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\def\RunningAuthor{Aman Gupta et al.}
\firstPage{511}
\articleType{Original Article}
\receivedDate{24.09.2019}
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\title{Combined Treatment with Oral Hypoglycemic Agents and Insulin in Longer Run May Lead to Cognitive Derangement Secondary to Hypoglycemia}
\author{Aman~Gupta\textsuperscript{*}\textsuperscript{1},  
            Abhishek~Kumar~Singh\textsuperscript{1}, 
            Ramesh~Deka~C\textsuperscript{2}~\\[5pt]{\textsuperscript{1}Amity Institute of Neuropsychology and Neurosciences, Amity University Uttar Pradesh, Sector-125, Noida-201313, India }~\\{\textsuperscript{2}Department of Medical Education \& Research, Amity University Uttar Pradesh India,  Previously Director, All India Institute of Medical Sciences,  Ansari Nagar, New Delhi-110029, India}}

\begin{abstract}
To determine the risk associated with combined therapy of oral hypoglycemic agents and insulin in the development of cognitive decline secondary to hypoglycemia. The study comprised of two arms, in arm 1 (n=30) diabetic patients on OHA and insulin combined therapy were observed for cognitive derangement based on Mini Cog score (Pearson's correlation r was calculated between the two) and the patients were also ruled out for hypoglycemia episodes. Similarly, in arm 2(n=30), only OHA therapy patients were evaluated on the same parameters using Pearson's correlation. Mean Mini Cog scores were found to be 1.79 in patients on combinational therapy of OHA and insulin. In the case of patients only on OHA for diabetes control mean Mini Cog, the score was 2.0. Pearson's coefficient r 1 between OHA plus insulin duration of therapy in years with Mini Cog score was \textbf{\space }-0.5831 at a statistically significant p value of 0.0007. While on the other hand, patients only on OHA therapy (in years) were not significantly correlated with Mini Cog scores.(r 2= - 0.0149 ; p value =0.93771).In the arm 1 (OHA + Insulin(n=30)), the average number of hypoglycemia episodes were found to be 2.633 as compared to the OHA only group in which mean hypoglycemia episodes were 0.866. There was a significant difference in the hypoglycemia episodes, as confirmed by the student t-test (4.06368) at a p value = 0.000147. Based on the study findings, combined Treatment with Oral Hypoglycemic agents and insulin in longer run may lead to cognitive derangement secondary to hypoglycemia.*Significance level {\textless}0.01, Negative correlations are indicative of lower the values of battery scores higher would be cognitive derangement. 
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Diabetes,\newline diabetes complications,\newline OHA,\newline Insulin therapy,\newline hypoglycemia
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Aman~Gupta~\\ Phone:\ 919953270158~\\  Email:\ gupta.draman@gmail.com
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{Introduction}
Diabetes is one of the key disease burdens of the globe. Multiple studies have been conducted to find an association between diabetes and cognitive decline and dementia. Oral hypoglycemic agents are the backbone for managing type 2 Diabetes in an early phase \unskip~\citep{659612:15530268}. Sulphonylureas are associated with hypoglycemia episodes\unskip~\citep{659612:15530262}. In a metanalysis \unskip~\citep{659612:15530263} did find adding more than one therapy to OHA may lead to hypoglycemia. In another study, it was found that adding insulin to metformin can have a higher risk of developing hypoglycemia \unskip~\citep{659612:15530264}. Research suggests that the risk of hypoglycemia increases with age, duration of Diabetes and combinational therapy of OHA and Insulin\unskip~\citep{659612:15530265}.


