigating finerenone, findings suggested cardiovascular and kidney benefits in both patients with type 2 diabetes and those with chronic kidney disease.

Tirzepatide is also beneficial in terms of effects on weight loss and quality-of-life.

GLP-1 inhibitors are also successful in reducing body weight, with semaglutide the most effective in this class. A recent network meta-analysis investigating the benefits and harms of available drug treatments for type 2 diabetes found that SGLT-2 inhibitors, GLP-1 receptor agonists, and finerenone showed the most benefits in terms of, eg, overall mortality reduction, fewer hospital admissions, and reducing end-stage kidney disease. Predictably, the absolute benefits of these drugs are dependent on individual baseline risk levels. The authors recommend a risk-stratified approach for future treatment recommendations, tailored depending on each patient’s risk profile.

Pre-diabetes

In pre-diabetes, glycaemic values are in between normal and those that define diabetes. Like type 2 diabetes, it is characterised by decreased insulin sensitivity and impaired insulin secretion. Measures of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) based on World Health Organisation criteria can be used to diagnose the condition, although there are alternative diagnostic definitions depending on the guidelines used.

Pre-diabetes identifies people at risk of progression to diabetes, but the estimated risks vary depending on the definition used (isolated IFG, or isolated IGT, a combined measure of these, or HbA1c).

Intensive lifestyle intervention (ie, dietary modification and increased physical activity) and pharmacological intervention (ie, metformin) can reduce progression to diabetes. In the Diabetes Prevention Programme (a large trial in the US that compared metformin, placebo, and lifestyle interventions), intensive lifestyle intervention was found to be more effective than metformin.

Multiple clinical guidelines, including those from the National Institute for Health and Care Excellence, stress lifestyle intervention as the preferred initial step to reduce risk of diabetes, with metformin recommended for use in certain circumstances, eg, if the individual’s participation in intensive lifestyle change programmes has not worked, or they are unable to participate. Unfortunately, not all individuals have access to the type of lifestyle intervention programme that proved so effective in improving glycaemic values in research studies. Orlistat may also be offered to help with obesity management where appropriate in order to improve glycaemic parameters.

References on request

Type 2 diabetes is a complex chronic disease, which requires a multifactorial behavioural and pharmacological approach to treatment in order to prevent or delay complications and maintain quality-of-life. This includes management of blood glucose levels, weight, cardiovascular risk factors, comorbidities, and complications. A holistic, person-centred approach is essential to enhance engagement, and careful consideration of social determinants of health and preference of the person living with diabetes must guide individualisation of treatment goals and strategies.¹ This module will summarise the latest guidelines on the management of type 2 diabetes in non-pregnant adults.

Principles of glycaemic control

Achieving recommended glycaemic targets has been shown to substantially reduce the onset and progression of microvascular complications in patients with type 2 diabetes. Target HbA1c for adults with a life expectancy of >10 years is approximately 53mmol/mol. Aiming for a lower HbA1c level than this may be associated with significant hypoglycaemia and other adverse treatment effects. Higher HbA1c targets are appropriate in cases of limited life expectancy, advanced complications, or if factors such as frailty are present.¹ Monitoring of blood pressure, lipids, and other risk factors such as smoking and alcohol intake is extremely important in people with type 2 diabetes; however, detailed discussion of these is beyond the scope of this module.

DESMOND

Diabetes Education and Self-Management for Ongoing and Newly Diagnosed (DESMOND) is a free HSE course available to people with type 2 diabetes. Patients are provided with up-to-date information and practical skills to manage their diabetes, including diet and exercise, blood glucose monitoring, smoking cessation, eye care, and foot care.²

Weight loss of 5-to-15 per cent should be a primary target of management for many people living with type 2 diabetes. Weight loss of 5-to-10 per cent confers metabolic improvement, and weight loss of 5-to-15 per cent or more can have a disease-modifying effect and lead to remission of diabetes.¹

Physical activity significantly impacts cardiovascular health in type 2 diabetes. Individuals living with type 2 diabetes are advised to undertake 30 minutes of moderate exercise at least five times per week.¹

Oral medications for lowering glucose

Metformin
Metformin has traditionally been recommended as first-line therapy for the management of type 2 diabetes due to its high efficacy in lowering HbA1c, minimal hypoglycaemia risk, weight neutrality, good safety profile, and low cost. Metformin should not be used in people with an estimated glomerular filtration rate (eGFR) <30ml/min per 1.73m,² and dose reduction should be considered when the eGFR is <45ml/min per 1.73m.² Metformin use may lower serum vitamin B12; therefore, periodic monitoring and supplementation are recommended.¹

Sodium-glucose cotransporter-2 (SGLT2) inhibitors
SGLT2 inhibitors reduce plasma glucose by enhancing urinary excretion of glucose. They have intermediate-to-high glycaemic efficacy, with lower glycaemic efficacy at lower eGFR. Cardiorenal outcome trials have demonstrated their efficacy in reducing the risk of major adverse cardiovascular events, cardiovascular death, myocardial infarction (MI), hospitalisation for heart failure, and improving renal outcomes in individuals with type 2 diabetes.

