CME INDIA Presentation by Dr. Kalyan Kumar Gangopadhyay, MBBS, MD. FRCP, CCST, Consultant in Endocrinology, CMRI, Peerless Hospital, CK Birla Hospitals, Kolkata.

What Parameters we decide to start initial therapy?

Retard β cell failure
CVOT
HHF
CKD
Impact on other parameters
Adverse effects

What happens to Beta Cells?

In 2024 Will Insulin Be Relegated as Last Line Therapy of T2DM?

What happens after Bariatric Surgery – Diabetes Remission?

In 2024 Will Insulin Be Relegated as Last Line Therapy of T2DM?

Understanding Rediffentiation is the Future Therapy for T 2 DM

In 2024 Will Insulin Be Relegated as Last Line Therapy of T2DM?
  • In Type 2 Diabetes, beta-cell failure may stem from dedifferentiation rather than cell death.
  • When normal beta cells face mild hyperglycemia or insulin resistance, they respond by increasing insulin production, maintaining euglycemia. According to current understanding, oxidative stress or endoplasmic reticulum stress can lead to beta-cell dysfunction, resulting in the increased secretion of incompletely processed proinsulin. If left unchecked, this process may induce apoptosis.
  • Talchai et al.’s proposition suggests that stressed beta cells might undergo dedifferentiation, reducing the expression of beta-cell-specific genes, including transcription factors like MafA and the proinsulin-processing enzyme.
  • This dedifferentiation could elucidate the heightened proinsulin secretion observed in Type 2 Diabetes. Furthermore, dedifferentiation may involve the acquisition of expression for embryonic progenitor-cell markers like Ngn3. Subsequently, these cells may start expressing non-beta-cell hormones such as somatostatin and glucagon.

It is known that Early insulin therapy improves beta-cell function and glycaemic control

In 2024 Will Insulin Be Relegated as Last Line Therapy of T2DM?

Key publications – Early Insulin therapy 

Beneficial effects of insulin on glycemic control and beta-cell function in newly diagnosed type 2 diabetes with severe hyperglycemia after short-term intensive insulin therapy

Chen HS, Wu TE, Jap TS, et al showed that in new-onset Type 2 diabetic patients with severe hyperglycemia, a 6-month course of insulin therapy appears to be more effective than oral antidiabetic (OAD) treatment in achieving adequate glycemic control and significantly improving beta-cell function

β-cell function preservation after 3.5 years of intensive diabetes therapy

In Diabetes Care. 2012, study by Harrison LB, Adams-Huet B, Raskin P et al conclusively showed that the preservation of β-cell function for a minimum of 3.5 years is achievable through early and intensive therapy for Type 2 Diabetes. This preservation can be attained by employing either insulin combined with metformin or triple oral therapy, following an initial 3-month period of insulin-based treatment

Short-term intensive insulin therapy in type 2 diabetes mellitus: a systematic review and meta-analysis

Kramer C K et al in Lancet Diabetes Endocrinol. 2013 showed that Intensive insulin therapy over a short-term duration has the potential to enhance the underlying pathophysiology in early Type 2 Diabetes Mellitus. Consequently, this approach may serve as a treatment strategy to modify the natural history of diabetes.

Effect of intensive insulin therapy on β-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial

Weng J et al in 2008 showed that in individuals diagnosed with new-onset Type 2 Diabetes, early intensive insulin therapy demonstrates favorable outcomes in terms of recovering and maintaining β-cell function, as well as achieving protracted glycaemic remission. This contrasts with the outcomes observed with treatment using oral hypoglycaemic agents.

In 2024 Will Insulin Be Relegated as Last Line Therapy of T2DM?

What is the message from ORIGIN Trial?

  • When employed to maintain normal fasting plasma glucose levels for an extended period exceeding 6 years, insulin glargine demonstrated a neutral impact on cardiovascular outcomes and incidents of cancers. While it effectively decreased the occurrence of new-onset diabetes, it was also associated with an increase in hypoglycemia and a modest rise in weight.

In 2024 Will Insulin Be Relegated as Last Line Therapy of T2DM?

Glycemia Reduction in Type 2 Diabetes — Glycemic Outcomes.

  • In 2022, GRADE investigators showed that Glargine when compared with the sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or sitagliptin, a dipeptidyl peptidase 4 inhibitor insighted a new path.
  • When combined with metformin, all four medications resulted in a decrease in glycated hemoglobin levels. However, glargine and liraglutide exhibited a significantly, albeit modestly, greater effectiveness in attaining and sustaining target glycated hemoglobin levels.

What EDICT showed?

  • The findings from this exploratory study indicate that the combination therapy involving metformin, pioglitazone, and exenatide in patients newly diagnosed with Type 2 Diabetes Mellitus (T2DM) is more effective and leads to fewer hypoglycaemic events compared to the sequential add-on therapy with metformin, sulfonylurea, and subsequent introduction of basal insulin.

In 2024 Will Insulin Be Relegated as Last Line Therapy of T2DM?

