Early Combination Therapy in T2 Diabetes (Evidence from Asia) – What Physicians Must Know?

CME INDIA Presentation by Dr. Manoj Chawla, Director and Consultant Diabetologist – Lina Diabetes Care & Mumbai Diabetes Research Centre (Mumbai, India); Consulting Diabetologist at: P D Hinduja Hospital, Khar; SL Raheja Fortis, Mahim, Mumbai; BSES MG Hospital, Andheri(W), Mumbai; Elected All India Executive Committee Member, RSSDI-2022Co Founder – DRS, DTECH India.

It was a moment of pride that for the first time in history exclusive Diabetes India symposium was held at Hamberg, Germany on 2nd October, 2023.The visionary leadership of Dr. Banshi Saboo is worth appreciating. This article is based on a presentation by Dr. Manoj Chawla at EASD, Hamberg.

Burden of diabetes in India

Diabetes control is far from being optimal

Early diabetes – perception & practice

Consequences of delayed intervention

How can we treat the disease aggressively in the early stages?

• Early introduction of combination therapy offers a good base for treating the disease aggressively.
  • It can target multiple pathophysiologies simultaneously resulting in improved glycemic control.
  • Thus, offering a reasonable option to get patients to achieve their goals.
  • This approach helps address glucotoxicity sooner.

When to initiate a Combination Therapy/What do the latest guidelines say?

Type 2 Diabetes in India – Preferred cut off value of HbA1C for initiating dual and triple therapy

Courtesy: Das AK, Saxena G, Naik S. HbA1C in Management of Type II Diabetes Mellitus: A Cross-sectional Survey of Indian Physicians. The Journal of the Association of Physicians of India. 2019 Jul 1;67(7):18-21.

To initiate

• Dual therapy, chose HbA1c level of 8.0-8.4%
• while for triple therapy, select HbA1c level of 9.0-9.4%

Early Combination Therapy

• Combination therapy is often required and should include therapeutic agents with complementary mechanisms of action.
• For patients with A1C > 9% who are not on antihyperglycemic agents, metformin plus another 2 agents in addition to lifestyle therapy should be initiated.
• Although a medication’s efficacy declines somewhat when added as a third agent, the addition may be required to ensure effective treatment.
• Symptomatic patients with A1C >9% are likely to achieve great benefit from the addition of insulin, although maximum doses with 2 or 3 other agents may be adequate if the patient has no significant symptoms.

Which oral second-line option/s can have a good balance between benefits and risks?

• DPP-4i & SGLT2i provide effective glycaemic control by acting on multiple pathophysiologies while not increasing the risk of hypoglycaemia, weight gain or any major side effects.

Courtesy: Diabetes Care. 2023; 46 (Suppl 1): S140-S157

Asian evidence for Early Combination Therapy

VERIFY – a multinational and multiethnic study

Randomized, double-blind, two arm, parallel-group study consisting of a screening visit, a 3-week run-in period with treatment intensification over a 5-year treatment period.

Indian patients on metformin monotherapy tend to fail early

• Indian patients on monotherapy tend to fail earlier than the global VERIFY population (1.5 years vs. 3 years).
• Median time to failure for Initial monotherapy was 78.4 weeks in Indian patients¹ compared to 156.9 weeks in global patients.
• 50% Indian patients failed* initial monotherapy with metformin at 1.5 years vs. 3 years for global patients.
• Median (interquartile range: IQR) time to failure: (Failure defined as HbA1c ≥7.0% confirmed at two consecutive visits 3 months apart)

• Data from patients in the VERIFY trial

Time to second treatment failure: Early combination therapy Vs. Initial monotherapy

Courtesy: Phadke KV, et al.: India sub-set analysis of VERIFY study.

• Early combination treatment approach with vildagliptin and metformin in Indian patients with newly diagnosed type 2 diabetes significantly and consistently improves long-term glycemic durability compared with metformin monotherapy

Initial combination therapy with vildagliptin plus metformin in drug-naïve patients with T2DM: a 24-week real-life study from Asia

• Initial combination therapy of vildagliptin and metformin is associated with significant and clinically relevant HbA1c reduction in a relatively young drug naïve T2DM Asian study population with high baseline HbA1c and often associated with CV risk factor
• This study concludes: “Overall, in a relatively young drug-naïve T2DM Asian study population with high baseline HbA1c and often associated with cardiovascular risk factors, vildagliptin/metformin combination therapy was associated with significant and clinically relevant HbA1c reduction from baseline. This effect was seen at week 12, was maintained over 24 weeks, and was accompanied by good tolerability.”

Vildagliptin/ Metformin Effectiveness in real-world settings: EDGE – Evidence of Indian Subset

• Study had Retrospective data of 3756 patients with T2DM on SU monotherapy.
• Using Vildagliptin resulted in better glycaemic control without tolerability issues than other OADs as add-on to SU.
• This study supports the use of DPP-4 inhibitors for treatment intensification of first-line SU if metformin is not an option.

