Expert Opinion on Diabetes Management Challenges and Role of Basal Insulin/GLP-1 RA Fixed-Ratio Combination in People with Type 2 Diabetes from Indonesia

Figures & data

Figure 1 Algorithm of type 2 diabetes management in Indonesia.

Notes: Adapted with permission from Indonesian Society of Endocrinology. Guideline of Management and Prevention of Type 2 Diabetes Mellitus in Indonesia 2021. Indonesian Society of Endocrinology Publisher 2021. Available from: https://pbperkeni.or.id/unduhan. Accessed July 25, 2022.²⁴

Abbreviations: AG-I, alpha-glucosidase inhibitors; DPP-4i, dipeptidyl peptidase-4 inhibitors; GLP-1 RA, glucagon-like peptide-1 receptor agonists; GN, repaglinide; HBA_1c, glycated hemoglobin; SGLT-2i, sodium-glucose cotransporter-2 inhibitors; SU, sulfonylurea; TZD, thiazolidinediones.

Figure 2 General strategy of insulin therapy in adult outpatients with T2DM.

Notes: Adapted with permission from Indonesian Society of Endocrinology. Practical Guideline of Insulin Therapy in Patients with Diabetes Mellitus 2021. Available from: https://pbperkeni.or.id/unduhan. Accessed July 25, 2022.²³

Abbreviations: BW, body weight; GLP1-RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycated haemoglobin; IU, International units; kg, kilogram; SMBG, self-monitoring of blood glucose.

Table 1 Practical Questions Regarding the Use of FRCs

Should the components of FRC be started simultaneously or sequentially? Is there an HbA1C threshold recommended to start FRC for Indonesian people with T2DM? Can FRCs be used as an alternative treatment option for selected patients managed with basal-bolus therapy? Can FRCs be used for deintensification? Should OADs be continued after starting an FRC? If not, what is the strategy for OAD discontinuation? Is there a preferred time of the day to use an FRC? Should FRCs be considered as intensification options after the failure of GLP-1 RA? How should the cardiovascular benefits of GLP-1 RAs be taken into account when initiating an FRC? What should be done when an FRC is no longer sufficient to provide good glycemic control? How to minimize GI side effects of GLP-1 RAs from FRCs.

Abbreviations: FRC, fixed-ratio combination of basal insulin and GLP-1 RA; GLP-1 RAs, glucagon-like peptide receptor agonists; HbA_1c, glycated hemoglobin; OADs, oral antidiabetic drugs; T2DM, type 2 diabetes mellitus.

Table 2 Option for Intensifying with FRC to Achieve Better Glycemic Control

Patients Without Comorbidities with Long Life Expectancies	Patients with Comorbidities or Those Over 80 Years Old
An SGLT-2 inhibitor can be added (depending on the estimated glomerular filtration rate)	The individualized HbA1c target level should be reassessed when the patient is frail, at high risk of hypoglycemia, or living alone.
A sulfonylurea can be added when SGLT2 inhibitors cannot be prescribed (eg, due to eGFR, access, or cost issues). However, the risk of hypoglycemia should be managed.	Leaving the treatment regimen unchanged is a reasonable option for these patients (unless severe catabolic symptoms are present).
Prandial insulin can be added, but MDI is not the preferred solution
Options for intensifying FRC, if recommended target of FPG or HbA1c are not achieved despite reaching maximum dose: Switching to the free combination of a GLP-1 RA and basal insulin and increasing the dose of basal insulin. Switching to a full-scale MDI, particularly if fasting C-peptide levels are low.

Abbreviations: eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; GLP-1 RA, glucagon-like peptide-1 receptor agonists; HbA_1c, glycated hemoglobin; MDI, multiple-daily insulin injection; SGLT-2, sodium–glucose co-transporter-2.