In patients with established cardiovascular disease, heart failure, or chronic kidney disease, early combination therapy with metformin should be considered at treatment initiation provided the eGFR is above the threshold for metformin initiation. Their use should also be considered in those who are considered high risk for cardiovascular disease.¹

SGLT2 inhibitors are associated with increased risk of urinary tract infections. They are also associated with a low but serious risk of euglycaemic diabetic ketoacidosis (DKA).¹ Patients should be advised to hold the medication if they are unwell or fasting for a procedure, otherwise known as sick-day rules. Many centres provide patients with written information leaflets or alert cards, and the risk of euglycaemic DKA should be reiterated at each visit.

Glucagon-like peptide-1 (GLP-1) receptor agonists
GLP-1 receptor agonists increase glucose-dependent insulin secretion and glucagon suppression, slow gastric emptying, curb post-meal glycaemic increments, and reduce appetite, energy intake, and body weight. The most common side-effects of GLP-1 receptor agonists are nausea, vomiting, and diarrhoea, which tend to occur during initiation and dose escalation, and diminish over time. Gradual up-titration is recommended to mitigate gastrointestinal side-effects. Patients should be encouraged to eat slowly, stop eating when full, and not to eat when not hungry.

Studies have shown average weight loss of 5.5kg with semaglutide 1mg weekly; however, on stopping the drug people regain approximately one-third of the weight lost. GLP-1 receptor agonists are an appropriate second-line agent in patients whose primary target is weight loss and who do not have cardiovascular disease, heart failure, or chronic kidney disease.¹ GLP-1 receptor agonists are contraindicated in people at risk for medullary thyroid cancer.

In patients with pre-existing diabetic retinopathy and high glycaemic levels, their use can lead to increased retinopathy complications due to the magnitude and rapidity of HbA1c reduction. They are also associated with an increased risk of gallbladder and biliary diseases.¹

Dipeptidyl peptidase 4 (DPP-4) inhibitors
DPP-4 inhibitors inhibit the enzymatic inactivation of endogenous incretin hormones, resulting in glucose-dependent insulin release and a decrease in glucagon secretion. They have a more modest glucose-lowering effect and are weight neutral with minimal risk of hypoglycaemia.¹

Sulfonylurea
Sulfonylureas have high glucose-lowering efficacy; however, due to their glucose-independent stimulation of insulin secretion, they are associated with an increased risk of hypoglycaemia. They are also associated with weight gain. Use of sulfonylureas for early intensive blood glucose control has been shown to significantly reduce the risk of microvascular complications; however, some observational studies raised concerns about adverse cardiovascular outcomes with their use.¹

Thiazolidinediones (TZDs)
TZDs increase insulin sensitivity and have high glucose-lowering efficacy. In the PROactive trial,³ TZDs were shown to reduce secondary cardiovascular endpoints in adults with type 2 diabetes and macrovascular disease. The IRIS study demonstrated that in adults without diabetes, but with insulin resistance and a recent history of stroke or transient ischaemic attack (TIA), there was a lower risk of stroke or MI with pioglitazone.⁴ These benefits must be balanced with the possible side-effects of fluid retention and congestive heart failure, weight gain, and bone fracture. These side-effects can be mitigated by using lower doses and combining TZDs with other medications that promote weight loss and sodium excretion, such as SGLT2 inhibitors and GLP-1 receptor agonists.¹

Combination therapy

Early use of combination therapy allows tighter glycaemic control than monotherapy, and therefore, is indicated in those with a HbA1c >1.5 per cent above their target at diagnosis. Immediate and sustained glycaemic control should be particularly pursued in young adults with type 2 diabetes, aiming for HbA1c <53mmol/mol; therefore, combination therapy should be considered in this group at diagnosis. This allows the best opportunity to avoid complications of diabetes across their lifespan.¹

Insulin

Insulin therapy lowers glucose in a dose-dependent manner; however, its efficacy and safety are largely dependent on the education and support provided to facilitate self-management. Challenges of insulin therapy include weight gain, risk of hypoglycaemia, the need for regular glucose monitoring, and cost.