\begin{table*}[!htbp]
\caption{\boldmath {Different variables along with the respective range} }
\label{tw-f446a5dab5c5}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.6349\linewidth-2\tabcolsep}p{\dimexpr.3651\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Variables & Range\\
\tblmidrule 
Age (Years)  &
  35-75 \\
Weight (kg)  &
  45-92 \\
Duration of diabetes (Years)  &
  6-17 \\
No. of hypoglycemic episodes  &
  0-9\\
HBA1C values  &
  7-17\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {OHA+Insulin therapy versus OHA treatment groups versus corresponding Pearson's coefficient } }
\label{tw-00affda5a61a}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.25\linewidth-2\tabcolsep}p{\dimexpr.25\linewidth-2\tabcolsep}p{\dimexpr.2708\linewidth-2\tabcolsep}p{\dimexpr.2292\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Treatment Group-Therapy duration in years & Mean Mini Cog Score & Pearson's Correlation & p value \mbox{}\protect\newline ({\textless}0.05 )\\
\tblmidrule 
 OHA + Insulin(n=30) &
  1.79 &
   -0.5831 &
  0.0007*\\
 OHA only (n=30) &
  2 &
  -0.0149 &
  0.93771**\\
*Significant &
  **Not Significant &
   &
  \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {OHA+Insulin therapy versus OHA treatment groups versus corresponding Hypoglycemia episodes in both arms } }
\label{tw-ed89cfeeff27}
\def\arraystretch{1.1}
\ignorespaces 
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\begin{tabulary}{\linewidth}{p{\dimexpr.25\linewidth-2\tabcolsep}p{\dimexpr.2119\linewidth-2\tabcolsep}p{\dimexpr.2881\linewidth-2\tabcolsep}p{\dimexpr.25\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Treatment Group-Therapy duration in years & Mean number Hypoglycemia Episodes & t-test value & p value({\textless}0.05 )\\
\tblmidrule 
 OHA + Insulin(n=30) &
  2.633333333 &
   4.06368  &
  0.000147* \mbox{}\protect\newline *Significant\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
In a retrospective study conducted in Japan, multiple factors like age, cognitive decline, combinational therapy with of Insulin and sulphonylureas have been cited as risk factors for severe hypoglycemia \unskip~\citep{659612:15530266}.

In a study conducted by \unskip~\citep{659612:15530267}, about 66\% of the patients on combination therapy of OHA and Insulin suffered with moderate hypoglycemia \unskip~\citep{659612:15530270}  investigated the association between hypoglycemia episodes and cognitive decline and did find that linear correlation between the two. In another study, it was found that in the case of severe hypoglycemia episodes, the risk of development of cognitive decline was much higher\unskip~\citep{659612:15530271}. Another aspect to be kept in consideration with respect to the pathophysiology of cognitive decline is advanced glycemic end products (AGEs), which are produced secondary to uncontrolled long-duration diabetes \unskip~\citep{659612:15530272}. Brain insulin resistance has also been found correlated with cognitive decline in Diabetes\unskip~\citep{659612:15530275}.

Cerebral microinfarcts also add to the pathophysiology of dementia in Diabetes type 2\unskip~\citep{659612:15530276}.

\unskip~\citep{659612:15530277} explained the importance of sleep in memory consolidation. Others indicated REM sleep is more important for memory consolidation. 

\unskip~\citep{659612:15530273} presented a correlation between different pathophysiologies involved in the cognitive derangement in Diabetes \unskip~\citep{659612:15530274} and role of sleep in memory consolidation and mechanism of cognitive decline in case of poor sleep or decreased sleep (Refer Figure~\ref{f-529a45147afb}).

In the current study, we hypothesized that combinational OHA and Insulin therapy has a higher risk of developing cognitive derangement as compared to OHA only group. We further hypothesized that higher cognitive decline in the OHA plus Insulin therapy group can be secondary to hypoglycemia as the combinational therapy had a higher incidence of hypoglycemia episodes. 
    
\section{Materials and Methods}
Patients were enrolled from either outpatient department or hospitalized patients from Sarvodaya Hospital and Research Center, Faridabad, Delhi NCR, India. Ethical clearance was sought from the University Ethics Committee of Amity University Uttar Pradesh, Noida, All the subjects have provided written informed consent to participate in the study.


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\centering \makeatletter\IfFileExists{images/f63ca9ad-36b9-43bd-99ac-4ca4104b1ed8-upicture1.png}{\includegraphics{images/f63ca9ad-36b9-43bd-99ac-4ca4104b1ed8-upicture1.png}}{}
\makeatother 
\caption{\boldmath {Proposed hypothesis}}
\label{f-529a45147afb}
\end{figure*}
\egroup

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\centering \makeatletter\IfFileExists{images/4552f069-ce44-4e4f-9151-03d8f8c4f4db-upicture2.png}{\includegraphics{images/4552f069-ce44-4e4f-9151-03d8f8c4f4db-upicture2.png}}{}
\makeatother 
\caption{\boldmath {Box and Whisker Plot -OHA +Insulin Therapy(years)versus Mini-Cog Score}}
\label{f-3c475f024a52}
\end{figure*}
\egroup

\bgroup
\fixFloatSize{images/14a10a9b-821e-431c-ba41-5fde79fd516d-upicture3.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/14a10a9b-821e-431c-ba41-5fde79fd516d-upicture3.png}{\includegraphics{images/14a10a9b-821e-431c-ba41-5fde79fd516d-upicture3.png}}{}
\makeatother 
\caption{\boldmath {Box and Whisker Plot -only OHA Therapy (years)versus Mini-Cog Score}}
\label{f-54f61b2d6b38}
\end{figure*}
\egroup

