CME INDIA Presentation by Dr. Santosh Malpani, MD, Dip. Endocrine, United Diabetes and Endocrine Clinic, Nanded.

 Suspect, Diagnose and Treat.

Why we are concerned?

• T1 and T2 are complex heterogeneous diseases.
• All patients don’t fit in this binary classification.
• Some share features of both T1 and T2 DM – Hybrid form of T1 and T2.
• LADA or Type 1.5 DM is slowly progressive form of autoimmune diabetes with serum immune markers of T1D but not requiring insulin at diagnosis.
• 2–12% of all patients with diabetes belong to this category.
• Considerable variability according to ethnicity, type of autoantibody used for screening.
• There are no guidelines for its management for such cases.

Let us think about this case

We need to differentiate

Diagnostic criteria for LADA

• Adult-onset diabetes (>30 years at diagnosis).
• Presence of diabetes-associated autoantibodies.
• Absence of insulin requirement for at least 6 months after diagnosis.

(None of these criteria are categorical; given that LADA is clinically and metabolically a hybrid of T1D and T2D)

Characteristics of LADA- Phenotypical Features

• UKPDS and the Botnia study show that the autoantibody frequency (GADA) in patients diagnosed with T2D is higher in younger patients compared with older patients.
• C-peptide levels decrease more slowly in LADA than in T1D, and this marker may be used to stage LADA patients according to their residual b-cell function and progression.
• The risk of progression to insulin deficiency is variable and depends on:
  • Age at diagnosis.Autoantibody level.
  • Presence of multiple islet autoantibodies.
• Compared with antibody-negative T2D, patients with LADA are:
  • Younger at diabetes diagnosis.
  • Lower BMI.
  • Personal or family history of autoimmune diseases.
• Metabolic syndrome tends to have a similar or higher frequency in LADA compared with adult-onset T1D.
• Compared with autoantibody-negative T2D patients, LADA patients show a:
  • Lower frequency of Metabolic Syndrome.
  • Lower (HOMA-IR).
  • Lower blood pressure.
  • Less diabetic dyslipidemia.
• Although patients with LADA have less major cardiovascular risk factors, there is no difference in cardiovascular outcomes in them compared with T2D patients after adjustment for traditional cardiovascular risk factors.
• LADA subjects at diabetes onset have a lower risk of microvascular complications that becomes higher secondary to worse glycemic control compared with T2D subjects

Characteristics of LADA- Autoantibodies

• Action LADA study showed that approximately 90% of LADA subjects with diabetes-associated autoantibodies are GADA positive.
• Patients with high GADA levels tend toward a T1D-like phenotype with lower BMI and lower prevalence of metabolic syndrome.
• UKPDS and all other studies found that high GADA levels were associated with an increased risk of insulin requirement.
• Fraction of autoantibody-positive cases could have false positive autoantibodies; the confusion can be solved placing more emphasis on C-peptide levels.
• Other autoantibodies target different IA-2 epitopes (IA-2A), insulin (IAA), the islet-specific zinc transporter isoform 8 (ZnT8A), and tetraspanin 7, while other GADA epitopes are less frequent in LADA.
• Diabetes-associated autoantibody positivity is predictive for progression both to:
  • Non–insulin-dependent diabetes.
  • To future insulin dependency after the diagnosis of diabetes.
• UKPDS found at least 50% of positive patients required insulin treatment 6 years postdiagnosis.
• LADA is the increased risk of other organ-specific autoantibodies and autoimmune diseases.
  • GADA – thyroid autoimmunity.
  • IA-2 autoantibodies – high risk of celiac disease–associated autoimmunity.

Treatment- Overview of Current Approaches

• Improve metabolic control.
  • Preserve the insulin-secreting capacity.

Insulin Sensitizers – Metformin

• Although there is little evidence for the use of metformin, there is no evidence against it.
• Metformin:
  • Increases insulin sensitivity in T1D.
  • Could improve long-term glycemic control.
  • Might reduce weight.
  • Might LDL cholesterol levels.
  • Reduces risk of atherosclerosis progression.
• LADA patients who have phenotype of T2 DM may benefit with metformin therapy.