Long-term efficacy of sulfonylureas: a United Kingdom Prospective Diabetes Study perspective

  • The United Kingdom Prospective Diabetes Study indicates that sulfonylureas are effective as a first-line therapy for individuals with Type 2 Diabetes Mellitus. The longevity of the achieved glycemic control depends on the preservation of beta-cell function.
  • However, sulfonylureas seem to neither increase nor decrease the underlying rate of beta-cell function loss. As these medications enhance insulin secretion, they are likely most beneficial when administered close to the time of diabetes diagnosis, when beta-cell function is at its peak.
  • Their effectiveness can be prolonged by strategic combination with agents that improve glycemia through different mechanisms, including insulin.

In 2024 Will Insulin Be Relegated as Last Line Therapy of T2DM?

Lesson from ADOPT Trial

  • Rosiglitazone demonstrated superior efficacy in preserving renal function compared to Metformin and Glyburide when utilized as an initial treatment for early-stage type 2 diabetes.

TOSCA IT Trial

  • In this extended, practical study, the occurrence of cardiovascular events was comparable between sulfonylureas (mainly glimepiride and gliclazide) and pioglitazone when used as supplementary treatments to metformin. Both these readily accessible and cost-effective treatments prove to be viable choices in terms of effectiveness and adverse events, albeit pioglitazone demonstrated a lower incidence of hypoglycemic events.

Parameters used to decide on initial therapy: CVOT/HHF

  • Liraglutide, semaglutide (injected), dulaglutide, albiglutide, and efpeglenatide, among the GLP1 receptor agonists (GLP1 RAs), have shown efficacy in safeguarding against major adverse cardiovascular events.

In 2024 Will Insulin Be Relegated as Last Line Therapy of T2DM?

CRM risk reduction for patients with ASCVD/indicators of high risk
3P-MACE risk reduction in SGLT2 inhibitor CVOTs by the presence of established ASCVD

In 2024 Will Insulin Be Relegated as Last Line Therapy of T2DM?

In 2024 Will Insulin Be Relegated as Last Line Therapy of T2DM?

CKD: Benefits, no one can ignore

  • RENAAL = The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death Baseline creat =1.9 (eGFR 30 – 40 ???) Results A total of 327 patients in the losartan group reached the primary end point, as compared with 359 in the placebo group (risk reduction, 16 percent; P=0.02). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 percent; P=0.006) and end-stage renal disease (risk reduction, 28 percent; P=0.002) but had no effect on the rate of death.
  • IDNT = Incl – T2DM, HTN, ACR>900, Creat 1.2 – 3, primary composite end point of a doubling of the base-line serum creatinine concentration, the development of end stage renal disease, or death from any cause the mean duration of follow-up was 2.6years. Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group (P=0.02) and 23 percent lower than that in the amlodipine group (P=0.006). The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group (P=0.003) and 37 percent lower in the irbesartan group than in the amlodipine group (P<0.001). Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups (P=0.07 for both comparisons).
  • IRMA 2 HTN Baseline GFR 109, ACR58 – Primary – ACR, Sec – GFR – no diff INNOVATION Telmisartan Normo v/s HTN Baseline – ACR 164, GFR – 100 Primary – ACR No change in GFR.

In 2024 Will Insulin Be Relegated as Last Line Therapy of T2DM?
In 2024 Will Insulin Be Relegated as Last Line Therapy of T2DM?

Impact on other parameters

MAFLD/ Liver Fibrosis/OSA

  • As of the present, non-alcoholic fatty liver disease (NAFLD) stands out as the most prevalent liver disorder, affecting approximately 70% of individuals with diabetes. Notably, specific drugs tailored for the treatment of NAFLD are currently unavailable. In addition to their established anti-hyperglycemic effects and their unexpected roles in cardio- and nephroprotection, GLP-1 receptor agonists (GLP-1 RAs) have demonstrated a noteworthy impact on body weight, as well as clinical, biochemical, and histological markers associated with fatty liver and fibrosis in patients grappling with NAFLD. Consequently, GLP-1 RAs hold promise as therapeutic tools that could address both diabetes mellitus and NAFLD.
  • Nevola R, Epifani R, Imbriani S, et al in 2023 opined about prospect of GLP-1 RAs being employed as a strategic “weapon” for managing both diabetes mellitus and NAFLD.

In 2024 Will Insulin Be Relegated as Last Line Therapy of T2DM?

OSA

  • In the EMPA-REG OUTCOME study, individuals with obstructive sleep apnea (OSA) exhibited increased comorbidity and a higher incidence of cardiovascular (CV) and renal events. Empagliflozin demonstrated positive effects on risk factors, as well as CV and renal outcomes, independent of the presence of preexisting OSA. Furthermore, there is an indication that empagliflozin could potentially lower the risk of developing new-onset OSA.

In 2024 Will Insulin Be Relegated as Last Line Therapy of T2DM?

Where OHA stands in 2024?

In 2024 Will Insulin Be Relegated as Last Line Therapy of T2DM?
In 2024 Will Insulin Be Relegated as Last Line Therapy of T2DM?