\bgroup
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\centering \makeatletter\IfFileExists{images/702ec410-7480-4d07-bf5d-7e7a13cf16f5-upicture4.png}{\includegraphics{images/702ec410-7480-4d07-bf5d-7e7a13cf16f5-upicture4.png}}{}
\makeatother 
\caption{\boldmath {Scatter Plot -OHA +Insulin Therapy (years)versus Mini-Cog Score}}
\label{f-5fbf551f0c3f}
\end{figure*}
\egroup

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\centering \makeatletter\IfFileExists{images/2c1e9b87-a415-464c-b586-90a89c0fbe13-upicture5.png}{\includegraphics{images/2c1e9b87-a415-464c-b586-90a89c0fbe13-upicture5.png}}{}
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\caption{\boldmath {Scatter Plot -only OHA Therapy (years)versus Mini-Cog Score}}
\label{f-12cdc3658f68}
\end{figure*}
\egroup

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\centering \makeatletter\IfFileExists{images/4d490432-04fa-4515-875f-9ac4e0ddba0f-uflow-chat.png}{\includegraphics{images/4d490432-04fa-4515-875f-9ac4e0ddba0f-uflow-chat.png}}{}
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\caption{\boldmath {Describesthe study pattern and distribution between the two arms}}
\label{f-1d6072feb1a2}
\end{figure*}
\egroup
The study comprised of two arms (refer Figure~\ref{f-1d6072feb1a2}), in arm 1 (n=30) diabetic patients on OHA and insulin combined therapy were observed for cognitive derangement based on Mini Cog score (Pearson's correlation r was calculated between the two)and the patients were also ruled out for hypoglycemia episodes. Similarly, in arm 2(n=30), only OHA therapy patients were evaluated on the same parameters using Pearson's correlation. Demographics details can be referred to as per the Table~\ref{tw-f446a5dab5c5}. The current study was a single point prevalence study.

\textbf{Inclusion and Exclusion criteria}

\textbf{Inclusion criteria }


  
  \begin{enumerate}
  \item \relax 35 {\textendash}80 years of age
  \item \relax Type 2 DM patients as per ``American Diabetic Association ''
  \item \relax Greater than equal to 5 years of Diabetic History
  \item \relax Greater than 7 HBA1C 
  \item \relax Willing to participate in the study and provide informed consent
  \end{enumerate}
  \textbf{Exclusion criteria}


  
  \begin{enumerate}
  \item \relax Age less than 35 years 
  \item \relax Pregnant women and Children
  \item \relax Substance abuse
  \item \relax Significant Neurological, Psychiatric disease
  \end{enumerate}
  \textbf{Cognitive batteries}

We used Mini Cog battery for cognitive assessment post getting written permission from 

 ``The Alzheimer's Association'' \BreakURLText{(http://www.alz.org).}

\textbf{Statistical analysis}

We used IBM SPSS trial version for the statistical analysis. Mini Cog depicted the cognitive decline of the patients. To establish an association between Mini Cog and duration of OHA plus Insulin therapy in years, Pearson's correlation coefficient (r) was used. Similarly, Pearson's correlation coefficient (r) was also calculated for the arm on only OHA therapy to find an association with Mini Cog scores. 

Both the groups were also assessed for hypoglycemia episodes and the t-test was used to compare the results of both the arms at a p value less than 0.05 and 95\% confidence interval.
    
\section{Results and Discussion}
\textbf{OHA and Insulin combinational therapy was associated with higher Cognitive derangement as compare to OHA only arm}

Mean Mini Cog scores were found to be 1.79 in patients on combinational therapy of OHA and insulin. In the case of patients only on OHA for diabetes control, mean Mini- Cog score was 2.0. Pearson's coefficient r 1 between OHA plus insulin duration of therapy in years with Mini Cog score was \textbf{\space }-0.5831 at a statistically significant p value of 0.0007. While on the other hand, patients only on OHA therapy (in years)were not significantly correlated with Mini Cog scores.(r 2= - 0.0149 ; p value =0.93771). Refer to Table~\ref{tw-00affda5a61a} for details.

\textbf{Higher Cognitive derangement in OHA and Insulin combinational therapy may be associated with hypoglycemia episodes in this arm}

In the arm 1 (OHA + Insulin(n=30)), the average number of hypoglycemia episodes were found to be 2.633 as compared to the OHA only group in which mean hypoglycemia episodes were 0.866. There was a significant difference in the hypoglycemia episodes, as confirmed by the student t-test (4.06368) at a p value = 0.000147. Refer to Table~\ref{tw-ed89cfeeff27} for details. 