More studies are required. Metformin appears to improve whole-body and peripheral IR in youth who are overweight/obese with type 1 diabetes (1)

Insulin Sensitizers – Thiazolidinediones

• Thiazolidinediones is a:
  • Stronger insulin sensitizer.
  • Have anti-inflammatory activity on β cells.
  • Can increase their survival during the non-insulin-dependent stage of LADA.
• Brooks-Worrell et al. treated T-LADA patients with rosiglitazone for 3 years and found that the levels of IFN-γ and IL-12 secreted by autoreactive T cells in the intervention group were lower than those in the control group, suggesting that rosiglitazone can delay islet failure by inhibiting autoreactive T cells.
• Clinical studies in China showed that rosiglitazone alone or in combination with insulin can maintain C-peptide levels and protect islet β-cell function in LADA patients.
• The panel concluded that although there is little evidence for the use of metformin, there is no evidence against its use.
• For TZD, the potential risk of atypical bone fractures, macular edema, and weight gain could be a limitation to the use of these compounds. (2)

Insulin

• Therapy with insulin is essential in all cases with undetectable C-peptide.
• A major question is whether insulin therapy should be the initial treatment for LADA?
• There are no data from large randomized, controlled trials with sufficient length of follow-up to draw a conclusion.
• STUDY: Results suggest that small doses of insulin effectively prevent beta cell failure in slowly progressive type 1 diabetes. Authors recommend avoiding SU treatment and instead administering insulin to NIDDM patients with high GADA titer. (3)
• Conclusions: Early insulin treatment in LADA leads to better preservation of metabolic control and was safe. Superior preservation of C-peptide could not be significantly demonstrated. Only baseline level of C-peptide significantly influenced C-peptide level after 3 years. Further studies exploring the best treatment in LADA are warranted. (4)

Sulfonylureas

• There is limited evidence to suggest the efficacy of SU in subjects with LADA.
• It cannot be excluded that treatment of LADA with SU results in a decreased insulin secretion.
• SU are not therefore recommended for the treatment of LADA, nor are they generally recommended as first-line therapy for T2D.
• Study: In a multicenter, randomized, nonblinded clinical study, Japanese patients with LADA, randomized to insulin or glibenclamide (n 5 30 in each group), were followed for up to 5 years. During follow-up, the SU group had worse metabolic control and a more rapid decline in C-peptide level compared with the group treated with insulin (P 5= 0.005). (Ref-5)
• The International LADA panel concluded that sulfonylureas are not recommended for the treatment of LADA, as deterioration of b-cell function as a consequence of this treatment cannot be ruled out. (5)

Dipeptidyl Peptidase 4 Inhibitors

• Small clinical trials with DPP‐4i in patients with LADA suggest that this class of hypoglycemic agents might improve glycemic control and preserve b‐cell function with a good safety profile compared with placebo, glimepiride, and pioglitazone.
• Although these studies have several limitations (i.e., post hoc analyses, small sample size, short periods of follow-up, interstudy heterogeneity), DPP-4i agents represent a potential therapeutic alternative for effective management of LADA.
• Study: Saxagliptin was effective in lowering blood glucose levels and generally well tolerated in GADA-positive patients. Interestingly, saxagliptin appears to improve β-cell function in these patients, although a longer treatment duration may be needed to confirm this finding. (6)
• Study: β-cell function after intervention was similar in patients with insulin- and sitagliptin-treated LADA, regardless of the strength of autoimmunity. Further, participants with low levels of GAD antibodies did not experience progressive deterioration of β-cell function over a 21-month period. Taken together, these findings could be useful for clinicians’ choices of treatment in people with LADA. (7)
• Study: The data suggested that adding 2000 IU/day vitamin D3 to saxagliptin might preserve β-cell function in patients with LADA. (8)
• The International LADA panel concluded that DPP-4i may improve glycemic control in LADA patients with a good safety profile. Larger randomized studies are warranted to prove that DPP-4i might preserve C-peptide secretion. (9)