Comprehensive education on self-monitoring of blood glucose, diet, injection technique, self-titration of insulin, and prevention and treatment of hypoglycaemia are essential when initiating insulin therapy.¹

Starting doses of basal insulin are estimated based on body weight (0.1-0.2 units/kg per day) and the degree of hyperglycaemia. Short- and rapid-acting insulin can be added to basal insulin to intensify treatment and optimise prandial blood glucose levels. Premixed insulins combine basal insulin with mealtime insulin in the same pen. This offers convenience for some but reduces treatment flexibility.¹

Patients should continue metformin, SGLT2 inhibitors, and GLP-1 receptor agonists to avoid weight gain and limit insulin dose and hypoglycaemia risk. Sulfonylureas should be discontinued due to the increased risk of hypoglycaemia.¹

Combination GLP-1-insulin therapy
A fixed-ratio combination of a GLP-1 receptor agonist (liraglutide) with a basal insulin analog (insulin degludec) is available as Xultophy. This combination results in greater glycaemic lowering efficacy than its individual components, with less weight gain and lower rates of hypoglycaemia than with intensive insulin regimes, as well as better gastrointestinal tolerability than with a GLP-1 receptor agonist alone.¹

Screening and monitoring

In primary care, under the Diabetes Cycle of Care, now part of the chronic disease management (CDM) programme, GMS patients with type 2 diabetes are entitled to two visits a year.

Blood glucose monitoring
Regular capillary blood glucose monitoring helps with self-management and medication adjustment, particularly in those using insulin. In those not using insulin, regular glucose monitoring is of limited benefit while adding burden and cost.¹

RetinaScreen
Anyone with diabetes can develop diabetic retinopathy, which can lead to significant vision loss if untreated. The longer someone has diabetes, the more likely they are to develop the condition. Poor glycaemic control in diabetes can make diabetic retinopathy worse and can increase the risk of developing sight problems.

Risk factors for diabetic retinopathy

• Poor blood glucose control;
• High blood pressure;
• Raised triglycerides;
• Pregnancy (not gestational diabetes).
  During pregnancy, diabetes can worsen diabetic retinopathy. Common signs and symptoms include:
• Blurred or distorted vision (linked to blood glucose levels);
• Floaters (small black spots) and flashing lights;
• Trouble reading or seeing faraway objects;
• Loss of central vision;
• Sudden loss of vision (blindness);
• New colour blindness or seeing colours as faded;
• Poor night vision.

Diabetic retinopathy eye screening is a key part of diabetes care. The National Diabetic Retinal Screening Programme, Diabetic RetinaScreen, offers free, regular diabetic retinopathy screening to all people with diabetes aged 12 and older. See www.diabeticretinascreen.ie for further information.

Foot care
Patients with diabetes are at a 15-to-40-fold higher risk of a lower limb amputation than a non-diabetic patient. Early recognition and management of independent risk factors for ulcers and amputations can prevent or delay the onset of adverse outcomes.

All individuals with diabetes should receive an annual foot examination to identify their risk stratification and appropriate referral to specialists if required. In addition, all patients should be educated regarding foot care and the importance of their annual foot screen along with the management they may require. In 2021, the HSE National Clinical Programme for Diabetes published the Diabetic Foot Model of Care, which outlines the care diabetes patients should receive in relation to monitoring and treating diabetic foot issues.⁵

Driving guidelines

People with diabetes who are treated with insulin or sulfonylureas must check their blood glucose level before driving and every two hours while driving. If blood glucose is <5.0mmol/l, they should not drive. If a person develops hypoglycaemia while driving, they should stop the car, switch off the engine, take the keys out of the ignition, and move from the driver’s seat. They should take appropriate action to treat their hypoglycaemia and they should not drive again until 45 minutes after their blood glucose level has returned to normal.

People with type 2 diabetes must inform the National Driver Licence Service (NDLS) if they are treated with insulin or tablets which carry a risk of inducing hypoglycaemia, eg, sulfonylureas.⁶

Continuous glucose monitoring (CGM)

CGM devices provide interstitial glucose readings from sites in the abdomen or arm and make use of alarms and alerts to improve glycaemic control and reduce frequency of hypoglycaemia. ‘Time in range’ is defined as the percentage of time that CGM readings are in the range of 3.9-10.0mmol/L. Time in range is associated with the risk of microvascular complications and can be used for assessment of glycaemic management.

A HbA1c <53mmol/mol is equivalent to a time in range of >70 per cent, with additional recommendations to aim for time below range of less than 4 per cent. Like HbA1c targets, a lower percentage time in range is appropriate in cases of limited life expectancy, advanced complications, or if factors such as frailty are present. In the Republic of Ireland, CGM devices are not automatically funded for people with type 2 diabetes. Individual applications can be made for reasons such as hypo unawareness or severe needle phobia.

Support

Diabetes Ireland is the national charity dedicated to helping people with diabetes. It achieves this by providing support and education (including free online educational courses and support groups) to everyone affected by diabetes. It also raises public awareness of diabetes and its symptoms, and actively funds research into finding a cure for diabetes. See www.diabetes.ie.

Resources

• Irish College of General Practitioners (ICGP). A practical guide to integrated type 2 diabetes care. 2016.⁷
• HSE National Clinical Programme for Diabetes. Available at www.hse.ie/eng/about/who/cspd/ncps/diabetes.