Table 3 Expert Opinion on OAD Regimen and Initiation of FRC in Indonesian Perspective

OAD Regimen Therapy	Expert Opinion
Metformin + SU	SUs should be stopped as per label indication. Although the combination of SUs is currently not recommended per label, the use of modern second-generation SUs (glimepiride, gliclazide MR) with dose reduction is recommended based on clinical judgment.
Metformin + DPP-4 inhibitors	DPP-4 inhibitors should be stopped as per label indication. They have no additional value to GLP-1 RA.
Metformin + acarbose	Acarbose should be stopped as per label indication.
Metformin + TZD	TZD should be stopped as per label indication.
Metformin + SGLT2 inhibitors	In combination with FRC are potentially beneficial combination and are not associated with any other safety concerns.
SU monotherapy	Should be stopped and recommended metformin in combination with FRC per label. Although the combination of SU is currently not recommended as per label, the use of modern second-generation SUs (glimepiride, gliclazide MR) with dose reduction is recommended based on clinical judgment.
DPP-4 inhibitor monotherapy	Should be stopped and recommended metformin in combination with FRC per label. DPP-4 inhibitors have no additional value to GLP-1RAs.
SGLT2 inhibitor monotherapy	In combination with FRC are potentially beneficial combination and are not associated with any other safety concerns.
TZD monotherapy	Should be stopped. Safety concerns are noted if combined with insulin therapy due to fluid retention and weight gain; therefore, discontinuation is considered.
Acarbose monotherapy	Should be stopped. Safety concerns on GI adverse events have been noted. It has to be immediately stopped if any GI effect occurs.

Abbreviations: DPP-4, dipeptidyl peptidase-4; GI, gastrointestinal; GLP-1 RAs, glucagon-like peptide receptor agonists; OADs, oral antidiabetic drugs; SU, sulfonylureas; SGLT2, sodium–glucose cotransporter 2; TZD, thiazolidinediones.

Table 4 Expert Opinion on Other Practical Questions on the Clinical Situation and Treatment Strategies for Diabetes Management in Indonesia

Previous Regimen Therapy	Treatment Strategy Based on the Clinical Situation
Basal insulin	Intensification from basal to FRC if patients have: – Elevated HbA1c and persistent high PPG, but normal FPG – Experience recurrent nocturnal hypoglycemia – Basal insulin dose >0.5 units/kg BW/day
Once-daily insulin premix/once-daily co-formulation	Switching to FRC may be suggested if the patient experiences: – Frequent hypoglycemia events without any improvement in glycemic control – Significant weight gain after premix initiation
OAD and GLP-1 RA	Intensification from OAD and GLP-1 RA to FRC, if patient experiences: – HbA1C and/or FPG are not achieved – Nausea due to single GLP-1 RA injection
	If the patient has established CV disease, add basal insulin on top of GLP-1 RA with proven CV benefit.
Basal plus/basal bolus	Deintensification from basal plus/bolus to FRC, if the patient experiences: – Significant weight gain after basal plus/bolus initiation – Hypoglycemia – Low adherence due to complex regimen
FRC	Intensification to multiple daily injection (MDI) if patient experiences: – Classic catabolic symptoms – A need of basal high insulin dose (>60 units/day)

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; BW, body weight; CV, cardiovascular; FRC, fixed-ratio combination; FPG, fasting plasma glucose; GLP-1 RAs, glucagon-like peptide-1 receptor agonists; HbA1c, glycated hemoglobin; OADs, oral antidiabetic drugs; PPG, prandial plasma glucose.

Table 5 PERKENI 2021 Guidelines—Recommendation on Insulin Dose Adjustment

Fasting Plasma Glucose (mg/dL)	Basal Insulin Dose (Units)
>130 mg/dL	Increase dose by 2–3 units every 3–7 days
80–130 mg/dL	Maintain insulin dose
<80 mg/dL or there is any hypoglycemic symptoms	Reduce dose by 2–3 units

Note: Adapted with permission from Indonesian Society of Endocrinology. Practical Guideline of Insulin Therapy in Patients with Diabetes Mellitus 2021. Available from: https://pbperkeni.or.id/unduhan. Accessed July 25, 2022.²³

Indonesian Society of Endocrinology. Guideline of Management and Prevention of Type 2 Diabetes Mellitus in Indonesia 2021. Indonesian Society of Endocrinology Publisher 2021.

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Indonesian Society of Endocrinology. Practical Guideline of Insulin Therapy in Patients with Diabetes Mellitus 2021.  Available from: https://pbperkeni.or.id/unduhan. Accessed July 25, 2022.

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