Sodium–Glucose Cotransporter 2 Inhibitors

• No interventional studies have been conducted in LADA patients.
• International, multicenter, randomized clinical trials in over 5,000 T1D patients confirm the efficacy and safety of adding SGLT2i to existing insulin regimens.
• Dapagliflozin, has been recently approved by the European Medicines Agency for use in adults with T1D with BMI of at least 27 kg/m2 who failed to achieve adequate glycemic control despite optimal insulin therapy.
• SGLT inhibition confers additional benefits in terms of:
  • HbA1c reduction.
  • Reduced glucose variability.
  • Small reduction in weight, and reduced total daily insulin doses without increasing the risk of hypoglycemia.
• There is an increased risk of ketoacidosis, often not associated with hyperglycemia, especially in patients not overweight (BMI>27).
• Patients should be advised to monitor for ketosis regularly, even daily, as recommended.
• Discontinue SGLT2i prior to scheduling surgical procedures or exposure to metabolically stressful conditions associated with potential symptoms or signs of ketoacidosis
• The International LADA panel concluded that the approved use of SGLT2i in both T2D and selected T1D patients, in particular those overweight, suggests that they may be promising agents in LADA. However, no studies have been performed in LADA and attention should be paid to ketoacidosis in patients with medium to low C-peptide. (10)

Glucagon‐Like Peptide 1 Receptor Agonists

• A post hoc analysis of pooled data from three randomized phase III trials (AWARD-2, -4, and -5; patients with GADA assessment) indicated that dulaglutide is effective in reducing HbA1c in LADA patients.
• Dulaglutide treatment resulted in a comparable decrease in HbA1c values in GADA-negative (21.09%) and GADA-positive (20.94%) patients at 1-year post-diagnosis, and it appears to be slightly more effective in LADA patients with low autoantibody levels compared with those with high autoantibody levels. (11)

Immune Intervention

• There is only one immune intervention study in LADA patients.
• Alum-formulated recombinant GADA (GAD-alum) was used in a small phase 2 study that was placebo-controlled with dose escalation in GADA-positive non–insulin requiring patients.
• Study: After 5 years, fasting C-peptide levels declined in the placebo group compared with the two highest dose intervention groups. The authors concluded that in this small study, the primary outcome of safety was achieved, with evidence of a beneficial effect on b-cell function. (12)
• Study: Results: Preliminary results show feasibility and safety, with almost stable beta cell function and metabolic control during follow-up so far (5 months).
• Conclusions: Intra-lymphatic GAD-alum treatment is an option to preserve beta cell function in LADA-patients. An ongoing trial in 14 LADA-patients show feasibility and safety. Clinical and immunological responses will determine how to proceed with future trials.
• The International LADA Panel Conclusion: The panel concluded that current data on immune intervention in LADA are very limited, and more extensive phase 2 studies are required before drawing any conclusions. (9)

Lifestyle modification

• LADA is associated with factors that favor insulin resistance and T2D, including:
• Low birth weight.
• Overweight/ obesity.
• Physical inactivity.
• Smoking.
• Consumption of sweetened drinks.
• The role of obesity and insulin resistance as risk factors for LADA is abundantly documented.
• It may therefore be possible to treat LADA by a combination of lifestyle changes much as is done in T2D.
  • Medically assisted weight loss, if necessary.
  • Increased physical activity.
  • Cessation of smoking.
• The International LADA Conclusion: The panel concluded that lifestyle modifications are important in treatment of T2D. Intervention studies examining the role of weight reduction and physical activity in the development of LADA are required. (9)

Diagnostic Challenges in LADA – Panel Recommendations

• All newly diagnosed T2D patients should be screened for GADA positivity.
• If there is a strong suspicion of LADA in a GADA-negative individual, other islet autoantibodies (e.g., ICA or IA-2A, ZnT8A) should be assayed.
• Although elevated levels of GADA have been associated with a greater risk of insulin requirement compared with low levels, GADA levels cannot be used in clinical practice for therapeutic choice as assays are not standardized.
• If economic issues represent an obstacle, at least one of the following clinical factors should be sought to select patients in whom to measure GADA:
  • Family history of T1D or autoimmune diseases.
  • Normal/slightly overweight BMI (<27).
  • Young age at onset (<60 years).
  • Poor metabolic control.
• C-peptide levels as a proxy for insulin secretion in islet-cell related autoantibody–positive patients with concomitant measurement of blood glucose levels should be done to ensure that it is between 80 and 180 mg/dL to avoid the effect of abnormally low or high glucose values.
• C-peptide can be measured in samples collected at fasting, random time points, or postprandially.
• In case of treatment failure, C-peptide measurement should be repeated to identify progression to insulin deficiency and the need for insulin treatment.