Multiple studies have been conducted to find an association between Diabetes and cognitive derangement, which have been bringing forward concepts pertaining to the insulin resistance and dementia. memory impairment \unskip~\citep{659612:15530278}. Another group did find the relation between Alzhimer's disease and diabetes\unskip~\citep{659612:15530279}. Researchers \unskip~\citep{659612:15530280} proposed its good to have diabetes in control to reduce the risk of cognitive decline. Animal models have also been successful to build up relationship between diabetes and dementia\unskip~\citep{659612:15530281}.

In the current study, we hypothesized that combinational OHA and Insulin therapy has a higher risk of developing cognitive derangement as compared to OHA only group. We further hypothesized that higher cognitive decline in the OHA plus Insulin therapy group can be secondary to hypoglycemia as the combinational therapy had a higher incidence of hypoglycemia episodes.

Current study results revealed that mean Mini Cog scores to be 1.79 in patients on combinational therapy of OHA and insulin and the same was 2.0 for the OHA only arm. Pearson's coefficient r 1 between OHA plus insulin duration of therapy in years with Mini Cog score was \textbf{\space }-0.5831 at a statistically significant p value of 0.0007. While on the other hand, patients only on OHA therapy (in years)were not significantly correlated with Mini Cog scores.(r 2= - 0.0149 ; p value =0.93771).Figure~\ref{f-3c475f024a52} depicts Box and Whisker Plot -only OHA plus Insulin Therapy (years)versus Mini-Cog Score and Figure~\ref{f-54f61b2d6b38} indicate Box and Whisker Plot -only OHA Therapy (years)versus Mini-Cog Score.

With reference to Figure~\ref{f-5fbf551f0c3f}  Scatter Plot -OHA plus Insulin Therapy (years)versus Mini-Cog Score and Figure~\ref{f-12cdc3658f68} depicts Scatter Plot -only OHA Therapy (years)versus Mini-Cog Score. 

We can mark the difference in the presentation in both the cases. These results are in line with earlier studies, which Research suggests that the risk of hypoglycemia increases with age, duration of Diabetes and combinational therapy of OHA and Insulin\unskip~\citep{659612:15530265}. 

With respect to hypoglycemia episodes, in the arm 1 (OHA + Insulin(n=30)), the average number of hypoglycemia episodes were found to be 2.633 as compared to the OHA only group in which mean hypoglycemia episodes were 0.866. There was a significant difference in the hypoglycemia episodes, as confirmed by the student t-test (4.06368) at a p value = 0.000147. These results are also aligned with previous studies like a retrospective study conducted in Japan, which indicated multiple factors like age, cognitive decline, combinational therapy with of Insulin and  Sulphonylureas have been cited as risk factors for severe hypoglycemia \unskip~\citep{659612:15530266}.

Different studies have provided evidence of cognitive decline secondary to hypoglycemia episodes. \unskip~\citep{659612:15530270} investigated the association between hypoglycemia episodes and cognitive decline and did find that linear correlation between the two. In another study, it was found that in the case of severe hypoglycemia episodes, the risk of development of cognitive decline was much higher\unskip~\citep{659612:15530271}.
    
\section{Conclusions}
The current study provides significant findings related to the optimal usage of drugs for the management of type 2 diabetes by virtue of its results. To our knowledge, no other similar study has been conducted in north India. Cognitive assessment was based on the Mini-Cog battery, which has already been validated.

We compared two arms of the study: OHA plus insulin therapy and only OHA treatment based on the correlation of individual arms with Mini Cog scores. We further evaluated, an association of these two categories of patients with a probability of hypoglycemia episodes and their significance levels. Based on the study findings, combined Treatment with Oral Hypoglycemic agents and insulin in the longer run may lead to cognitive derangement secondary to hypoglycemia. 

We studied multiple aspects related to cognitive decline and diabetes. Uncontrolled Diabetes has been associated with cognitive derangement and so is hypoglycemia episodes. OHA and Insulin therapy, in combination, has a higher risk of hypoglycemia episodes, later, in turn, can increase the probability of cognitive decline.

Combinational therapy with OHA and insulin can be necessary to manage the poorly controlled diabetes. Hence, it is very important to keep track of the treatment strategy while managing uncontrolled diabetes. Further, large scale studies are required to further validate the concept. Randomized double-blind placebo-controlled clinical trials can provide further support to current evidence.
\section*{Acknowledgements}We thank ``The Alzheimer's Association'' \BreakURLText{(http://www.alz.org} ) for support with respect to usage of Mini COG used in the study. 
    

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