Metformin Sustained-Release and Vildagliptin Fixed-Dose Combination for Optimizing Glycemic Control: A Review with Real-World Case Reports

• Early initiation of combination therapy helps in early achievement of glycemic goals.
• Early initiation of metformin and vildagliptin FDC results in significant glycemic control with good tolerability and compliance
• Metformin SR–vildagliptin FDC has lower adverse events, compared to metformin IR–vildagliptin FDC; A case series of ten patients with T2DM treated with metformin SR–vildagliptin FDC is presented to assess the real-world effectiveness of this combination.

Evidence with Novel Dual Combinations

Safety: Sitagliptin + Dapagliflozin

• No serious adverse events were reported during the study.
• The most common AEs reported (dapagliflozin/ sitagliptin vs. sitagliptin alone) in ≥1% of patients:  nasopharyngitis (3.8 Vs 3.1%), urinary tract infections (2.3 Vs 0%), hypoglycemia (2.3 Vs 1.5%), headache (2.3 vs. 1.6), genital fungal infections (1.6 vs. 0), abdominal pain (1.6 vs. 0).

(N=258 T2DM patients uncontrolled on metformin randomized to either dapagliflozin 10 mg + sitagliptin 100 mg or sitagliptin 100 mg and followed up for 16 weeks; Phase 3 trial, data on file)

Evidence with Novel Triple Combinations

UDI Trio FDC Study

Clinical Study to Evaluate the Efficacy and Safety of Fixed Dose Combination of Dapagliflozin, Sitagliptin and Metformin Hydrochloride ER Tablets in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin Monotherapy

Learning Points

• Asian patients with T2DM have demonstrated a faster progression of disease – thus demanding an early aggressive approach to slow the disease progression.
• Early combination therapy in T2DM patients has demonstrated greater durability of HbA1c lowering – both in clinical trials and in real-world settings.
• Due to the loss of patent of several drugs, Asian countries such as India have several dual/ triple combinations to aggressively manage HbA1c reduction.
• DPP4i/ SGLT2i represents an important combination that provides glucose lowering while acting on pathophysiological defects as well as not having any major adverse events.

References:

1. Das AK, Saxena G, Naik S. HbA1C in Management of Type II Diabetes Mellitus: A Cross-sectional Survey of Indian Physicians. The Journal of the Association of Physicians of India. 2019 Jul 1;67(7):18-21.
2. American Diabètes Association. Diabetes Care. 2019;42:S61-S70.
3. Garber AJ, et al. Endocr Pract. 2019;25:69-90
4. Diabetes Care. 2023; 46 (Suppl 1): S140-S157
5.  Phadke U, et al. Durability of glycemic control with early Vildagliptin-metformin combination versus sequential metformin monotherapy in newly diagnosed type 2 diabetes: India sub-set analysis of VERIFY study. Oral paper presented at: 15th Annual Conference of RSSDI Delhi Chapter; 2019 Dec 15; Delhi, India. 2. Matthews DR et al. Diabet Med. 2019;36:505-13
6. Matthews D, et al. Diabetes Ther. 2020 Nov;11(11):2465-2476;  2. Matthews DR et al. Lancet. 2019;394:1519-29
7. Chawla M, Kim TH, Mirasol RC, Faruque P, Cooke K, Hours-Zesiger P, Shete A. Initial combination therapy with vildagliptin plus metformin in drug-naïve patients with T2DM: a 24-week real-life study from Asia. Curr Med Res Opin. 2018 Sep;34(9):1605-1611. doi: 10.1080/03007995.2018.1476333. Epub 2018 Jun 12. PMID: 29764225.
8. K.M. Prasanna Kumar, U. Phadke, H. Brath, A. Gawai, P.M. Paldánius, C. Mathieu,Effectiveness of vildagliptin versus other oral antidiabetes drugs as add-on to sulphonylurea monotherapy: Post hoc analysis from the EDGE study,Primary Care Diabetes,Volume 10, Issue 6,2016,Pages 452-458.
9. Chawla M, Chawla P, Jethwani P, Shah K, Reddy S. Metformin Sustained-Release and Vildagliptin Fixed-Dose Combination for Optimizing Glycemic Control: A Review with Real-World Case Reports. Clin Pract. 2023 Mar 28;13(2):497–504. doi: 10.3390/clinpract13020045. PMCID: PMC10136586.
10. ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, Collins BS, Hilliard ME, Isaacs D, Johnson EL, Kahan S, Khunti K, Leon J, Lyons SK, Perry ML, Prahalad P, Pratley RE, Seley JJ, Stanton RC, Gabbay RA, on behalf of the American Diabetes Association. 7. Diabetes Technology: Standards of Care in Diabetes-2023. Diabetes Care. 2023 Jan 1;46(Suppl 1):S111-S127. doi: 10.2337/dc23-S007. PMID: 36507635; PMCID: PMC9810474.

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