Treatment Decision based on C – Peptide level

• C-peptide levels< 0.3 nmol/L:
  • Multiple insulin regimen is recommended.
  • If this occurs at diagnosis, then patients can be considered to have T1D and approved national/international guidelines for T1D can be followed.
• C-peptide levels >= 0.3- <= 0.7 nmol/L:
  • Defined by the panel as the “gray area” where a modified ADA/EASD algorithm for T2D is recommended.
  • The modification consists of avoiding the use of hypoglycemic drugs that may have an effect in deteriorating b-cell function.
  • Insulin in combination with other therapies to control/ prevent diabetic complications should be considered.
  • The advantages/disadvantages and even dangers of using certain classes of agents need to be taken into account when prescribed alone.
  • Follow-up of patients in this C-peptide category should take place at least every 6 months.
• C-peptide levels >0.7 nmol/L:
  • Use a slightly modified ADA/EASD algorithm for T2D.
  • Difference being that LADA patients should be followed with repeated C-peptide measurements if there is a deterioration of glucose control.
  • Some of these cases will have false positive autoantibodies and therefore be true T2D.

GADA Screening

Credit: Buzzetti R, Tuomi T, Mauricio D, et al From an International Expert Panel. Diabetes. 2020 Oct;69(10):2037-2047. doi: 10.2337/dbi20-0017. Epub 2020 Aug 26. PMID: 32847960; PMCID: PMC7809717.

Algorithm for glucose-lowering medications in LADA patients

Credit: Buzzetti R, Tuomi T, Mauricio D, et al From an International Expert Panel. Diabetes. 2020 Oct;69(10):2037-2047. doi: 10.2337/dbi20-0017. Epub 2020 Aug 26. PMID: 32847960; PMCID: PMC7809717.

Credit: Buzzetti R, Tuomi T, Mauricio D, et al From an International Expert Panel. Diabetes. 2020 Oct;69(10):2037-2047. doi: 10.2337/dbi20-0017. Epub 2020 Aug 26. PMID: 32847960; PMCID: PMC7809717.

Quick Take-Aways

CME INDIA Tail Piece

• Patients identified as having LADA account up to 12% of all patients with diabetes attending clinics from western world. A recent Indian study established a LADA prevalence of 5.1% among T2D patients and has shown the role of GAD autoantibody in the screening for LADA. (13)
• Type 1 diabetes has been identified as an autoimmune disease since the 1970s, the concept of latent autoimmune diabetes mellitus was not noted until 1993, when it was used to describe slow-onset type 1 autoimmune diabetes occurring in adults. (14)

References:

1. Ferrari S, Butler PW, Kendler DL, Miller PD, Roux C, Wang AT, Huang S, Wagman RB, Lewiecki EM. Further Nonvertebral Fracture Reduction Beyond 3 Years for Up to 10 Years of Denosumab Treatment. J Clin Endocrinol Metab. 2019 Aug 1;104(8):3450-3461. doi: 10.1210/jc.2019-00271. PMID: 31125092.
2. Buzzetti R, Tuomi T, Mauricio D, Pietropaolo M, Zhou Z, Pozzilli P, Leslie RD. Management of Latent Autoimmune Diabetes in Adults: A Consensus Statement From an International Expert Panel. Diabetes. 2020 Oct;69(10):2037-2047. doi: 10.2337/dbi20-0017. Epub 2020 Aug 26. PMID: 32847960; PMCID: PMC7809717.
3. Maruyama T, Shimada A, Kanatsuka A, Kasuga A, Takei I, Yokoyama J, Kobayashi T. Multicenter prevention trial of slowly progressive type 1 diabetes with small dose of insulin (the Tokyo study): preliminary report. Ann N Y Acad Sci. 2003 Nov;1005:362-9. doi: 10.1196/annals.1288.060. PMID: 14679093.
4. Thunander M, Thorgeirsson H, Törn C, Petersson C, Landin-Olsson M. β-cell function and metabolic control in latent autoimmune diabetes in adults with early insulin versus conventional treatment: a 3-year follow-up. Eur J Endocrinol. 2011 Feb;164(2):239-45. doi: 10.1530/EJE-10-0901. Epub 2010 Nov 18. PMID: 21088056; PMCID: PMC3022338.
5. Maruyama T, Tanaka S, Shimada A, Funae O, Kasuga A, Kanatsuka A, Takei I, Yamada S, Harii N, Shimura H, Kobayashi T. Insulin intervention in slowly progressive insulin-dependent (type 1) diabetes mellitus. J Clin Endocrinol Metab. 2008 Jun;93(6):2115-21. doi: 10.1210/jc.2007-2267. Epub 2008 Apr 8. PMID: 18397986.
6. Buzzetti R, Pozzilli P, Frederich R, Iqbal N, Hirshberg B. Saxagliptin improves glycaemic control and C-peptide secretion in latent autoimmune diabetes in adults (LADA). Diabetes Metab Res Rev. 2016 Mar;32(3):289-96. doi: 10.1002/dmrr.2717. Epub 2015 Oct 28. PMID: 26385269.
7. Hals, IK, Fiskvik Fleiner, H, Reimers, N, et al. Investigating optimal β-cell-preserving treatment in latent autoimmune diabetes in adults: Results from a 21-month randomized trial. Diabetes Obes Metab. 2019; 21: 2219– 2227. https://doi.org/10.1111/dom.13797
8. Zhang Z, Yan X, Wu C, Pei X, Li X, Wang X, Niu X, Jiang H, Zeng X, Zhou Z. Adding vitamin D3 to the dipeptidyl peptidase-4 inhibitor saxagliptin has the potential to protect β-cell function in LADA patients: A 1-year pilot study. Diabetes Metab Res Rev. 2020 Jul;36(5):e3298. doi: 10.1002/dmrr.3298. Epub 2020 Feb 20. PMID: 32043288.
9. Buzzetti R, Tuomi T, Mauricio D, Pietropaolo M, Zhou Z, Pozzilli P, Leslie RD. Management of Latent Autoimmune Diabetes in Adults: A Consensus Statement From an International Expert Panel. Diabetes. 2020 Oct;69(10):2037-2047. doi: 10.2337/dbi20-0017. Epub 2020 Aug 26. PMID: 32847960; PMCID: PMC7809717.
10. Buzzetti R, Pozzilli P, Frederich R, Iqbal N, Hirshberg B. Saxagliptin improves glycaemic control and C-peptide secretion in latent autoimmune diabetes in adults (LADA). Diabetes Metab Res Rev. 2016 Mar;32(3):289-96. doi: 10.1002/dmrr.2717. Epub 2015 Oct 28. PMID: 26385269.
11. Pozzilli P, Leslie RD, Peters AL, Buzzetti R, Shankar SS, Milicevic Z, Pavo I, Lebrec J, Martin S, Schloot NC. Dulaglutide treatment results in effective glycaemic control in latent autoimmune diabetes in adults (LADA): A post-hoc analysis of the AWARD-2, -4 and -5 Trials. Diabetes Obes Metab. 2018 Jun;20(6):1490-1498. doi: 10.1111/dom.13237. Epub 2018 Feb 21. PMID: 29377522.
12. Agardh CD, Lynch KF, Palmér M, Link K, Lernmark A. GAD65 vaccination: 5 years of follow-up in a randomised dose-escalating study in adult-onset autoimmune diabetes. Diabetologia. 2009 Jul;52(7):1363-8. doi: 10.1007/s00125-009-1371-2. Epub 2009 Apr 30. PMID: 19404608.
13. Manisha, A.M., Shangali, A.R., Mfinanga, S.G. et al. Prevalence and factors associated with latent autoimmune diabetes in adults (LADA): a cross-sectional study. BMC Endocr Disord 22, 175 (2022). https://doi.org/10.1186/s12902-022-01089-1dzsw
14. Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR (February 1993). “Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease”. Diabetes. 42 (2): 359–62. doi:10.2337/diab.42.2.359. PMID 8425674.

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