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When approaching management of a person with diabetes, tasks can be divided into canonical and new tasks.
- Control hyperglycemia
- Reduce excess body weight
- Reduce microvascular events (retinopathy, nephropathy, neuropathy)
- Reduce macrovascular events (cardiovascular disease [CVD], myocardial infarction [MI], stroke, amputations)
- Consider contraindications due to comorbidities (such as chronic kidney disease [CKD], liver disease, congestive heart disease [CHD]/heart failure [HF])
- Avoid adverse effects of glucose-lowering therapy (including excess CV risk, hypoglycemia, weight gain, HF, genitourinary infections, bone loss).
- Prevent diabetes progression
- Reduce mortality (CV and non-CV)
- Prevent HF outcomes
- Prevent CKD progression
- Ameliorate non-alcoholic fatty liver disease/ non-alcoholic fatty liver
- Help patients to maintain compliance and improve adherence and persistence to treatment
- Reduce psychological burden of disease and improve QoL
- Keep an eye on costs of healthcare.
Understanding the incretin effect in type 2 diabetes (T2D)
The incretin effect is the increased insulin release observed after oral glucose ingestion compared to after intravenous glucose infusion. The incretin effect is diminished in T2D. Two hormones released after food ingestion are responsible: GLP-1 and GIP.
In terms of the GLP-1 effects in humans, the gluco-regulatory role of incretins is:
- Beta cells: Increases glucose-dependent insulin secretion
- Promotes satiety and reduces appetite
- Alpha cells: Decreases glucagon secretion
- Stomach: Slows gastric emptying
- GLP-1 is secreted upon the ingestion of food.
GLP-1 Receptor Agonists (RAs)
GLP-1 RAs deliver on potential in T2D in terms of glucose lowering, low risk of hypoglycaemia and weight loss.
GLP-1 RAs have shown multiple favourable effects. The targets are insulin secretion, glucagon suppression, naturiuresis and duriresis, appetite suppression and cell survival. Immediate effects include a decrease in inflammation, coagulation, postprandial lipids and an increase in LV function, beta cells survival and function and potential neuroprotection. Final effects are decrease in HbA1c, bodyweight, blood pressure, albuminuria, cardiovascular events, and hepatic injury.
As per the ADA 2021, GLP-1 RA is the first line of therapy for patients with established CV risk or CV risk factors. A patient-centred approach should be used to guide the choice of pharmacologic agents. Considerations include effect on cardiovascular and renal comorbidities, efficacy, hypoglycaemia risk, impact on weight, cost, risk for side effects, and patient preferences.
Cardiovascular benefits of GLP1-RAs
CVD risk starts before the diagnosis of type 2 diabetes but increases afterwards. While a majority of people with T2D do not have established CVD, most are at risk for a CV event. Individuals with T2D and established CVD represent only 32% of the individuals with type 2 diabetes.
GLP-1 RA CVOTs: The REWIND study design was more representative of the general type 2 diabetes population. Once-weekly dulaglutide demonstrated 12% reduction of major adverse cardiovascular events (MACE) in a broad T2D population. Dulaglutide was the first & only GLP-1 RA to demonstrate both primary & secondary prevention in T2D patients. Caution should be used when comparing GLP-1 RAs CVOT trials due to differences in study design, population, and key inclusion/exclusion criteria. Once Weekly dulaglutide’s powerful and sustained efficacy can help patients maintain HbA1c of <7% for up to 2 years. In the REWIND study, HbA1c reduction with dulaglutide was sustained for >5 years.
Key takeaways of REWIND
The majority of patients in the study had no established CVD. There was a statistically significant 12% reduction in MACE-3. Dulaglutide is the first and only GLP-1 RA to demonstrate primary and secondary prevention of major adverse CV events in patients with type 2 diabetes at CV risk. Adverse events in REWIND were consistent with those in the dulaglutide clinical trials.
Selected adverse events and precautions for use:
Gastrointestinal events: The most frequently reported adverse events in clinical trials were gastrointestinal, including nausea, vomiting, and diarrhoea. In general, these events were mild or moderate in severity and transient in nature.
Set expectations that patients may experience nausea and use suggested methods to ease nausea, such as - eat smaller meals, eat slowly, and avoid fried or fatty foods. Nausea typically occurred upon treatment initiation with dulaglutide and subsided after the first two weeks.
Dehydration: Sometimes leading to acute renal failure or worsening renal impairment, has been reported. Patients treated with dulaglutide should be advised of the potential risk of dehydration, particularly in relation to gastrointestinal adverse effects, and take precautions to avoid fluid depletion.
Addition to sulfonylurea/insulin: When dulaglutide is added to existing therapy with a sulfonylurea or insulin, a reduction in sulfonylurea/insulin dose may be considered to reduce the risk of hypoglycaemia.
Self-monitoring of blood glucose is necessary to adjust the dose of sulfonylurea/insulin, particularly when dulaglutide therapy is started and insulin is reduced. Diabetic ketoacidosis has been reported in insulin-dependent patients after rapid discontinuation or dose reduction of insulin. A stepwise approach to insulin dose reduction is recommended.
Persistence and adherence
In a study, 84% of patients preferred the dulaglutide pen over the semaglutide pen (12%), no device preference was 4%. Dulaglutide experience could give patients the motivation they need to start and stay on a new treatment. Once weekly, it starts working after the first dose, and has a preattached hidden needle, with a preset dose.
The target patient
The target patient is a patient with T2D on oral medication and an HbA1c of between 8% and 10%.
This is because of fasting plasma glucose (FPG|) and postprandial glucose (PPG) contributions to HbA1c. FPG correlates poorly with HbA1c levels. PPG contributes more to HbA1c levels than FPG at lower HbA1c levels, and vice versa.
Dulaglutide as first injectable
Who is the right patient to benefit the most from once-weekly dulaglutide?
T2D patient characteristics: Inadequately controlled on multiple oral antidiabetic drugs and need to start injectable therapy. Struggling to get blood sugar under control over time HbA1C: 8%-10%. Weight gain is a clinical concern (BMI>25Kg/m2).
Cardiovascular risk is a clinical concern (hypertensive, smoker, etc.) The patient is looking for a simple therapy easy to fit into his/ her lifestyle, and is motivated to take ownership of long-term health.
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