In 2024 will insulin be relegated as last line therapy of T2DM?

  • In most cases more than before.
  • But not always.
  • No substitute for insulin if in a catabolic state.
In 2024 Will Insulin Be Relegated as Last Line Therapy of T2DM?

Also Read:

References:

  1. Weng J, Li Y, Xu W, Shi L, Zhang Q, Zhu D, Hu Y, Zhou Z, Yan X, Tian H, Ran X, Luo Z, Xian J, Yan L, Li F, Zeng L, Chen Y, Yang L, Yan S, Liu J, Li M, Fu Z, Cheng H. Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet. 2008 May 24;371(9626):1753-60. doi: 10.1016/S0140-6736(08)60762-X. PMID: 18502299.
  2. Chen HS, Wu TE, Jap TS, Hsiao LC, Lee SH, Lin HD. Beneficial effects of insulin on glycemic control and beta-cell function in newly diagnosed type 2 diabetes with severe hyperglycemia after short-term intensive insulin therapy. Diabetes Care. 2008 Oct;31(10):1927-32. doi: 10.2337/dc08-0075. Epub 2008 Jun 12. PMID: 18556343; PMCID: PMC2551629.
  3. Harrison LB, Adams-Huet B, Raskin P, Lingvay I. β-cell function preservation after 3.5 years of intensive diabetes therapy. Diabetes Care. 2012 Jul;35(7):1406-12. doi: 10.2337/dc11-2170. PMID: 22723578; PMCID: PMC3379585.
  4. Kramer CK, Zinman B, Retnakaran R. Short-term intensive insulin therapy in type 2 diabetes mellitus: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2013 Sep;1(1):28-34. doi: 10.1016/S2213-8587(13)70006-8. Epub 2013 Feb 4. PMID: 24622264.
  5. ORIGIN Trial Investigators; Gerstein HC, Bosch J, Dagenais GR, Díaz R, Jung H, Maggioni AP, Pogue J, Probstfield J, Ramachandran A, Riddle MC, Rydén LE, Yusuf S. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012 Jul 26;367(4):319-28. doi: 10.1056/NEJMoa1203858. Epub 2012 Jun 11. PMID: 22686416.
  6. Nathan DM, Buse JB, Kahn SE, Krause-Steinrauf H, Larkin ME, Staten M, Wexler D, Lachin JM; GRADE Study Research Group. Rationale and design of the glycemia reduction approaches in diabetes: a comparative effectiveness study (GRADE). Diabetes Care. 2013 Aug;36(8):2254-61. doi: 10.2337/dc13-0356. Epub 2013 May 20. Erratum in: Diabetes Care. 2022 Mar 1;45(3):759. PMID: 23690531; PMCID: PMC3714493.
  7. Glycemia Reduction in Type 2 Diabetes — Glycemic Outcomes.The GRADE Study Research Group. September 22, 2022 N Engl J Med 2022; 387:1063-1074.DOI: 10.1056/NEJMoa2200433
  8. Abdul-Ghani MA, Puckett C, Triplitt C, Maggs D, Adams J, Cersosimo E, DeFronzo RA. Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. Diabetes Obes Metab. 2015 Mar;17(3):268-75. doi: 10.1111/dom.12417. Epub 2015 Jan 7. PMID: 25425451; PMCID: PMC5577982.
  9. Holman RR. Long-term efficacy of sulfonylureas: a United Kingdom Prospective Diabetes Study perspective. Metabolism. 2006 May;55(5 Suppl 1):S2-5. doi: 10.1016/j.metabol.2006.02.006. PMID: 16631806.
  10. Glycemic Durability of Rosiglitazone, Metformin, or Glyburide MonotherapyN Engl J Med 2006; 355:2427-2443DOI: 10.1056/NEJMoa066224
  11. TOSCA.IT . September 13, 2017DOI:https://doi.org/10.1016/S2213-8587(17)30317-0
  12. RAAS, renin-angiotensin-aldosterone system; RRR, relative risk reduction; SGLT-2, sodium-glucose co-transporter-2.Fioretto P & Pontremoli R. Nat Rev Nephrol 2022;18:78–79
  13. Nevola R, Epifani R, Imbriani S, Tortorella G, Aprea C, Galiero R, Rinaldi L, Marfella R, Sasso FC. GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives. Int J Mol Sci. 2023 Jan 15;24(2):1703. doi: 10.3390/ijms24021703. PMID: 36675217; PMCID: PMC9865319.
  14. Neeland IJ, Eliasson B, Kasai T, Marx N, Zinman B, Inzucchi SE, Wanner C, Zwiener I, Wojeck BS, Yaggi HK, Johansen OE; EMPA-REG OUTCOME Investigators. The Impact of Empagliflozin on Obstructive Sleep Apnea and Cardiovascular and Renal Outcomes: An Exploratory Analysis of the EMPA-REG OUTCOME Trial. Diabetes Care. 2020 Dec;43(12):3007-3015. doi: 10.2337/dc20-1096. Epub 2020 Oct 1. PMID: 33004464; PMCID: PMC7770278.


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